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80,140	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RYBELSUS® safely and effectively. See full prescribing information for RYBELSUS. RYBELSUS (semaglutide) tablets, for oral use Initial U.S. Approval: 2017 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). • RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Warnings and Precaution, Pulmonary Aspiration During General Anesthesia or Deep Sedation (5.8) 11/2024 ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1). Limitations of Use • Has not been studied in patients with a history of pancreatitis (1, 5.2). • Not for treatment of type 1 diabetes mellitus (1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Instruct patients to take RYBELSUS at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water only. Waiting less than 30 minutes, or taking with food, beverages (other than plain water) or other oral medications will lessen the effect of RYBELSUS. Waiting more than 30 minutes to eat may increase the absorption of RYBELSUS (2.1). • Swallow tablets whole. Do not split, crush, or chew tablets (2.1). • Start RYBELSUS with 3 mg once daily for 30 days. After 30 days on the 3 mg dosage, increase the dosage to 7 mg once daily (2.2). • Dosage may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dosage (2.2). • See the Full Prescribing Information for instructions on switching between OZEMPIC® and RYBELSUS (2.3). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Tablets: 3 mg, 7 mg and 14 mg (3). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4). • Prior serious hypersensitivity reaction to semaglutide or any of the excipients in RYBELSUS (4). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2). • Diabetic Retinopathy Complications: Has been reported in a cardiovascular outcomes trial with semaglutide injection. Patients with a history of diabetic retinopathy should be monitored (5.3). • Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary (5.4). • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions (5.5). • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue RYBELSUS if suspected and promptly seek medical advice (5.6). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.7) • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.8). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-457-7455 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS---------------------------------- Oral Medications: RYBELSUS delays gastric emptying. Instruct patients to closely follow RYBELSUS administration instructions (7.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Pregnancy: May cause fetal harm (8.1). • Lactation: Breastfeeding not recommended (8.2). • Females and Males of Reproductive Potential: Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide (8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5472293 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Recommended Dosage 2.3 Switching Patients between OZEMPIC and RYBELSUS 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Pancreatitis 5.3 Diabetic Retinopathy Complications 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin 5.5 Acute Kidney Injury 5.6 Hypersensitivity Reactions 5.7 Acute Gallbladder Disease 5.8 Pulmonary Aspiration During General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus 14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus 14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5472293 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)]. • RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE RYBELSUS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use • RYBELSUS has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. • RYBELSUS is not indicated for use in patients with type 1 diabetes mellitus. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Instruct patients to take RYBELSUS at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water only [see Clinical Pharmacology (12.3)]. Waiting less than 30 minutes, or taking RYBELSUS with food, beverages (other than plain water) or other oral medications will lessen the effect of RYBELSUS by decreasing its absorption. Waiting more than 30 minutes to eat may increase the absorption of RYBELSUS. • Swallow tablets whole. Do not split, crush, or chew tablets. 2.2 Recommended Dosage • Start RYBELSUS with 3 mg once daily for 30 days. The 3 mg dosage is intended for treatment initiation and is not effective for glycemic control. • After 30 days on the 3 mg dosage, increase the dosage to 7 mg once daily. • The dosage may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dosage. • Taking two 7 mg RYBELSUS tablets to achieve a 14 mg dosage is not recommended. • If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day. 2.3 Switching Patients between OZEMPIC and RYBELSUS • Patients treated with RYBELSUS 14 mg daily can be transitioned to OZEMPIC subcutaneous injection 0.5 mg once weekly. Patients can start OZEMPIC the day after their last dose of RYBELSUS. • Patients treated with once weekly OZEMPIC 0.5 mg subcutaneous injection can be transitioned to RYBELSUS 7 mg or 14 mg. Patients can start RYBELSUS up to 7 days after their last injection of OZEMPIC. There is no equivalent dose of RYBELSUS for OZEMPIC 1 mg. Reference ID: 5472293 3 DOSAGE FORMS AND STRENGTHS RYBELSUS tablets are available as: • 3 mg: white to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side. • 7 mg: white to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side. • 14 mg: white to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side. 4 CONTRAINDICATIONS RYBELSUS is contraindicated in patients with: • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS [see Warnings and Precautions (5.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether RYBELSUS causes thyroid C- cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In glycemic control trials, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patient years) versus 1 in comparator-treated patients (<0.1 events per 100 patient years). After initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, RYBELSUS should be discontinued and appropriate management initiated; if confirmed, RYBELSUS should not be restarted. 5.3 Diabetic Retinopathy Complications In a pooled analysis of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Reference ID: 5472293 In a 2-year cardiovascular outcomes trial with semaglutide injection involving patients with type 2 diabetes and high cardiovascular risk, diabetic retinopathy complications (which was a 4 component adjudicated endpoint) occurred in patients treated with semaglutide injection (3.0%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of RYBELSUS in patients reporting severe adverse gastrointestinal reactions. 5.6 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. RYBELSUS is contraindicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS [see Adverse Reactions (6.2)]. Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with RYBELSUS. 5.7 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)]. 5.8 Pulmonary Aspiration During General Anesthesia or Deep Sedation RYBELSUS delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Reference ID: 5472293 6 Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking RYBELSUS, including whether modifying preoperative fasting recommendations or temporarily discontinuing RYBELSUS could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS. ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Pancreatitis [see Warnings and Precautions (5.2)] • Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.4)] • Acute Kidney Injury [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Acute Gallbladder Disease [see Warnings and Precautions (5.7)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes [see Clinical Studies (14)]. These data reflect exposure of 1071 patients to RYBELSUS with a mean duration of exposure of 41.8 weeks. The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these trials, 63% were White, 6% were Black or African American, and 27% were Asian; 19% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 9.4 years and had a mean HbA1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 1.4% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of adult patients with type 2 diabetes participating in 9 placebo- and active-controlled trials [see Clinical Studies (14)]. In this pool, 4116 patients with type 2 diabetes were treated with RYBELSUS for a mean duration of 59.8 weeks. The mean age of patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, 65% were White, 6% were Black or African American, and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA1c of 8.2%. At baseline, 16.6% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 28.5%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 5.4% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in adult patients with type 2 diabetes in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on RYBELSUS than on placebo and occurred in at least 5% of patients treated with RYBELSUS. Reference ID: 5472293 Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of RYBELSUS-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=362) % RYBELSUS 7 mg (N=356) % RYBELSUS 14 mg (N=356) % Nausea 6 11 20 Abdominal Pain 4 10 11 Diarrhea 4 9 10 Decreased appetite 1 6 9 Vomiting 3 6 8 Constipation 2 6 5 In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving RYBELSUS than placebo (placebo 21%, RYBELSUS 7 mg 32%, RYBELSUS 14 mg 41%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients receiving RYBELSUS 7 mg (4%) and RYBELSUS 14 mg (8%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (1%). In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5% were associated with RYBELSUS (frequencies listed, respectively, as placebo; 7 mg; 14 mg): abdominal distension (1%, 2%, 3%), dyspepsia (0.6%, 3%, 0.6%), eructation (0%, 0.6%, 2%), flatulence (0%, 2%, 1%), gastroesophageal reflux disease (0.3%, 2%, 2%), and gastritis (0.8%, 2%, 2%). Other Adverse Reactions Pancreatitis In the pool of placebo- and active-controlled trials with RYBELSUS, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patient years) versus 1 in comparator- treated patients (<0.1 events per 100 patient years). Diabetic Retinopathy Complications In the pool of placebo- and active-controlled trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Hypoglycemia Table 2 summarizes the incidence of hypoglycemia by various definitions in the placebo-controlled trials. Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials In Patients with Type 2 Diabetes Mellitus Placebo RYBELSUS 7 mg RYBELSUS 14 mg Monotherapy (26 weeks) N=178 N=175 N=175 Severe 0% 1% 0% Plasma glucose <54 mg/dL 1% 0% 0% Reference ID: 5472293 Add-on to metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin in patients with moderate renal impairment (26 weeks) N=161 - N=163 Severe* 0% - 0% Plasma glucose <54 mg/dL 3% - 6% Add-on to insulin with or without metformin (52 weeks) N=184 N=181 N=181 Severe* 1% 0% 1% Plasma glucose <54 mg/dL 32% 26% 30% *“Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when RYBELSUS was used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Increases in Amylase and Lipase In placebo-controlled trials, patients exposed to RYBELSUS 7 mg and 14 mg had a mean increase from baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%, respectively. These changes were not observed in placebo-treated patients. Cholelithiasis In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. Increases in Heart Rate In placebo-controlled trials, RYBELSUS 7 mg and 14 mg resulted in a mean increase in heart rate of 1 to 3 beats per minute. There was no change in heart rate in placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: ileus Hypersensitivity: anaphylaxis, angioedema, rash, urticaria Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy Nervous system disorders: dizziness, dysgeusia Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin RYBELSUS stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Reference ID: 5472293 7 When initiating RYBELSUS, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. 7.2 Oral Medications RYBELSUS causes a delay of gastric emptying, and thereby has the potential to impact the absorption of other oral medications. Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered with RYBELSUS in a drug interaction study [see Clinical Pharmacology (12.3)]. When coadministering oral medications instruct patients to closely follow RYBELSUS administration instructions. Consider increased clinical or laboratory monitoring for medications that have a narrow therapeutic index or that require clinical monitoring [see Dosage and Administration (2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data with RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy. RYBELSUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal exposures below the maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and ≥10-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data). The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease associated maternal and fetal risk Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure. In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.06-, 0.6-, and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation Reference ID: 5472293 Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures. In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.9-, 9.9-, and 29-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (>9X human exposure). In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-, and 14-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg twice weekly (>6X human exposure). Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the placenta and reaches fetal tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through lactation day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup viability were observed. 8.2 Lactation Risk Summary There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats. SNAC and/or its metabolites concentrated in the milk of lactating rats. When a substance is present in animal milk, it is likely that the substance will be present in human milk (see Data). There are no data on the presence of SNAC in human milk. Since the activity of UGT2B7, an enzyme involved in SNAC clearance, is lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC from breastfeeding and because there are alternative formulations of semaglutide that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS. Data In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in maternal plasma. SNAC and/or its metabolites were detected in milk of lactating rats following a single maternal administration on lactation day 10. Mean levels of SNAC and/or its metabolites in milk were approximately 2-12 fold higher than in maternal plasma. 8.3 Females and Males of Reproductive Potential Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of RYBELSUS have not been established in pediatric patients. 8.5 Geriatric Use In the pool of glycemic control trials, 1229 (30%) RYBELSUS-treated patients were 65 years of age and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over [see Clinical Studies (14)]. In Reference ID: 5472293 0 ro D E- G- Q- A- A ~~ - F- 1- A W- L- V- R- G- R- G- oH OH 0 PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS-treated patients were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of age and over. No overall differences in safety or effectiveness for RYBELSUS have been observed between patients 65 years of age and older and younger adult patients. 8.6 Renal Impairment The safety and effectiveness of RYBELSUS was evaluated in a 26-week clinical study that included 324 patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73m2) [see Clinical Studies (14.1)]. In patients with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. No dose adjustment of RYBELSUS is recommended for patients with renal impairment. 8.7 Hepatic Impairment In a study in subjects with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. No dose adjustment of RYBELSUS is recommended for patients with hepatic impairment. 10 OVERDOSAGE In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of RYBELSUS of approximately 1 week. 11 DESCRIPTION RYBELSUS tablets, for oral use, contain semaglutide, a GLP-1 receptor agonist. The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. Structural formula: Semaglutide is a white to almost white hygroscopic powder. Each tablet of RYBELSUS contains 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC). 12 CLINICAL PHARMACOLOGY Reference ID: 5472293 12.1 Mechanism of Action Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. 12.2 Pharmacodynamics All pharmacodynamic evaluations were performed after 12 weeks of treatment (including dose escalation) at steady state semaglutide injection 1 mg. Fasting and Postprandial Glucose Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes, treatment with semaglutide injection 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative reduction compared to placebo of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2 hour postprandial glucose, and 30 mg/dL (22%) for mean 24 hour glucose concentration. Insulin Secretion Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes treated with semaglutide compared with placebo. Glucagon Secretion Semaglutide lowers the fasting and postprandial glucagon concentrations. Glucose dependent insulin and glucagon secretion Semaglutide lowers high blood glucose concentrations by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner. During induced hypoglycemia, semaglutide did not alter the counter regulatory responses of increased glucagon compared to placebo and did not impair the decrease of C-peptide in patients with type 2 diabetes. Gastric emptying Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially. Cardiac electrophysiology (QTc) The effect of subcutaneously administered semaglutide on cardiac repolarization was tested in a thorough QTc trial. At an average exposure level 4-fold higher than that of the maximum recommended dose of RYBELSUS, semaglutide does not prolong QTc intervals to any clinically relevant extent. 12.3 Pharmacokinetics Absorption Semaglutide is co-formulated with salcaprozate sodium which facilitates the absorption of semaglutide after oral administration. The absorption of semaglutide predominantly occurs in the stomach. Reference ID: 5472293 I u trio sic factor Sex Age group Race Ethnicity Body weight Upper GI di sease Renal function Male 65-74 years >=75 years Black or African American Asian Hispanic or Latino 56 kg 129kg With Upper GI disease Mild Moderate 0.5 Relative Exposure (Cavg) Ratio and 90% CI t---+--t ~ I 1-+-1 1-+-i 2 Population pharmacokinetics (PK) estimated semaglutide exposure to increase in a dose-proportional manner. In patients with type 2 diabetes, the mean population-PK estimated steady-state concentrations following once daily oral administration of 7 and 14 mg semaglutide were approximately 6.7 nmol/L and 14.6 nmol/L, respectively. Following oral administration, maximum concentration of semaglutide is reached 1 hour post-dose. Steady-state exposure is achieved following 4-5 weeks administration. Population-PK estimated absolute bioavailability of semaglutide to be approximately 0.4%-1%, following oral administration. Distribution The estimated volume of distribution of semaglutide following oral administration in healthy subjects is approximately 8 L. Semaglutide is extensively bound to plasma albumin (>99%). Elimination With an elimination half-life of approximately 1 week, semaglutide is present in the circulation for about 5 weeks after the last dose. The clearance of semaglutide following oral administration in healthy subjects is approximately 0.04 L/h. Metabolism The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. Excretion The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine as intact semaglutide. Specific Populations Based on a population pharmacokinetic analysis, age, sex, race, ethnicity, upper GI disease, and renal impairment do not have a clinically meaningful effect on the pharmacokinetics of semaglutide. The exposure of semaglutide decreases with an increase in body weight. However, RYBELSUS doses of 7 mg and 14 mg provide adequate systemic exposure over the body weight range of 40-188 kg evaluated in the clinical trials. The effects of intrinsic factors on the pharmacokinetics of semaglutide are shown in Figure 1. Figure 1. Impact of intrinsic factors on semaglutide exposure Semaglutide exposure (Cavg) relative to reference subject profile: White, non-Hispanic or Latino female aged 18-64 years, with body weight of 85 kg, without upper GI disease or renal impairment, dosed 14 mg. Body weight categories (56 and 129 kg) represent the 5% and 95% percentiles in the dataset. Abbreviations: Cavg: average semaglutide concentration. GI: gastrointestinal. CI: confidence interval. Reference ID: 5472293 Patients with Renal impairment - Renal impairment does not impact the pharmacokinetics of semaglutide in a clinically relevant manner. This was shown in a study with 10 consecutive days of once daily oral doses of semaglutide in patients with different degrees of renal impairment (mild, moderate, severe, end staged renal disease) compared with subjects with normal renal function. This was also shown for subjects with both type 2 diabetes and renal impairment based on data from clinical studies (Figure 1). Patients with Hepatic impairment - Hepatic impairment does not have any impact on the exposure of semaglutide. The pharmacokinetics of semaglutide were evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function in a study with 10 consecutive days of once daily oral doses of semaglutide. Patients with disease in the upper GI tract - Upper GI disease (chronic gastritis and/or gastroesophageal reflux disease) does not impact semaglutide pharmacokinetics in a clinically relevant manner. This was shown in a study in patients with type 2 diabetes with or without upper GI disease dosed for 10 consecutive days with once daily oral doses of semaglutide. Pediatric Patients- Semaglutide has not been studied in pediatric patients. Drug Interaction Studies In vitro studies have shown very low potential for semaglutide to inhibit or induce CYP enzymes, and to inhibit drug transporters. The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral medicinal products. Trials were conducted to study the potential effect of semaglutide on the absorption of oral medications taken with semaglutide administered orally at steady-state exposure. No clinically relevant drug-drug interaction with semaglutide (Figure 2) was observed based on the evaluated medications. Total exposure (AUC) of thyroxine (adjusted for endogenous levels) was increased by 33% following administration of a single dose of levothyroxine 600 µg concurrently administered with semaglutide. Maximum exposure (Cmax) was unchanged [see Drug Interactions (7.2)]. Figure 2. Impact of semaglutide on the exposure of treatment with other oral medications Reference ID: 5472293 Co-administered Relative exposure medication Ratio and 90% CI Lisinopril AUC0-∞ Cmax S-warfarin AUC0-∞ Cmax R-warfarin AUC0-∞ Cmax Metformin AUC0-12h Cmax Digoxin AUC0-∞ Cmax Ethinylestradiol AUC0-24h Cmax Levonorgestrel AUC0-24h Cmax Furosemide AUC0-∞ Cmax Rosuvastatin AUC0-∞ Cmax Levothyroxine bcAUC0-48h bcCmax 0.5 1 2 Relative exposure in terms of AUC and Cmax for each medication when given with semaglutide compared to without semaglutide. Metformin and oral contraceptive drug (ethinylestradiol/levonorgestrel) were assessed at steady state. Effect on levothyroxine is measured as baseline corrected total T4 (thyroxine) concentration. Lisinopril, warfarin (S-warfarin/R-warfarin), digoxin, furosemide, rosuvastatin and levothyroxine were assessed after a single dose. Abbreviations: AUC: area under the curve. Cmax: maximum concentration. CI: confidence interval. No clinically relevant change in semaglutide exposure was observed when taken with omeprazole. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of semaglutide or of other semaglutide products. During the 26-78 week treatment periods in 5 clinical trials [see Clinical Studies (14.2 and 14.3)] and 1 clinical trial in Japanese adults with type 2 diabetes mellitus, 14/2924 (0.5%) of RYBELSUS-treated patients developed anti-semaglutide antibodies. Of these 14 RYBELSUS-treated patients, 7 patients (0.2% of the total RYBELSUS-treated study population) developed antibodies that cross-reacted with native GLP-1. No identified clinically significant effect of anti-semaglutide antibodies on pharmacokinetics of RYBELSUS was observed. There is insufficient information to characterize the effects of anti-semaglutide antibodies on pharmacodynamics, safety, or effectiveness of semaglutide. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day [9-, 33- and 113 fold the maximum recommended human dose (MRHD) of RYBELSUS 14 mg, based on AUC] were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (3-, 9-, and 33-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (>3X human exposure). In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.8-, 1.8- and 11-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose Reference ID: 5472293 - levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at ≥0.01 mg/kg/day, at clinically relevant exposures. Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)]. Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, rat bone marrow micronucleus). In a combined fertility and embryo-fetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7- and 2.1-fold the MRHD) were administered to male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length was observed at all dose levels, together with a small reduction in numbers of corpora lutea at ≥0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight. 13.2 Animal Toxicology and/or Pharmacology Increase in lactate levels and decrease in glucose levels in the plasma and cerebrospinal fluid (CSF) were observed in mechanistic studies with SNAC in rats. Small but statistically significant increases in lactate levels (up to 2-fold) were observed in a few animals at approximately the clinical exposure. At higher exposures these findings were associated with moderate to marked adverse clinical signs (lethargy, abnormal respiration, ataxia, and reduced activity, body tone and reflexes) and marked decreases in plasma and CSF glucose levels. These findings are consistent with inhibition of cellular respiration and lead to mortality at SNAC concentrations >100-times the clinical Cmax. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies RYBELSUS has been studied as monotherapy and in combination with metformin, sulfonylureas, sodium- glucose co-transporter-2 (SGLT-2) inhibitors, insulins, and thiazolidinediones in patients with type 2 diabetes. The efficacy of RYBELSUS was compared with placebo, empagliflozin, sitagliptin, and liraglutide. RYBELSUS has also been studied in patients with type 2 diabetes with mild and moderate renal impairment. In patients with type 2 diabetes, RYBELSUS produced clinically significant reduction from baseline in HbA1c compared with placebo. The efficacy of RYBELSUS was not impacted by baseline age, gender, race, ethnicity, BMI, body weight, diabetes duration and level of renal impairment. 14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus In a 26-week double-blind trial (NCT02906930), 703 adult patients with type 2 diabetes inadequately controlled with diet and exercise were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg or RYBELSUS 14 mg once daily or placebo. Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes was 3.5 years, and the mean BMI was 32 kg/m2 . Overall, 75% were White, 5% were Black or African American, and 17% were Asian; 26% identified as Hispanic or Latino ethnicity. Monotherapy with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3). Table 3. Results at Week 26 in a Trial of RYBELSUS as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Reference ID: 5472293 Placebo RYBELSUS 7 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 178 175 175 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26b -0.3 -1.2 -1.4 Difference from placebob [95% CI] −0.9 [−1.1; −0.6]c −1.1 [−1.3; −0.9]c Patients (%) achieving HbA1c <7% 31 69 77 FPG (mg/dL) Baseline (mean) 160 162 158 Change at week 26b -3 -28 -33 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 8.6% and 8.6% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 15%, 2% and 1% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. b Estimated using an ANCOVA model based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 88.6 kg, 89.0 kg and 88.1 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -1.4 kg, -2.3 kg and -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -0.9 kg (-1.9, 0.1) and for RYBELSUS 14 mg was -2.3 kg (-3.1, -1.5). 14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus Combination with Metformin In a 26-week trial (NCT02863328), 822 adult patients with type 2 diabetes were randomized to RYBELSUS 14 mg once daily or empagliflozin 25 mg once daily, all in combination with metformin. Patients had a mean age of 58 years and 50% were men. The mean duration of type 2 diabetes was 7.4 years, and the mean BMI was 33 kg/m2. Overall, 86% were White, 7% were Black or African American, and 6% were Asian; 24% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to empagliflozin 25 mg once daily (see Table 4). Table 4. Results at Week 26 in a Trial of RYBELSUS Compared to Empagliflozin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin RYBELSUS 14 mg Empagliflozin 25 mg Intent-to-Treat (ITT) Population (N)a 411 410 HbA1c (%) Baseline (mean) 8.1 8.1 Change at week 26b -1.3 -0.9 Difference from empagliflozinb [95% CI] -0.4 [-0.6, -0.3]c Patients (%) achieving HbA1c <7% 67 40 FPG (mg/dL) Baseline (mean) 172 174 Change at week 26b -36 -36 Reference ID: 5472293 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.6% and 3.7% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 91.9 kg and 91.3 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to week 26 were -3.8 kg and -3.7 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for RYBELSUS 14 mg was -0.1 kg (-0.7, 0.5). Combination with Metformin or Metformin with Sulfonylurea In a 26-week, double-blind trial (NCT02607865), 1864 adult patients with type 2 diabetes on metformin alone or metformin with sulfonylurea were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg, RYBELSUS 14 mg or sitagliptin 100 mg once daily. Patients had a mean age of 58 years and 53% were men. The mean duration of type 2 diabetes was 8.6 years, and the mean BMI was 32 kg/m2. Overall, 71% were White, 9% were Black or African American, and 13% were Asian; 17% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin 100 mg once daily (see Table 5). Table 5. Results at Week 26 in a Trial of RYBELSUS Compared to Sitagliptin 100 mg Once Daily in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea RYBELSUS 7 mg RYBELSUS 14 mg Sitagliptin 100 mg Intent-to-Treat (ITT) Population (N)a 465 465 467 HbA1c (%) Baseline (mean) 8.4 8.3 8.3 Change at week 26b -1.0 -1.3 -0.8 Difference from sitagliptinb [95% CI] -0.3 [-0.4; -0.1]c -0.5 [-0.6; -0.4]c Patients (%) achieving HbA1c <7% 44 56 32 FPG (mg/dL) Baseline (mean) 170 168 172 Change at week 26b -21 -31 -15 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.8%, 6.2% and 4.5% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1% and 2.8% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 91.3 kg, 91.2 kg and 90.9 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The mean changes from baseline to week 26 were -2.2 kg, -3.1 kg and -0.6 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for RYBELSUS 7 mg was -1.6 kg (-2.0, -1.1) and RYBELSUS 14 mg was -2.5 kg (-3.0, -2.0). Reference ID: 5472293 Combination with Metformin or Metformin with SGLT-2 Inhibitors In a 26-week, double-blind, double-dummy trial (NCT02863419), 711 adult patients with type 2 diabetes on metformin alone or metformin with SGLT-2 inhibitors were randomized to RYBELSUS 14 mg once daily, liraglutide 1.8 mg s.c. injection once daily or placebo. Patients had a mean age of 56 years and 52% were men. The mean duration of type 2 diabetes was 7.6 years, and the mean BMI was 33 kg/m2. Overall, 73% were White, 4% were Black or African American, and 13% were Asian; 6% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in statistically significant reductions in HbA1c compared to placebo. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in non- inferior reductions in HbA1c compared to liraglutide 1.8 mg (see Table 6). Table 6. Results at Week 26 in a Trial of RYBELSUS Compared to Liraglutide and Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with SGLT-2i Placebo Liraglutide 1.8 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 142 284 285 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26b -0.2 -1.1 -1. 2 Difference from placebob [95% CI] -1.1 [-1.2 ; -0.9]c Difference from liraglutideb [95% CI] -0.1 [-0.3; 0.0] Patients (%) achieving HbA1c <7% 14 62 68 FPG (mg/dL) Baseline (mean) 167 168 167 Change at week 26b -7 -34 -36 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 4.2% and 2.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2% and 3.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 93.2 kg, 95.5 kg and 92.9 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.5 kg, -3.1 kg and -4.4 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -3.8 kg (-4.7, -3.0). The difference from liraglutide 1.8 mg for RYBELSUS 14 mg was -1.2 (-1.9, -0.6). Combination in patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment with Metformin alone, Sulfonylurea alone, Basal Insulin alone, or Metformin in Combination with either Sulfonylurea or Basal Insulin In a 26-week, double-blind trial (NCT02827708), 324 adult patients with moderate renal impairment (eGFRCKD- EPI 30−59 mL/min/1.73 m2) were randomized to RYBELSUS 14 mg or placebo once daily. RYBELSUS was added to the patient’s stable pre-trial antidiabetic regimen. The insulin dose was reduced by 20% at randomization for patients on basal insulin. Dose reduction of insulin and sulfonylurea was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. Reference ID: 5472293 Patients had a mean age of 70 years and 48% were men. The mean duration of type 2 diabetes was 14 years, and the mean BMI was 32 kg/m2. Overall, 96% were White, 4% were Black or African American, and 0.3% were Asian; 6.5% identified as Hispanic or Latino ethnicity. 39.5% of patients had an eGFR value of 30 to 44 mL/min/1.73 m2. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo (see Table 7). Table 7. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Patients with Moderate Renal Impairment Placebo RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 161 163 HbA1c (%) Baseline (mean) 7.9 8.0 Change at week 26b -0.2 -1.0 Difference from placebob [95% CI] -0.8 [-1.0; -0.6]c Patients (%) achieving HbA1c <7% 23 58 FPG (mg/dL) Baseline (mean) 164 164 Change at week 26b -7 -28 aThe intent-to-treat population includes all randomized patients including patients on rescue medication. At week 26, the primary HbA1c endpoint was missing for 3.7% and 5.5% of patients randomized to placebo and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 10% and 4.3% of patients randomized to placebo and RYBELSUS 14 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, renal status and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 90.4 kg and 91.3 kg in the placebo and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.9 kg and -3.4 kg in the placebo and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -2.5 kg (-3.2, -1.8). Combination with Insulin with or without Metformin In a 26-week double blind trial (NCT03021187), 731 adult patients with type 2 diabetes inadequately controlled on insulin (basal, basal/bolus or premixed) with or without metformin, were randomized to RYBELSUS 3 mg, 7 mg and 14 mg once daily or placebo once daily. All patients reduced their insulin dose by 20% at randomization to reduce the risk of hypoglycemia. Patients were allowed to increase the insulin dose only up to the starting insulin dose prior to randomization. Patients had a mean age of 61 years and 54% were men. The mean duration of type 2 diabetes was 15 years, and the mean BMI was 31 kg/m2. Overall, 51% were White, 7% were Black or African American, and 36% were Asian; 13% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 7 mg and 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo once daily (see Table 8). Table 8. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Insulin alone or with Metformin Reference ID: 5472293 Placebo RYBELSUS 7 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 184 182 181 HbA1c (%) Baseline (mean) 8.2 8.2 8.2 Change at week 26b -0.1 -0.9 -1.3 Difference from placebob [95% CI] -0.9 [-1.1; -0.7]c -1.2 [-1.4; -1.0]c Patients (%) achieving HbA1c <7% 7 43 58 FPG (mg/dL) Baseline (mean) 150 153 150 Change at week 26b 5 -20 -24 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.3%, 4.4%, and 4.4% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 4.9%, 1.1 % and 2.2% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 86.0 kg, 87.1 kg and 84.6 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.4 kg, -2.4 kg and -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -2.0 kg (-3.0, -1.0), and for RYBELSUS 14 mg was -3.3 kg (-4.2, -2.3). 14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease PIONEER 6 (NCT02692716) was a multi-center, multi-national, placebo-controlled, double-blind trial. In this trial, 3,183 adult patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to RYBELSUS 14 mg once daily or placebo for a median observation time of 16 months. The trial compared the risk of a Major Adverse Cardiovascular Event (MACE) between RYBELSUS 14 mg and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Patients eligible to enter the trial were 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for cardiovascular disease. In total, 1,797 patients (56.5%) had established cardiovascular disease without chronic kidney disease, 354 patients (11.1%) had chronic kidney disease only, and 544 patients (17.1%) had both cardiovascular disease and kidney disease; 488 patients (15.3%) had cardiovascular risk factors without established cardiovascular disease or chronic kidney disease. The mean age at baseline was 66 years, and 68% were men. The mean duration of diabetes was 14.9 years, and mean BMI was 32 kg/m2 . Overall, 72% were White, 6% were Black or African American, and 20% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (12%), history of ischemic stroke (8%) and history of a myocardial infarction (36%). In total, 99.7% of the patients completed the trial and the vital status was known at the end of the trial for 100%. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of RYBELSUS 14 mg to placebo for time to first MACE using a risk margin of 1.3. Type-1 error was controlled across multiple Reference ID: 5472293 tests using a hierarchical testing strategy. Non-inferiority to placebo was established, with a hazard ratio equal to 0.79 (95% CI: 0.57, 1.11) over the median observation time of 16-months. The proportion of patients who experienced at least one MACE was 3.8% (61/1591) for RYBELSUS 14 mg and 4.8% (76/1592) for placebo. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RYBELSUS tablets are available as follows: Tablet Strength Description Package Configuration NDC No. 3 mg White to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side Bottle of 30 tablets 0169-4303-30 7 mg White to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side Bottle of 30 tablets 0169-4307-30 14 mg White to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side Bottle of 30 tablets 0169-4314-30 Storage and Handling Store at 68° to 77°F (20 to 25°C); excursions permitted to 59° to 86°F (15° to 30°C) [see USP Controlled Room Temperature]. Store and dispense in the original bottle. Store tablet in the original bottle until use to protect tablets from moisture. Store product in a dry place away from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Thyroid C-cell Tumors Inform patients that semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1)]. Pancreatitis Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue RYBELSUS promptly and contact their physician if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting) [see Warnings and Precautions (5.2)]. Diabetic Retinopathy Complications Inform patients to contact their physician if changes in vision are experienced during treatment with RYBELSUS [see Warnings and Precautions (5.3)]. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Inform patients that the risk of hypoglycemia is increased when RYBELSUS is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)]. Dehydration and Renal Failure Reference ID: 5472293 Advise patients treated with RYBELSUS of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.5)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of RYBELSUS. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking RYBELSUS and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)]. Acute Gallbladder Disease Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.7)]. Pulmonary Aspiration During General Anesthesia or Deep Sedation Inform patients that RYBELSUS may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS [see Warnings and Precautions (5.8)]. Pregnancy Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1), (8.3)]. Lactation Advise females not to breastfeed during treatment with RYBELSUS [see Use in Specific Populations (8.2)]. Females and Males of Reproductive Potential Discontinue RYBELSUS at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.3)]. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For information about RYBELSUS contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-833-457-7455 Version: 7 RYBELSUS® and OZEMPIC® are registered trademarks of Novo Nordisk A/S. PATENT INFORMATION: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk Reference ID: 5472293 Medication Guide RYBELSUS® (reb-EL-sus) (semaglutide) tablets, for oral use Read this Medication Guide before you start using RYBELSUS and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about RYBELSUS? RYBELSUS may cause serious side effects, including:  Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, RYBELSUS and medicines that work like RYBELSUS caused thyroid tumors, including thyroid cancer. It is not known if RYBELSUS will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.  Do not use RYBELSUS if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is RYBELSUS? RYBELSUS is a prescription medicine used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes.  It is not known if RYBELSUS can be used in people who have had pancreatitis.  RYBELSUS is not for use in patients with type 1 diabetes. It is not known if RYBELSUS is safe and effective for use in children under 18 years of age. Do not use RYBELSUS if:  you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).  you have had a serious allergic reaction to semaglutide or any of the ingredients in RYBELSUS. See the end of this Medication Guide for a complete list of ingredients in RYBELSUS. Symptoms of a serious allergic reaction include: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat Before using RYBELSUS, tell your healthcare provider if you have any other medical conditions, including if you:  have or have had problems with your pancreas or kidneys.  have a history of vision problems related to your diabetes.  are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).  are pregnant or plan to become pregnant. It is not known if RYBELSUS will harm your unborn baby. You should stop using RYBELSUS 2 months before you plan to become pregnant. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.  are breastfeeding or plan to breastfeed. Breastfeeding is not recommended during treatment with RYBELSUS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RYBELSUS may affect the way some medicines work and some medicines may affect the way RYBELSUS works. Before using RYBELSUS, talk to your healthcare provider about low blood sugar and how to manage it. Tell your healthcare provider if you are taking other medicines to treat diabetes, including insulin or sulfonylureas. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Reference ID: 5472293 . How should I take RYBELSUS?  Take RYBELSUS exactly as your healthcare provider tells you to.  Take RYBELSUS by mouth on an empty stomach when you first wake up.  Take RYBELSUS with a sip of plain water (no more than 4 ounces).  Do not split, crush or chew. Swallow RYBELSUS whole.  After 30 minutes, you can eat, drink, or take other oral medicines.  If you miss a dose of RYBELSUS, skip the missed dose and go back to your regular schedule. Your dose of RYBELSUS and other diabetes medicines may need to change because of: change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, fever, trauma, infection, surgery or because of other medicines you take. What are the possible side effects of RYBELSUS? RYBELSUS may cause serious side effects, including:  See “What is the most important information I should know about RYBELSUS?”  inflammation of your pancreas (pancreatitis). Stop using RYBELSUS and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.  changes in vision. Tell your healthcare provider if you have changes in vision during treatment with RYBELSUS.  low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use RYBELSUS with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: o dizziness or light-headedness o blurred vision o anxiety, irritability, or mood changes o sweating o slurred speech o hunger o confusion or drowsiness o shakiness o weakness o headache o fast heartbeat o feeling jittery  kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.  serious allergic reactions. Stop using RYBELSUS and get medical help right away, if you have any symptoms of a serious allergic reaction including: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat  gallbladder problems. Gallbladder problems have happened in some people who take RYBELSUS. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include: o pain in your upper stomach (abdomen) o yellowing of skin or eyes (jaundice) o fever o clay-colored stools  food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). RYBELSUS may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking RYBELSUS before you are scheduled to have surgery or other procedures. The most common side effects of RYBELSUS may include nausea, stomach (abdominal) pain, diarrhea, decreased appetite, vomiting and constipation. Nausea, vomiting and diarrhea are most common when you first start RYBELSUS. Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of RYBELSUS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Reference ID: 5472293 . How should I store RYBELSUS?  Store RYBELSUS at room temperature between 68°F and 77°F (20°C to 25°C).  Store in a dry place away from moisture.  Store tablets in the original closed RYBELSUS bottle until you are ready to take one. Do not store in any other container.  Keep RYBELSUS and all medicines out of the reach of children. General information about the safe and effective use of RYBELSUS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RYBELSUS for a condition for which it was not prescribed. Do not give RYBELSUS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RYBELSUS that is written for health professionals. What are the ingredients in RYBELSUS? Active Ingredient: semaglutide Inactive Ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC). Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark RYBELSUS® is a registered trademark of Novo Nordisk A/S. PATENT Information: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk For more information, go to www.RYBELSUS.com or call 1-833-GLP-PILL. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5472293 .	custom-source	2025-02-12T15:46:30.019663	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213051s023lbl.pdf', 'application_number': 213051, 'submission_type': 'SUPPL ', 'submission_number': 23}
80,138	1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MOUNJARO safely and effectively. See full prescribing information for MOUNJARO. MOUNJARO® (tirzepatide) Injection, for subcutaneous use Initial U.S. Approval: 2022 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning.  Tirzepatide causes thyroid C-cell tumors in rats. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1).  MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). --------------------------- RECENT MAJOR CHANGES ------------------------- Warnings and Precautions Severe Gastrointestinal Adverse Reactions (5.6) 11/2024 Pulmonary Aspiration During General Anesthesia or Deep Sedation (5.9) 11/2024 ---------------------------- INDICATIONS AND USAGE -------------------------- MOUNJARO® is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) Limitations of Use:  Has not been studied in patients with a history of pancreatitis (1, 5.2)  Is not indicated for use in patients with type 1 diabetes mellitus (1) ------------------------DOSAGE AND ADMINISTRATION----------------------  The recommended starting dosage is 2.5 mg injected subcutaneously once weekly (2.1)  After 4 weeks, increase to 5 mg injected subcutaneously once weekly (2.1)  If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.  The maximum dosage is 15 mg subcutaneously once weekly (2.1).  Administer once weekly at any time of day, with or without meals. (2.2)  Inject subcutaneously in the abdomen, thigh, or upper arm. (2.2)  Rotate injection sites with each dose. ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL in single-dose pen or single-dose vial (3) ------------------------------- CONTRAINDICATIONS -----------------------------  Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4, 5.1)  Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO (4, 5.4) ------------------------WARNINGS AND PRECAUTIONS ----------------------  Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. (5.2)  Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary. (5.3)  Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue MOUNJARO if suspected and promptly seek medical advice. (5.4)  Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. (5.5)  Severe Gastrointestinal Adverse Reactions: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients. (5.6)  Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy: Has not been studied in patients with non- proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Monitor patients with a history of diabetic retinopathy for progression. (5.7)  Acute Gallbladder Disease: Has occurred in clinical trials. If cholelithiasis is suspected, gallbladder studies and clinical follow up are indicated. (5.8)  Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.9) -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions, reported in ≥5% of patients treated with MOUNJARO are: nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------- DRUG INTERACTIONS ----------------------------- MOUNJARO delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. (7.2) ------------------------USE IN SPECIFIC POPULATIONS----------------------  Pregnancy: Based on animal study, may cause fetal harm. (8.1)  Females of Reproductive Potential: Advise females using oral contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation. (7.2, 8.3, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide. Revised: 11/2024 Reference ID: 5472245 2 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage 2.2 Important Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Pancreatitis 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin 5.4 Hypersensitivity Reactions 5.5 Acute Kidney Injury 5.6 Severe Gastrointestinal Adverse Reactions 5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy 5.8 Acute Gallbladder Disease 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation FULL PRESCRIBING INFORMATION 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Monotherapy Use of MOUNJARO in Adult Patients with Type 2 Diabetes Mellitus 14.3 MOUNJARO Use in Combination with Metformin, Sulfonylureas, and/or SGLT2 Inhibitors in Adult Patients with Type 2 Diabetes Mellitus 14.4 MOUNJARO Use in Combination with Basal Insulin with or without Metformin in Adult Patients with Type 2 Diabetes Mellitus 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. WARNING: RISK OF THYROID C-CELL TUMORS  In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].  MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO [see Contraindications (4) and Warnings and Precautions (5.1)]. INDICATIONS AND USAGE MOUNJARO® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use  MOUNJARO has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].  MOUNJARO is not indicated for use in patients with type 1 diabetes mellitus. Reference ID: 5472245 1 3 2 DOSAGE AND ADMINISTRATION 2.1 Dosage  The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. Follow the dosage escalation below to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)]. The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.  After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.  If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.  The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.  If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.  The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours). 2.2 Important Administration Instructions  Prior to initiation, train patients and caregivers on proper injection technique [see Instructions for Use].  Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose).  Administer MOUNJARO once weekly, any time of day, with or without meals.  Inject MOUNJARO subcutaneously in the abdomen, thigh, or upper arm.  Rotate injection sites with each dose.  Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use MOUNJARO if particulate matter or discoloration is seen.  When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other. 3 DOSAGE FORMS AND STRENGTHS Injection: Clear, colorless to slightly yellow solution in pre-filled single-dose pens or single-dose vials, each available in the following strengths:  2.5 mg/0.5 mL  5 mg/0.5 mL  7.5 mg/0.5 mL  10 mg/0.5 mL  12.5 mg/0.5 mL  15 mg/0.5 mL 4 CONTRAINDICATIONS MOUNJARO is contraindicated in patients with:  A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].  Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with MOUNJARO [see Warnings and Precautions (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary Reference ID: 5472245 4 thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined. MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists. In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 MOUNJARO-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). MOUNJARO has not been studied in patients with a prior history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on MOUNJARO. After initiation of MOUNJARO, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue MOUNJARO and initiate appropriate management. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving MOUNJARO in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1), Drug Interactions (7.1)]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.4 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with MOUNJARO. If hypersensitivity reactions occur, discontinue use of MOUNJARO; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous serious hypersensitivity reaction to tirzepatide or any of the excipients in MOUNJARO [see Contraindications (4), Adverse Reactions (6.2)]. Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with MOUNJARO. 5.5 Acute Kidney Injury MOUNJARO has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhea [see Adverse Reactions (6.1)]. These events may lead to dehydration, which if severe could cause acute kidney injury. In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of MOUNJARO in patients with renal impairment reporting severe gastrointestinal adverse reactions. 5.6 Severe Gastrointestinal Adverse Reactions Use of MOUNJARO has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions 6.1]. In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions occurred more frequently among patients receiving MOUNJARO (5 mg 1.3%, 10 mg 0.4%, 15 mg 1.2%) than placebo (0.9%). MOUNJARO has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients. Reference ID: 5472245 5 6 5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. MOUNJARO has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In MOUNJARO placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation MOUNJARO delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking MOUNJARO, including whether modifying preoperative fasting recommendations or temporarily discontinuing MOUNJARO could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking MOUNJARO. ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information:  Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]  Pancreatitis [see Warnings and Precautions (5.2)]  Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]  Hypersensitivity Reactions [see Warnings and Precautions (5.4)]  Acute Kidney Injury [see Warnings and Precautions (5.5)]  Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)]  Diabetic Retinopathy Complications [see Warnings and Precautions (5.7)]  Acute Gallbladder Disease [see Warnings and Precautions (5.8)]  Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Two Placebo-Controlled Clinical Trials The data in Table 1 are derived from 2 placebo-controlled trials [1 monotherapy trial (SURPASS-1) and 1 trial in combination with basal insulin with or without metformin (SURPASS-5)] in adult patients with type 2 diabetes mellitus [see Clinical Studies (14.2, 14.4)]. These data reflect exposure of 718 patients to MOUNJARO and a mean duration of exposure to MOUNJARO of 36.6 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 54% were male. The population was 57% White, 27% Asian, 13% American Indian or Alaska Native, and 3% Black or African American; 25% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 9.1 years with a mean HbA1c of 8.1%. As assessed by baseline fundoscopic examination, 13% of the population had retinopathy. At baseline, eGFR was ≥90 mL/min/1.73 m2 in 53%, 60 to 90 mL/min/1.73 m2 in 39%, 45 to 60 mL/min/1.73 m2 in 7%, and 30 to 45 mL/min/1.73 m2 in 1% of patients. Reference ID: 5472245 6 Pool of Seven Controlled Clinical Trials Adverse reactions were also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in seven controlled clinical trials which included two placebo-controlled trials (SURPASS-1 and -5), three trials of MOUNJARO in combination with metformin, sulfonylureas, and/or SGLT2 Inhibitors (SURPASS-2, -3, -4) [see Clinical Studies (14.3)] and two additional trials conducted in Japan. In this pool, a total of 5119 adult patients with type 2 diabetes mellitus were treated with MOUNJARO for a mean duration of 48.1 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 58% were male. The population was 65% White, 24% Asian, 7% American Indian or Alaska Native, and 3% Black or African American; 38% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 9.1 years with a mean HbA1c of 8.3%. As assessed by baseline fundoscopic examination, 15% of the population had retinopathy. At baseline, eGFR was ≥90 mL/min/1.73 m2 in 52%, 60 to 90 mL/min/1.73 m2 in 40%, 45 to 60 mL/min/1.73 m2 in 6%, and 30 to 45 mL/min/1.73 m2 in 1% of patients. Common Adverse Reactions Table 1 shows common adverse reactions, not including hypoglycemia, associated with the use of MOUNJARO in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on MOUNJARO than on placebo and occurred in at least 5% of patients treated with MOUNJARO. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials Reported in ≥5% of MOUNJARO-treated Adult Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=235) % MOUNJARO 5 mg (N=237) % MOUNJARO 10 mg (N=240) % MOUNJARO 15 mg (N=241) % Nausea 4 12 15 18 Diarrhea 9 12 13 17 Decreased Appetite 1 5 10 11 Vomiting 2 5 5 9 Constipation 1 6 6 7 Dyspepsia 3 8 8 5 Abdominal Pain 4 6 5 5 Note: Percentages reflect the number of patients who reported at least 1 occurrence of the adverse reaction. In the pool of seven clinical trials, the types and frequency of common adverse reactions, not including hypoglycemia, were similar to those listed in Table 1. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving MOUNJARO than placebo (placebo 20.4%, MOUNJARO 5 mg 37.1%, MOUNJARO 10 mg 39.6%, MOUNJARO 15 mg 43.6%). More patients receiving MOUNJARO 5 mg (3.0%), MOUNJARO 10 mg (5.4%), and MOUNJARO 15 mg (6.6%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation and decreased over time. The following gastrointestinal adverse reactions were reported more frequently in MOUNJARO-treated patients than placebo-treated patients (frequencies listed, respectively, as: placebo; 5 mg; 10 mg; 15 mg): eructation (0.4%, 3.0%, 2.5%, 3.3%), flatulence (0%, 1.3%, 2.5%, 2.9%), gastroesophageal reflux disease (0.4%, 1.7%, 2.5%, 1.7%), abdominal distension (0.4%, 0.4%, 2.9%, 0.8%). Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of hypoglycemic events in the placebo-controlled trials. Reference ID: 5472245 7 Table 2: Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Adult Patients with Type 2 Diabetes Mellitus Placebo % MOUNJARO 5 mg % MOUNJARO 10 mg % MOUNJARO 15 mg % Monotherapy (40 weeks)* N=115 N=121 N=119 N=120 Blood glucose <54 mg/dL 1 0 0 0 Severe hypoglycemia** 0 0 0 0 Add-on to Basal Insulin with or without Metformin (40 weeks)* N=120 N=116 N=119 N=120 Blood glucose <54 mg/dL 13 16 19 14 Severe hypoglycemia** 0 0 2 1 * Reflects the study treatment period. Data include events occurring during 4 weeks of treatment-free safety follow up. Events after introduction of a new glucose-lowering treatment are excluded. ** Episodes requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Hypoglycemia was more frequent when MOUNJARO was used in combination with a sulfonylurea [see Clinical Studies (14)]. In a clinical trial up to 104 weeks of treatment, when administered with a sulfonylurea, hypoglycemia (glucose level <54 mg/dL) occurred in 13.8%, 9.9%, and 12.8%, and severe hypoglycemia occurred in 0.5%, 0%, and 0.6% of patients treated with MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Heart Rate Increase In the pool of placebo-controlled trials, treatment with MOUNJARO resulted in a mean increase in heart rate of 2 to 4 beats per minute compared to a mean increase of 1 beat per minute in placebo-treated patients. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, also were reported in 4.3%, 4.6%, 5.9% and 10% of subjects treated with placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. For patients enrolled in Japan, these episodes were reported in 7% (3/43), 7.1% (3/42), 9.3% (4/43), and 23% (10/43) of patients treated with placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. The clinical relevance of heart rate increases is uncertain. Hypersensitivity Reactions Hypersensitivity reactions have been reported with MOUNJARO in the pool of placebo-controlled trials, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2% of MOUNJARO-treated patients compared to 1.7% of placebo-treated patients. In the pool of seven clinical trials, hypersensitivity reactions occurred in 106/2,570 (4.1%) of MOUNJARO-treated patients with anti-tirzepatide antibodies and in 73/2,455 (3.0%) of MOUNJARO-treated patients who did not develop anti tirzepatide antibodies [see Clinical Pharmacology (12.6)]. Injection Site Reactions In the pool of placebo-controlled trials, injection site reactions were reported in 3.2% of MOUNJARO-treated patients compared to 0.4% of placebo-treated patients. In the pool of seven clinical trials, injection site reactions occurred in 119/2,570 (4.6%) of MOUNJARO-treated patients with anti-tirzepatide antibodies and in 18/2,455 (0.7%) of MOUNJARO-treated patients who did not develop anti tirzepatide antibodies [see Clinical Pharmacology (12.6)]. Acute Gallbladder Disease In the pool of placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, biliary colic and cholecystectomy) was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients. Reference ID: 5472245 8 Dysesthesia In the pool of placebo-controlled clinical trials, dysesthesia was reported by 0.4%, 0.4%, and 0.4% of patients treated with MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. No events were reported by patients receiving placebo. Dysgeusia In the pool of placebo-controlled clinical trials, dysgeusia was reported by 0.1% of MOUNJARO-treated patients and 0% of placebo-treated patients. Laboratory Abnormalities Amylase and Lipase Increase In the pool of placebo-controlled clinical trials, treatment with MOUNJARO resulted in mean increases from baseline in serum pancreatic amylase concentrations of 33% to 38% and serum lipase concentrations of 31% to 42%. Placebo- treated patients had a mean increase from baseline in pancreatic amylase of 4% and no changes were observed in lipase. The clinical significance of elevations in lipase or amylase with MOUNJARO is unknown in the absence of other signs and symptoms of pancreatitis. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of MOUNJARO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity: anaphylaxis, angioedema Gastrointestinal: ileus Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating MOUNJARO, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)]. 7.2 Oral Medications MOUNJARO delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with MOUNJARO. Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with MOUNJARO. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO. Hormonal contraceptives that are not administered orally should not be affected [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.2, 12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data with MOUNJARO use in pregnant women are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. MOUNJARO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals coincided with pharmacological effects on maternal weight and food consumption (see Data). Reference ID: 5472245 9 The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Animal Data In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide (0.03-, 0.07-, and 0.5-fold the MRHD of 15 mg once weekly based on AUC) during organogenesis, increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and decreased fetal weights coincided with pharmacologically-mediated reductions in maternal body weights and food consumption at 0.5 mg/kg. In pregnant rabbits given once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg tirzepatide (0.01-, 0.06-, and 0.2-fold the MRHD) during organogenesis, pharmacologically-mediated effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits occurred at all dose levels. Reduced fetal weights associated with decreased maternal food consumption and body weights were observed at 0.1 mg/kg. In a pre- and post-natal study in rats administered subcutaneous doses of 0.02, 0.10, or 0.25 mg/kg tirzepatide twice weekly from implantation through lactation, F1 pups from F0 maternal rats given 0.25 mg/kg tirzepatide had statistically significant lower mean body weight when compared to controls from post-natal day 7 through post-natal day 126 for males and post-natal day 56 for females. 8.2 Lactation Risk Summary There are no data on the presence of tirzepatide in animal or human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MOUNJARO and any potential adverse effects on the breastfed infant from MOUNJARO or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Use of MOUNJARO may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO [see Drug Interactions (7.2) and Clinical Pharmacology (12.2, 12.3)]. 8.4 Pediatric Use Safety and effectiveness of MOUNJARO have not been established in pediatric patients. 8.5 Geriatric Use In the pool of seven clinical trials, 1539 (30.1%) MOUNJARO-treated patients were 65 years of age or older, and 212 (4.1%) MOUNJARO-treated patients were 75 years of age or older at baseline. No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dosage adjustment of MOUNJARO is recommended for patients with renal impairment. In subjects with renal impairment including end-stage renal disease (ESRD), no change in tirzepatide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. Monitor renal function when initiating or escalating doses of MOUNJARO in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Warnings and Precautions (5.5)]. Reference ID: 5472245 H O H 0 H02C~N~N~o_.,......o -yN_.,......o~oJNH 0 C02H H O ~ 0 0 H-Y-~-)-E-G-T-F-T-S-D-Y-S-1-~)1-L-D-K-1-A-Q- ~ A-F-V-Q-W-L-1-A-G-G-P-S-S-G-A-P-P-P-5-NH2 Me Me Me Me 0 10 8.7 Hepatic Impairment No dosage adjustment of MOUNJARO is recommended for patients with hepatic impairment. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no change in tirzepatide PK was observed [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of an overdosage, contact Poison Control for latest recommendations. Appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A period of observation and treatment for these symptoms may be necessary, taking into account the half-life of tirzepatide of approximately 5 days. 11 DESCRIPTION MOUNJARO (tirzepatide) injection, for subcutaneous use, contains tirzepatide, a once weekly GIP receptor and GLP-1 receptor agonist. Tirzepatide is based on the GIP sequence and contains aminoisobutyric acid (Aib) in positions 2 and 13, a C-terminal amide, and Lys residue at position 20 that is attached to 1,20-eicosanedioic acid via a linker. The molecular weight is 4813.53 Da and the empirical formula is C225H348N48O68. Structural formula: MOUNJARO is a clear, colorless to slightly yellow, sterile, preservative-free solution for subcutaneous use. Each single- dose pen or single-dose vial contains a 0.5 mL solution of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg of tirzepatide and the following excipients: sodium chloride (4.1 mg), sodium phosphate dibasic heptahydrate (0.7 mg), and water for injection. Hydrochloric acid solution and/or sodium hydroxide solution may have been added to adjust the pH. MOUNJARO has a pH of 6.5 – 7.5. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It is an amino-acid sequence including a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1. Tirzepatide enhances first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose- dependent manner. 12.2 Pharmacodynamics Tirzepatide lowers fasting and postprandial glucose concentration, decreases food intake, and reduces body weight in patients with type 2 diabetes mellitus. First and Second-Phase Insulin Secretion Tirzepatide enhances the first- and second-phase insulin secretion. (Figure 1) Reference ID: 5472245 1st phase 250 .----, -200 ..J - ::> E 150 - C: = 100 :::l tn C: 50 2nd phase . .....;..----!----......--------------------------------·----..-----·----.. 0------------------------- 0 10 20 30 60 90 100 110 120 Time (minutes) --• Placebo-Baseline - Placebo-Week 28 (n=24) --•-- Tirzepatide 15 mg-Baseline -+- Tirzepatide 15 mg-Week 28 (n=41) 11 Figure 1: Mean insulin concentration at 0-120 minutes during hyperglycemic clamp at baseline and Week 28 Insulin Sensitivity Tirzepatide increases insulin sensitivity, as demonstrated in a hyperinsulinemic euglycemic clamp study after 28 weeks of treatment. Glucagon Secretion Tirzepatide reduces fasting and postprandial glucagon concentrations. Tirzepatide 15 mg reduced fasting glucagon concentration by 28% and glucagon AUC after a mixed meal by 43%, compared with no change for placebo after 28 weeks of treatment. Gastric Emptying Tirzepatide delays gastric emptying. The delay is largest after the first dose and this effect diminishes over time. Tirzepatide slows post-meal glucose absorption, reducing postprandial glucose. 12.3 Pharmacokinetics The pharmacokinetics of tirzepatide is similar between healthy subjects and patients with type 2 diabetes mellitus. Steady- state plasma tirzepatide concentrations were achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose-proportional manner. Absorption Following subcutaneous administration, the time to maximum plasma concentration of tirzepatide ranges from 8 to 72 hours. The mean absolute bioavailability of tirzepatide following subcutaneous administration is 80%. Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm. Distribution The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes mellitus is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%). Elimination The apparent population mean clearance of tirzepatide is 0.061 L/h with an elimination half-life of approximately 5 days, enabling once-weekly dosing. Reference ID: 5472245 12 Metabolism Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid and amide hydrolysis. Excretion The primary excretion routes of tirzepatide metabolites are via urine and feces. Intact tirzepatide is not observed in urine or feces. Specific Populations The intrinsic factors of age, gender, race, ethnicity, or body weight do not have a clinically relevant effect on the PK of tirzepatide. Patients with Renal Impairment Renal impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function. This was also shown for patients with both type 2 diabetes mellitus and renal impairment based on data from clinical studies [see Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Hepatic impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function [see Use in Specific Populations (8.7)]. Drug Interactions Studies Potential for Tirzepatide to Influence the Pharmacokinetics of Other Drugs In vitro studies have shown low potential for tirzepatide to inhibit or induce CYP enzymes, and to inhibit drug transporters. MOUNJARO delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications [see Drug Interactions (7.2)]. The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses. Following a first dose of tirzepatide 5 mg, acetaminophen maximum concentration (Cmax) was reduced by 50%, and the median peak plasma concentration (tmax) occurred 1 hour later. After coadministration at week 4, there was no meaningful impact on acetaminophen Cmax and tmax. Overall acetaminophen exposure (AUC0-24hr) was not influenced. Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean Cmax of ethinyl estradiol, norgestimate, and norelgestromin was reduced by 59%,66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in tmax of 2.5 to 4.5 hours was observed. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials. During the 40- to 104-week treatment periods with ADA sampling conducted up to 44 to 108 weeks in seven clinical trials in adults with type 2 diabetes mellitus [see Clinical Studies (14)], 51% (2,570/5,025) of MOUNJARO-treated patients developed anti-tirzepatide antibodies. In these trials, anti-tirzepatide antibody formation in 34% and 14% of MOUNJARO- treated patients showed cross-reactivity to native GIP or native GLP-1, respectively. Of the 2,570 MOUNJARO-treated patients who developed anti-tirzepatide antibodies during the treatment periods in these seven trials, 2% and 2% developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors, respectively, and 0.9% and 0.4% developed neutralizing antibodies against native GIP or GLP-1, respectively. There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of MOUNJARO. More MOUNJARO-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies [see Adverse Reactions (6.1)]. Reference ID: 5472245 13 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.1-, 0.4-, and 1-fold the MRHD of 15 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. A statistically significant increase in thyroid C-cell adenomas was observed in males (≥0.5 mg/kg) and females (≥0.15 mg/kg), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in males and females at all doses examined. In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly was not tumorigenic. Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay. In fertility and early embryonic development studies, male and female rats were administered twice weekly subcutaneous doses of 0.5, 1.5, or 3 mg/kg (0.3-, 1-, and 2-fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC). No effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. In female rats, an increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food consumption and body weight. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The effectiveness of MOUNJARO as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus was established in five trials. In these trials, MOUNJARO was studied as monotherapy (SURPASS-1); as an add-on to metformin, sulfonylureas, and/or sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) (SURPASS-2, -3, and -4); and in combination with basal insulin with or without metformin (SURPASS-5). In these trials, MOUNJARO (5 mg, 10 mg, and 15 mg given subcutaneously once weekly) was compared with placebo, semaglutide 1 mg, insulin degludec, and/or insulin glargine. In adult patients with type 2 diabetes mellitus, treatment with MOUNJARO produced a statistically significant reduction from baseline in HbA1c compared to placebo. The effectiveness of MOUNJARO was not impacted by age, gender, race, ethnicity, region, or by baseline BMI, HbA1c, diabetes duration, or renal function. 14.2 Monotherapy Use of MOUNJARO in Adult Patients with Type 2 Diabetes Mellitus SURPASS-1 (NCT03954834) was a 40-week double-blind trial that randomized 478 adult patients with type 2 diabetes mellitus with inadequate glycemic control with diet and exercise to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg, or placebo once weekly. Patients had a mean age of 54 years, and 52% were men. The mean duration of type 2 diabetes mellitus was 4.7 years, and the mean BMI was 32 kg/m2. Overall, 36% were White, 35% were Asian, 25% were American Indians/Alaska Natives, and 5% were Black or African American; 43% identified as Hispanic or Latino ethnicity. Monotherapy with MOUNJARO 5 mg, 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3). Table 3: Results at Week 40 in a Trial of MOUNJARO as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control with Diet and Exercise Placebo MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Modified Intent-to-Treat (mITT) Population (N)a 113 121 121 120 HbA1c (%) Baseline (mean) 8.1 8.0 7.9 7.9 Change at Week 40b -0.1 -1.8 -1.7 -1.7 Difference from placebob (95% CI) - -1.7c (-2.0, -1.4) -1.6c (-1.9, -1.3) -1.6c (-1.9, -1.3) Reference ID: 5472245 14 c Patients (%) achieving HbA1c <7%d 23 82c 85c 78c Fasting Serum Glucose (mg/dL) Baseline (mean) 155 154 153 154 Change at Week 40b 4 -40 -40 -39 Difference from placebob (95% CI) - -43c (-55, -32) -43c (-55, -32) -42c (-54, -30) Body Weight (kg) Baseline (mean) 84.5 87.0 86.2 85.5 Change at Week 40b -1.0 -6.3 -7.0 -7.8 Difference from placebob (95% CI) - -5.3c (-6.8, -3.9) -6.0c (-7.4, -4.6) -6.8c (-8.3, -5.4) a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 25%, 2%, 3%, and 2% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c data were missing for 12%, 6%, 7%, and 14% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using placebo-based multiple imputation. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. p<0.001 (two-sided) for superiority vs. placebo, adjusted for multiplicity. d Analyzed using logistic regression adjusted for baseline value and other stratification factors. 14.3 MOUNJARO Use in Combination with Metformin, Sulfonylureas, and/or SGLT2 Inhibitors in Adult Patients with Type 2 Diabetes Mellitus Add-on to metformin SURPASS-2 (NCT03987919) was a 40-week open-label trial (double-blind with respect to MOUNJARO dose assignment) that randomized 1879 adult patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin alone to the addition of MOUNJARO 5 mg, MOUNJARO 10 mg, or MOUNJARO 15 mg once weekly or subcutaneous semaglutide 1 mg once weekly. Patients had a mean age of 57 years and 47% were men. The mean duration of type 2 diabetes mellitus was 8.6 years, and the mean BMI was 34 kg/m2. Overall, 83% were White, 4% were Black or African American, and 1% were Asian; 70% identified as Hispanic or Latino ethnicity. Treatment with MOUNJARO 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with semaglutide 1 mg once weekly (see Table 4 and Figure 2). Table 4: Results at Week 40 in a Trial of MOUNJARO versus Semaglutide 1 mg in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin Semaglutide 1 mg MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Modified Intent-to-Treat (mITT) Population (N)a 468 470 469 469 HbA1c (%) Baseline (mean) 8.3 8.3 8.3 8.3 Change at Week 40b -1.9 -2.0 -2.2 -2.3 Difference from semaglutideb (95% CI) - -0.2c (-0.3, -0.0) -0.4d (-0.5, -0.3) -0.5d (-0.6, -0.3) Patients (%) achieving HbA1c <7%e 79 82 86f 86f Fasting Serum Glucose (mg/dL) Reference ID: 5472245 8.5 8.0 7.5 - ::,'?. e., u 7.0 .... 1i J: 6.5 6.0 5.5 0 4 • -e- MOUNJARO 5mg _.,_ MOUNJARO 10mg -+- MOUNJARO 15mg --a - Semaglutide 1 mg - -' - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - . - - - . - - . - - - - - - - - - - - - - . - .. - • 8 12 16 6.4 -----•6.2 6.0 5.9 .6.4 :lt6.3 16.0 6.0 20 24 40 Week40MI Week Post Randomization 15 c Baseline (mean) 171 174 174 172 Change at Week 40b -49 -55 -59 -60 Body Weight (kg) Baseline (mean) 93.7 92.5 94.8 93.8 Change at Week 40b -5.7 -7.6 -9.3 -11.2 Difference from semaglutideb (95% CI) - -1.9c (-2.8, -1.0) -3.6d (-4.5, -2.7) -5.5d (-6.4, -4.6) a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 3%, 2%, 1%, and 1% of patients randomized to semaglutide 1 mg, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c endpoint was missing for 5%, 4%, 5%, and 5% of patients randomized to semaglutide 1 mg, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using multiple imputation with retrieved dropout. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. p<0.05 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity. d p<0.001 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity. e Analyzed using logistic regression adjusted for baseline value and other stratification factors. f p<0.01 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity. Figure 2. Mean HbA1c (%) Over Time - Baseline to Week 40 Number of patients MOUNJARO 5mg 470 451 470 MOUNJARO 10mg 469 445 469 MOUNJARO 15mg 469 447 469 Semaglutide 1mg 468 443 468 Note: Displayed results are from modified Intent-to-Treat Full Analysis Set. (1) Observed mean value from Week 0 to Week 40, and (2) least-squares mean ± standard error at Week 40 multiple imputation (MI). Reference ID: 5472245 16 Add-on to metformin with or without SGLT2 inhibitor SURPASS-3 (NCT03882970) was a 52-week open-label trial that randomized 1444 adult patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin with or without SGLT2 inhibitor to the addition of MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or insulin degludec 100 units/mL once daily. In this trial, 32% of patients were on SGLT2 inhibitor. Insulin degludec was initiated at 10 units once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values. At Week 52, 26% of patients randomized to insulin degludec achieved the fasting serum glucose target of <90 mg/dL, and the mean daily insulin degludec dose was 49 U (0.5 U per kilogram). Patients had a mean age of 57 years, and 56% were men. The mean duration of type 2 diabetes mellitus was 8.4 years, and the mean baseline BMI was 34 kg/m2. Overall, 91% were White, 3% were Black or African American, and 5% were Asian; 29% identified as Hispanic or Latino ethnicity. Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with daily insulin degludec (see Table 5). Table 5: Results at Week 52 in a Trial of MOUNJARO versus Insulin Degludec in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin with or without SGLT2 Inhibitor Insulin Degludec MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Modified Intent-to-Treat (mITT)a Population (N) 359 358 360 358 HbA1c (%) Baseline (mean) 8.1 8.2 8.2 8.2 Change at Week 52b -1.3 -1.9 -2.0 -2.1 Difference from insulin degludecb (95% CI) - -0.6c (-0.7, -0.5) -0.8c (-0.9, -0.6) -0.9c (-1.0, -0.7) Patients (%) achieving HbA1c <7%d 58 79c 82c 83c Fasting Serum Glucose (mg/dL) Baseline (mean) 167 172 170 168 Change at Week 52b -51 -47 -50 -54 Body Weight (kg) Baseline (mean) 94.0 94.4 93.8 94.9 Change at Week 52b 1.9 -7.0 -9.6 -11.3 Difference from insulin degludecb (95% CI) - -8.9c (-10.0, -7.8) -11.5c (-12.6, -10.4) -13.2c (-14.3, -12.1) a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%,1%, 1%, and 2% of patients randomized to insulin degludec, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 52 the HbA1c endpoint was missing for 9%, 6%, 10%, and 5% of patients randomized to insulin degludec, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. p<0.001 (two-sided) for superiority vs. insulin degludec, adjusted for multiplicity. d Analyzed using logistic regression adjusted for baseline value and other stratification factors. Add-on to 1-3 oral anti-hyperglycemic agents (metformin, sulfonylurea or SGLT-2 inhibitor) SURPASS-4 (NCT03730662) was a 104-week open-label trial (52-week primary endpoint) that randomized 2002 adult patients with type 2 diabetes mellitus with increased cardiovascular risk to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or insulin glargine 100 units/mL once daily (1:1:1:3 ratio) on a background of metformin (95%) and/or sulfonylureas (54%) and/or SGLT2 inhibitors (25%). Reference ID: 5472245 c 17 Patients had a mean age of 64 years, and 63% were men. The mean duration of type 2 diabetes mellitus was 11.8 years, and the mean baseline BMI was 33 kg/m2. Overall, 82% were White, 4% were Black or African American, and 4% were Asian; 48% identified as Hispanic or Latino ethnicity. Across all treatment groups, 87% had a history of cardiovascular disease. At baseline, eGFR was ≥90 mL/min/1.73 m2 in 43%, 60 to 90 mL/min/1.73 m2 in 40%, 45 to 60 mL/min/1.73 m2 in 10%, and 30 to 45 mL/min/1.73 m2 in 6% of patients. Insulin glargine was initiated at 10 U once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values. At Week 52, 30% of patients randomized to insulin glargine achieved the fasting serum glucose target of <100 mg/dL, and the mean daily insulin glargine dose was 44 U (0.5 U per kilogram). Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with insulin glargine once daily (see Table 6). Table 6: Results at Week 52 in a Trial of MOUNJARO versus Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin and/or Sulfonylurea and/or SGLT2 Inhibitor Insulin Glargine MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Modified Intent-to-Treat (mITT) Population (N)a 998 328 326 337 HbA1c (%) Baseline (mean) 8.5 8.5 8.6 8.5 Change at Week 52b -1.4 -2.1 -2.3 -2.4 Difference from insulin glargineb (95% CI) - -0.7c (-0.9, -0.6) -0.9c (-1.1, -0.8) -1.0c (-1.2, -0.9) Patients (%) achieving HbA1c <7%d 49 75c 83c 85c Fasting Serum Glucose (mg/dL) Baseline (mean) 168 172 176 174 Change at Week 52b -49 -44 -50 -55 Body Weight (kg) Baseline (mean) 90.2 90.3 90.6 90.0 Change at Week 52b 1.7 -6.4 -8.9 -10.6 Difference from insulin glargineb (95% CI) - -8.1c (-8.9, -7.3) -10.6c (-11.4, -9.8) -12.2c (-13.0, -11.5) a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%, 0%, 0%, and 1% of patients randomized to insulin glargine, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 52 the HbA1c endpoint was missing for 9%, 9%, 6%, and 4% of patients randomized to insulin glargine, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. p<0.001 (two-sided) for superiority vs. insulin glargine, adjusted for multiplicity. d Analyzed using logistic regression adjusted for baseline value and other stratification factors. 14.4 MOUNJARO Use in Combination with Basal Insulin with or without Metformin in Adult Patients with Type 2 Diabetes Mellitus SURPASS-5 (NCT04039503) was a 40-week double-blind trial that randomized 475 patients with type 2 diabetes mellitus with inadequate glycemic control on insulin glargine 100 units/mL, with or without metformin, to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or placebo. The dose of background insulin glargine was adjusted using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting <100 mg/dL. Reference ID: 5472245 c 18 Patients had a mean age of 61 years, and 56% were men. The mean duration of type 2 diabetes mellitus was 13.3 years, and the mean baseline BMI was 33 kg/m2. Overall, 80% were White, 1% were Black or African American, and 18% were Asian; 5% identified as Hispanic or Latino ethnicity. The mean dose of insulin glargine at baseline was 34, 32, 35, and 33 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. At randomization, the initial insulin glargine dose in patients with HbA1c ≤8.0% was reduced by 20%. At week 40, mean dose of insulin glargine was 38, 36, 29, and 59 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. Treatment with MOUNJARO 5 mg once weekly, 10 mg once weekly and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 7). Table 7: Results at Week 40 in a Trial of MOUNJARO Added to Basal Insulin with or without Metformin in Adult Patients with Type 2 Diabetes Mellitus Placebo MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Modified Intent-to-Treat (mITT) Population (N)a 119 116 118 118 HbA1c (%) Baseline (mean) 8.4 8.3 8.4 8.2 Change at Week 40b -0.9 -2.1 -2.4 -2.3 Difference from placebob (95% CI) - -1.2c (-1.5, -1.0) -1.5c (-1.8, -1.3) -1.5c (-1.7, -1.2) Patients (%) achieving HbA1c <7%d 35 87c 90c 85c Fasting Serum Glucose (mg/dL) Baseline (mean) 164 163 163 160 Change at Week 40b -39 -58 -64 -63 Difference from placebob (95% CI) - -19c (-27, -11) -25c (-32, -17) -23c (-31, -16) Body Weight (kg) Baseline (mean) 94.2 95.8 94.6 96.0 Change at Week 40b 1.6 -5.4 -7.5 -8.8 Difference from placebob (95% CI) - -7.1c (-8.7, -5.4) -9.1c (-10.7, -7.5) -10.5c (-12.1, -8.8) a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 4%, 1%, 0%, and 1% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c endpoint was missing for 2%, 6%, 3%, and 7% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using placebo-based multiple imputation. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. c p<0.001 (two-sided) for superiority vs. placebo, adjusted for multiplicity. d Analyzed using logistic regression adjusted for baseline value and other stratification factors. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied MOUNJARO is a clear, colorless to slightly yellow solution available in cartons containing 4 pre-filled single-dose pens or 1 single-dose vial as follows: Reference ID: 5472245 19 Total Strength per Total Volume Pen NDC Vial NDC 2.5 mg/0.5 mL 0002-1506-80 0002-1152-01 5 mg/0.5 mL 0002-1495-80 0002-1243-01 7.5 mg/0.5 mL 0002-1484-80 0002-2214-01 10 mg/0.5 mL 0002-1471-80 0002-2340-01 12.5 mg/0.5 mL 0002-1460-80 0002-2423-01 15 mg/0.5 mL 0002-1457-80 0002-3002-01 16.2 Storage and Handling  Store MOUNJARO in a refrigerator at 2°C to 8°C (36°F to 46°F).  If needed, each single-dose pen or single-dose vial can be stored unrefrigerated at temperatures not to exceed 30ºC (86ºF) for up to 21 days.  Do not freeze MOUNJARO. Do not use MOUNJARO if frozen.  Store MOUNJARO in the original carton to protect from light. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Risk of Thyroid C-Cell Tumors Inform patients that MOUNJARO causes thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)]. Pancreatitis Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue MOUNJARO promptly and contact their healthcare provider if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting) [see Warnings and Precautions (5.2)]. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Inform patients that the risk of hypoglycemia is increased when MOUNJARO is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported with use of MOUNJARO. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking MOUNJARO and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.4)]. Acute Kidney Injury Advise patients treated with MOUNJARO of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.5]. Severe Gastrointestinal Adverse Reactions Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)]. Diabetic Retinopathy Complications Inform patients to contact their healthcare provider if changes in vision are experienced during treatment with MOUNJARO [see Warnings and Precautions (5.7]. Acute Gallbladder Disease Inform patients of the risk of acute gallbladder disease. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected [see Warnings and Precautions (5.8)]. Reference ID: 5472245 20 Pulmonary Aspiration During General Anesthesia or Deep Sedation Inform patients that MOUNJARO may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking MOUNJARO [see Warnings and Precautions (5.9)]. Pregnancy Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1)]. Contraception Use of MOUNJARO may reduce the efficacy of oral hormonal contraceptives. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO [see Drug Interactions (7.2), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)]. Administration Instruct patients how to prepare and administer the correct dose of MOUNJARO and assess their ability to inject subcutaneously to ensure the proper administration of MOUNJARO. Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose) [see Dosage and Administration (2.2)]. Missed Doses Inform patients if a dose is missed, it should be administered as soon as possible within 4 days after the missed dose. If more than 4 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once weekly dosing schedule [see Dosage and Administration (2.1)]. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2022, 2024, Eli Lilly and Company. All rights reserved. A4.0-MOU-0003-USPI-202411 Reference ID: 5472245 Medication Guide MOUNJARO® [mown-JAHR-OH] (tirzepatide) injection, for subcutaneous use What is the most important information I should know about MOUNJARO? MOUNJARO may cause serious side effects, including:  Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rats, MOUNJARO and medicines that work like MOUNJARO caused thyroid tumors, including thyroid cancer. It is not known if MOUNJARO will cause thyroid tumors, or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.  Do not use MOUNJARO if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is MOUNJARO?  MOUNJARO is an injectable prescription medicine that is used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes mellitus.  It is not known if MOUNJARO can be used in people who have had pancreatitis.  MOUNJARO is not for use in people with type 1 diabetes.  It is not known if MOUNJARO is safe and effective for use in children under 18 years of age. Do not use MOUNJARO if:  you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).  you have had a serious allergic reaction to tirzepatide or any of the ingredients in MOUNJARO. See the end of this Medication Guide for a complete list of ingredients in MOUNJARO. Before using MOUNJARO, tell your healthcare provider about all of your medical conditions, including if you:  have or have had problems with your pancreas or kidneys.  have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digesting food.  have a history of diabetic retinopathy.  are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).  are pregnant or plan to become pregnant. It is not known if MOUNJARO will harm your unborn baby. Tell your healthcare provider if you become pregnant while using MOUNJARO. ○ Birth control pills by mouth may not work as well while using MOUNJARO. If you take birth control pills by mouth, your healthcare provider may recommend another type of birth control for 4 weeks after you start MOUNJARO and for 4 weeks after each increase in your dose of MOUNJARO. Talk to your healthcare provider about birth control methods that may be right for you while using MOUNJARO.  are breastfeeding or plan to breastfeed. It is not known if MOUNJARO passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while using MOUNJARO. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. MOUNJARO may affect the way some medicines work, and some medicines may affect the way MOUNJARO works. Before using MOUNJARO, tell your healthcare provider if you are taking other medicines to treat diabetes including insulin or sulfonylureas which could increase your risk of low blood sugar. Talk to your healthcare provider about low blood sugar and how to manage it. Reference ID: 5472245 Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use MOUNJARO?  Read the Instructions for Use that comes with MOUNJARO.  Use MOUNJARO exactly as your healthcare provider tells you to. A healthcare provider should show you how to prepare and inject your dose of MOUNJARO before injecting for the first time.  MOUNJARO is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm.  Use MOUNJARO 1 time each week, at any time of the day.  You may change the day of the week you use MOUNJARO as long as the time between the 2 doses is at least 3 days (72 hours).  If you miss a dose of MOUNJARO, take the missed dose as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and take your next dose on the regularly scheduled day. Do not take 2 doses of MOUNJARO within 3 days of each other.  MOUNJARO may be taken with or without food.  Do not mix insulin and MOUNJARO together in the same injection.  You may give an injection of MOUNJARO and insulin in the same body area (such as your stomach area), but not right next to each other.  Change (rotate) your injection site with each weekly injection. Do not use the same site for each injection.  If you take too much MOUNJARO, call your healthcare provider. What are the possible side effects of MOUNJARO? MOUNJARO may cause serious side effects, including:  See “What is the most important information I should know about MOUNJARO?”  inflammation of your pancreas (pancreatitis). Stop using MOUNJARO and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.  low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use MOUNJARO with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: ○ dizziness or light-headedness ○ blurred vision ○ anxiety, irritability, or mood changes ○ sweating ○ slurred speech ○ hunger ○ confusion or drowsiness ○ shakiness ○ weakness ○ headache ○ fast heartbeat ○ feeling jittery  serious allergic reactions. Stop using MOUNJARO and get medical help right away if you have any symptoms of a serious allergic reaction including: ○ swelling of your face, lips, tongue or throat ○ fainting or feeling dizzy ○ problems breathing or swallowing ○ very rapid heartbeat ○ severe rash or itching  kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.  severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use MOUNJARO. Tell your healthcare provider if you have stomach problems that are severe or will not go away.  changes in vision. Tell your healthcare provider if you have changes in vision during treatment with MOUNJARO.  gallbladder problems. Gallbladder problems have happened in some people who use MOUNJARO. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include: ○ pain in your upper stomach (abdomen) ○ yellowing of skin or eyes (jaundice) ○ fever ○ clay-colored stools Reference ID: 5472245  food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). MOUNJARO may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking MOUNJARO before you are scheduled to have surgery or other procedures. The most common side effects of MOUNJARO include:  nausea  constipation  diarrhea  indigestion  decreased appetite  stomach (abdominal) pain  vomiting Talk to your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of MOUNJARO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store MOUNJARO?  Store MOUNJARO in the refrigerator between 36⁰F to 46⁰F (2⁰C to 8⁰C). Store MOUNJARO in the original carton until use to protect it from light.  If needed, each single-dose pen or single-dose vial can be stored at room temperature up to 86⁰F (30⁰C) for up to 21 days.  Do not freeze MOUNJARO. Do not use MOUNJARO if frozen. Keep MOUNJARO and all medicines out of the reach of children. General information about the safe and effective use of MOUNJARO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use MOUNJARO for a condition for which it was not prescribed. Do not give MOUNJARO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about MOUNJARO that is written for health professionals. What are the ingredients in MOUNJARO? Active ingredient: tirzepatide Inactive ingredients: sodium chloride, sodium phosphate dibasic heptahydrate, and water for injection. Hydrochloric acid solution and/or sodium hydroxide solution may have been added to adjust the pH. MOUNJARO® is a registered trademark of Eli Lilly and Company. Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2022, 2024, Eli Lilly and Company. All rights reserved. For more information, go to www.MOUNJARO.com or call 1-800-545-5979. This Medication Guide has been approved by the U.S. Food and Drug Administration Approved: November 2024 A4.0-MOU-0002-MG-202411 Reference ID: 5472245 INSTRUCTIONS FOR USE MOUNJARO® [mown-JAHR-OH] (tirzepatide) injection, for subcutaneous use 2.5 mg/0.5 mL single-dose vial 5 mg/0.5 mL single-dose vial 7.5 mg/0.5 mL single-dose vial 10 mg/0.5 mL single-dose vial 12.5 mg/0.5 mL single-dose vial 15 mg/0.5 mL single-dose vial Important information you need to know before injecting MOUNJARO Read this Instructions for Use before you start taking MOUNJARO and each time you get a new vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your needles or syringes with other people. You may give other people a serious infection or get a serious infection from them. Talk to your healthcare provider about how to inject MOUNJARO the right way. • MOUNJARO is a single-dose vial. • MOUNJARO is used 1 time each week. • Inject under the skin (subcutaneously) only. • You or another person may inject into your stomach (abdomen) or thigh. • Another person can inject into the back of your upper arm. Gather supplies needed to give your injection • 1 single-dose MOUNJARO vial • 1 syringe and 1 needle, supplied separately (for example, use a 1 mL syringe and needle as recommended by your healthcare provider) • 1 alcohol swab • gauze • 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions. Reference ID: 5472245 Guide to parts Needle and Syringe (not included) Vial Needle Shield Needle Plunger Tip Plunger Protective Cap Rubber Stopper (under Cap) Syringe Body 1 "· 3 U. ·tm ~·q !- Note: The needle and syringe are not included. The needle and syringe recommended by your healthcare provider may look different than the needle and syringe in this Instructions for Use. Preparing to inject MOUNJARO Remove the vial from the refrigerator. Check the vial label to make sure you have the right medicine and dose, and that it has not expired. Make sure the medicine: • is not frozen • is colorless to slightly yellow • is not cloudy • does not have particles Always use a new syringe and needle for each injection to prevent infections and blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people a serious infection or get a serious infection from them. Wash your hands with soap and water. Step 1: Pull off the plastic protective cap. Do not remove the rubber stopper. Step 2: Wipe the rubber stopper with an alcohol swab. Reference ID: 5472245 Step 3: Remove the outer wrapping from the syringe. Step 4: Remove the outer wrapping from the needle. The syringe that your healthcare provider recommended may have a pre-attached needle. If the needle is attached, skip to step 6. Step 5: Place the needle on top of the syringe and turn until it is tight and firmly attached. Step 6: Remove the needle shield by pulling straight off. Step 7: Hold the syringe in one hand with the needle pointing up. With the other hand pull down on the plunger until the plunger tip reaches the line on the syringe indicating that 0.5 mL of air has been drawn into the syringe. Step 8: Push the needle through the rubber stopper of the vial. Step 9: Push the plunger all the way in. This puts air into the vial and makes it easier to pull the solution from the vial. Reference ID: 5472245 Step 10: Turn the vial and syringe upside down. Make sure that the tip of the needle is in the liquid and slowly pull the plunger down until the plunger tip is past the 0.5 mL line. If there are air bubbles, tap the syringe gently a few times to let any air bubbles rise to the top. Step 11: Slowly push the plunger up until the plunger tip reaches the 0.5 mL line. Step 12: Pull the syringe out of the rubber stopper of the vial. Injecting MOUNJARO • Inject exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting. • Change (rotate) your injection site within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. • Do not inject where the skin has pits, is thickened, or has lumps. • Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not mix MOUNJARO with any other medicine. • Do not inject MOUNJARO in the same injection site used for other medicines. Reference ID: 5472245 Step 13: Choose your injection site. You can inject MOUNJARO under the skin (subcutaneously) of your stomach area (abdomen) or thighs. Someone else can inject in your stomach area, thighs, or the back of the upper arms. Step 14: Insert the needle into your skin. Step 15: Push down on the plunger to inject your dose. The needle should stay in your skin for at least 5 seconds to make sure you have injected all of your dose. Step 16: Pull the needle out of your skin. • If you see blood after you take the needle out of your skin, press the injection site with a piece of gauze or an alcohol swab. Do not rub the area. • Do not recap the needle. Recapping the needle can lead to a needle stick injury. Disposing of used needles and syringes • Put your used needle and syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you Reference ID: 5472245 should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Storing MOUNJARO • Store all unopened vials in the refrigerator at 36°F to 46°F (2°C to 8°C). • You may store the unopened vial at room temperature up to 86°F (30°C) for up to 21 days. • Do not freeze. Do not use if MOUNJARO has been frozen. • Store the vial in the original carton to protect from light. • Throw away all opened vials after use, even if there is medicine left in the vial. Keep MOUNJARO vials, syringes, needles, and all medicines out of the reach of children. If you have any questions or problems with your MOUNJARO, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. Manufactured by Eli Lilly and Company Indianapolis, IN 46285, USA MOUNJARO is a registered trademark of Eli Lilly and Company. Copyright © YYYY, Eli Lilly and Company. All rights reserved. MON-VL-0001-IFU-YYYYMMDD This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: July/2023 Reference ID: 5472245 - J II J' I INSTRUCTIONS FOR USE MOUNJARO™ (mown-JAHR-OH) (tirzepatide) injection, for subcutaneous use 2.5 mg/0.5 mL single-dose pen 5 mg/0.5 mL single-dose pen 7.5 mg/0.5 mL single-dose pen 10 mg/0.5 mL single-dose pen 12.5 mg/0.5 mL single-dose pen 15 mg/0.5 mL single-dose pen use 1 time each week Important information you need to know before injecting MOUNJARO Read this Instructions for Use and the Medication Guide before using your MOUNJARO Pen and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider about how to inject MOUNJARO the right way. • MOUNJARO is a single-dose prefilled pen. • MOUNJARO is used 1 time each week. • Inject under the skin (subcutaneously) only. • You or another person can inject into your stomach (abdomen) or thigh. • Another person can inject into the back of your upper arm. Storage and handling • Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C). • You may store your Pen at room temperature up to 86°F (30°C) for up to 21 days. • Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen. • Store your Pen in the original carton to protect your Pen from light. • The Pen has glass parts. Handle it carefully. If you drop the Pen on a hard surface, do not use it. Use a new Pen for your injection. • Keep your MOUNJARO Pen and all medicines out of the reach of children. Reference ID: 5472245 - Guide to parts Lock or Unlock Indicator Bottom and Needle End Top Preparing to inject MOUNJARO Remove the Pen from the refrigerator. Leave the gray base cap on until you are ready to inject. Check the Pen label to make sure you have the right medicine and dose, and that it has not expired. Inspect the Pen to make sure that it is not damaged. Expiration Date Make sure the medicine: • is not frozen • is colorless to slightly yellow • is not cloudy • does not have particles Wash your hands. Purple Injection Button Lock Ring Medicine Clear Base Gray Base Cap Reference ID: 5472245 Step Choose your injection site 1 Your healthcare provider can help you choose the injection site that is best for you. You or another person can inject the medicine in your stomach (abdomen) or thigh. Another person should give you the injection in the back of your upper arm. Change (rotate) your injection site each week. You may use the same area of your body but be sure to choose a different injection site in that area. Step Pull off the gray base cap 2 Make sure the Pen is locked. Do not unlock the Pen until you place the clear base on your skin and are ready to inject. Pull the gray base cap straight off and throw it away in your household trash. Do not put the gray base cap back on – this could damage the needle. Do not touch the needle. Step Place clear base on skin, then unlock 3 Clear Base Gray Base Cap Place the clear base flat against your skin at the injection site. Reference ID: 5472245 Unlock by turning the lock ring. Step Press and hold up to 10 seconds 4 Gray Plunger Press and hold the purple injection button for up to 10 seconds. Listen for: • First click = injection started • Second click = injection completed You will know your injection is complete when the gray plunger is visible. After your injection, place the used Pen in a sharps container. See Disposing of your used Pen. Disposing of your used Pen • Put your used Pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) Pens in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not recycle your used sharps disposal container. Commonly asked questions What if I see air bubbles in my Pen? Air bubbles are normal. What if my Pen is not at room temperature? It is not necessary to warm the Pen to room temperature. Reference ID: 5472245 What if I unlock the Pen and press the purple injection button before pulling off the gray base cap? Do not remove the gray base cap. Throw away the Pen and get a new Pen. What if there is a drop of liquid on the tip of the needle when I remove the gray base cap? A drop of liquid on the tip of the needle is normal. Do not touch the needle. Do I need to hold the injection button down until the injection is complete? This is not necessary, but it may help you keep the Pen steady against your skin. I heard more than 2 clicks during my injection—2 loud clicks and 1 soft one. Did I get my complete injection? Some people may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove the Pen from your skin until you hear the second loud click. I am not sure if my Pen worked the right way. Gray Plunger Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible. Also, see Step 4 of the instructions. If you do not see the gray plunger, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your Pen safely to avoid an accidental needle stick. What if there is a drop of liquid or blood on my skin after my injection? This is normal. Press a cotton ball or gauze over the injection site. Do not rub the injection site. Other information • If you have vision problems, do not use your Pen without help from a person trained to use the MOUNJARO Pen. Where to learn more • If you have questions or problems with your MOUNJARO Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider. • For more information about the MOUNJARO Pen, visit our website at www.mounjaro.com. Scan this code to launch www.mounjaro.com Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA MOUNJARO is a trademark of Eli Lilly and Company. Copyright © YYYY, Eli Lilly and Company. All rights reserved. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: May 2022 MOU-0001-IFU-YYYYMMDD Reference ID: 5472245 Reference ID: 5472245 Quick Reference Guide These are not complete instructions. Read the full INSTRUCTIONS FOR USE. Step Step Step Step 1 Choose your injection site 2 Pull off the gray base cap 3 Place clear base on skin, then unlock 4 Press and hold up to 10 seconds You or another person can inject the medicine in your stomach (abdomen) or thigh. Make sure the Pen is Locked. Clear Base Another person should give Pull the gray base cap Place the clear base flat Press and hold the purple injection you the injection in the back straight off and throw it away against your skin at the button for up to 10 seconds. of your upper arm. in your household trash. injection site. Listen for: Do not put the gray base cap Unlock by turning the • First click = injection started back on. lock ring. • Second click = injection completed Do not touch the needle. Injection is complete when you see the gray plunger. After your injection Place the used Pen in a sharps container. See Disposing of your used Pen in the full INSTRUCTIONS FOR USE.	custom-source	2025-02-12T15:46:30.054107	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215866s010s015s022lbl.pdf', 'application_number': 215866, 'submission_type': 'SUPPL ', 'submission_number': 10}
80,144	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ILARIS safely and effectively. See full prescribing information for ILARIS. ILARIS® (canakinumab) injection, for subcutaneous use Initial U.S. Approval: 2009 -------------------------RECENT MAJOR CHANGES------------------------------ Warnings and Precautions, Hypersensitivity Reactions (5.3) 11/2024 ---------------------------INDICATIONS AND USAGE----------------------------- ILARIS is an interleukin-1β blocker indicated for the treatment of: • Periodic Fever Syndromes (1.1): - Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older, including: • Familial Cold Auto-inflammatory Syndrome (FCAS) • Muckle-Wells Syndrome (MWS) - Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients - Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients - Familial Mediterranean Fever (FMF) in adult and pediatric patients • Active Still’s Disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in patients 2 years of age and older (1.2) • Gout flares in adults in whom non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate (1.3) -------------------------DOSAGE AND ADMINISTRATION---------------------- • CAPS: Recommended weight-based dosage is: - For patients > 40 kg: 150 mg subcutaneously, every 8 weeks - For patients ≥ 15 kg and < 40 kg: 2 mg/kg subcutaneously, every 8 weeks. For pediatric patients 15 kg to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. (2.2) • TRAPS, HIDS/MKD, and FMF: Recommended weight-based dosage is: - For patients > 40 kg: Starting dosage is 150 mg subcutaneously every 4 weeks. The dosage can be increased to 300 mg every 4 weeks if the clinical response is not adequate. (2.3) - For patients ≤ 40 kg: Starting dosage is 2 mg/kg subcutaneously every 4 weeks. The dosage can be increased to 4 mg/kg every 4 weeks if the clinical response is not adequate. (2.3) • Still’s disease (AOSD and SJIA): Recommended weight-based dosage for patients ≥ 7.5 kg is 4 mg/kg (maximum dose of 300 mg), subcutaneously, every 4 weeks. (2.4) • Gout Flares: Recommended dosage is 150 mg subcutaneously. In patients who require re-treatment, there should be an interval of at least 12 weeks before a new dose of ILARIS may be administered. (2.5) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- • Injection: 150 mg/mL solution in single-dose vials. (3) --------------------------------CONTRAINDICATIONS---------------------------- Confirmed hypersensitivity to canakinumab or to any of the excipients. (4) -------------------------WARNINGS AND PRECAUTIONS--------------------- • Serious Infections: ILARIS has been associated with an increased incidence of serious infections. Exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. Discontinue ILARIS if a patient develops a serious infection. Avoid administering ILARIS to patients during an active infection requiring medical intervention. (5.1) • Hypersensitivity Reactions and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) can occur; discontinue ILARIS, treat promptly, and monitor until reaction resolves. (5.3) • Immunizations: Avoid administration of live vaccines concurrently with ILARIS. Update all recommended vaccinations prior to initiation of therapy with ILARIS. (5.4) -------------------------------ADVERSE REACTIONS----------------------------- • CAPS: The most common adverse reactions (>10%) are nasopharyngitis, diarrhea, influenza, rhinitis, nausea, headache, bronchitis, gastroenteritis, pharyngitis, weight increased, musculoskeletal pain, and vertigo. (6) • TRAPS, HIDS/MKD, and FMF: The most common adverse reactions (≥10%) are injection-site reactions and nasopharyngitis. (6) • Still’s Disease: The most common adverse drug reactions (>10%) are infections (nasopharyngitis and upper respiratory tract infections), abdominal pain, and injection-site reactions. (6) • Gout Flares: The most common adverse reactions (>2%) reported by are nasopharyngitis, upper respiratory tract infections, urinary tract infections, hypertriglyceridemia, and back pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA 1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Periodic Fever Syndromes 1.2 Still’s Disease (Adult-Onset Still’s Disease [AOSD] and Systemic Juvenile Idiopathic Arthritis [SJIA]) 1.3 Gout Flares 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information 2.2 Recommended Dosage for Cryopyrin-Associated Periodic Syndromes (CAPS) 2.3 Recommended Dosage for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD), and Familial Mediterranean Fever (FMF) 2.4 Recommended Dosage for Still’s Disease, Including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) 2.5 Recommended Dosage for Gout Flares 2.6 Administration Instructions for ILARIS Injection 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Immunosuppression 5.3 Hypersensitivity Reactions 5.4 Immunizations 5.5 Macrophage Activation Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 TNF-Blocker and IL-1 Blocking Agent 7.2 Immunization 7.3 Cytochrome P450 Substrates 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Treatment of CAPS 14.2 Treatment of Periodic Fever Syndromes: TRAPS, HIDS/MKD, and FMF 14.3 Treatment of Still’s Disease: AOSD and SJIA 14.4 Treatment of Gout Flares 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5472537 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Periodic Fever Syndromes ILARIS® (canakinumab) is an interleukin-1β (IL-1β) blocker indicated for the treatment of the following autoinflammatory Periodic Fever Syndromes: Cryopyrin-Associated Periodic Syndromes (CAPS) ILARIS is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and pediatric patients 4 years of age and older, including: • Familial Cold Autoinflammatory Syndrome (FCAS) • Muckle-Wells Syndrome (MWS) Tumor Necrosis Factor Receptor (TNF) Associated Periodic Syndrome (TRAPS) ILARIS is indicated for the treatment of Tumor Necrosis Factor (TNF) Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients. Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) ILARIS is indicated for the treatment of Hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients. Familial Mediterranean Fever (FMF) ILARIS is indicated for the treatment of Familial Mediterranean Fever (FMF) in adult and pediatric patients. 1.2 Still’s Disease (Adult-Onset Still’s Disease [AOSD] and Systemic Juvenile Idiopathic Arthritis [SJIA]) ILARIS is indicated for the treatment of active Still’s Disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in patients 2 years of age and older. 1.3 Gout Flares ILARIS is indicated for the symptomatic treatment of adult patients with gout flares in whom non-steroidal anti- inflammatory drugs (NSAIDs) and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information ILARIS IS FOR SUBCUTANEOUS USE ONLY. 2.2 Recommended Dosage for Cryopyrin-Associated Periodic Syndromes (CAPS) The recommended weight-based dosage of ILARIS is: • For patients with CAPS > 40 kg: 150 mg subcutaneously, every 8 weeks • For patients with CAPS ≥ 15 kg and ≤ 40 kg: 2 mg/kg subcutaneously, every 8 weeks. • For pediatric patients with CAPS 15 kg to 40 kg with an inadequate response, the dosage can be increased to 3 mg/kg subcutaneously, every 8 weeks. 2.3 Recommended Dosage for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD), and Familial Mediterranean Fever (FMF) The recommended weight-based dosage of ILARIS for patients with TRAPS, HIDS/MKD, and FMF is: • For patients > 40 kg: 150 mg subcutaneously, every 4 weeks. The dosage can be increased to 300 mg every 4 weeks if the clinical response is not adequate. • For patients ≤ 40 kg: 2 mg/kg administered subcutaneously, every 4 weeks. The dosage can be increased to 4 mg/kg every 4 weeks if the clinical response is not adequate. Reference ID: 5472537 2.4 Recommended Dosage for Still’s Disease, Including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) The recommended weight-based dosage of ILARIS for patients with Still’s Disease (AOSD and SJIA) weighing ≥ 7.5 kg is 4 mg/kg (maximum dose of 300 mg) administered subcutaneously every 4 weeks. 2.5 Recommended Dosage for Gout Flares The recommended dose of ILARIS for adult patients with a gout flare is 150 mg administered subcutaneously. In patients who require re-treatment, there should be an interval of at least 12 weeks before a new dose of ILARIS may be administered. 2.6 Administration Instructions for ILARIS Injection STEP 1: ILARIS injection has a concentration of 150 mg/mL. Do not shake. The solution should be essentially free from particulates, clear to opalescent, colorless to slightly brownish-yellow tint. If the solution has a distinctly brown discoloration, is highly opalescent or contains visible particles, do not use. STEP 2: Using a sterile 1-mL syringe and 18-gauge x 2” needle, carefully withdraw the required volume depending on the dose to be administered and subcutaneously inject using a 27-gauge x 0.5” needle. Avoid injection into scar tissue as this may result in insufficient exposure to ILARIS. Discard unused product or waste material in accordance with the local requirements. 3 DOSAGE FORMS AND STRENGTHS Injection: 150 mg/mL, clear to slightly opalescent, colorless to a slightly brownish yellow tint solution, in single-dose vials. 4 CONTRAINDICATIONS Confirmed hypersensitivity to canakinumab or to any of the excipients [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections ILARIS has been associated with an increased risk of serious infections. Exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. Avoid administering ILARIS to patients during an active infection requiring medical intervention. Discontinue ILARIS if a patient develops a serious infection. Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) were reported during ILARIS treatment. A causal relationship of ILARIS to these events cannot be excluded. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Coadministration of ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections [see Drug Interactions (7.1)]. Drugs that affect the immune system by blocking TNF have been associated with an increased risk of new tuberculosis and reactivation of latent tuberculosis (TB). It is possible that use of IL-1 inhibitors, such as ILARIS, increases the risk of reactivation of tuberculosis or of opportunistic infections. Prior to initiating immunomodulatory therapies, including ILARIS, evaluate patients for active and latent tuberculosis infection. Appropriate screening tests should be performed in all patients. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Treat patients testing positive in tuberculosis screening according to standard medical practice prior to therapy with ILARIS. Instruct patients to seek medical advice if signs, symptoms, or high-risk exposure suggestive of tuberculosis (e.g., persistent cough, weight loss, subfebrile temperature) appear during or after ILARIS therapy. Reference ID: 5472537 6 Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS. 5.2 Immunosuppression The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies. 5.3 Hypersensitivity Reactions Hypersensitivity reactions have been reported with ILARIS. During clinical trials, no anaphylactic reactions attributable to treatment with canakinumab have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity [see Adverse Reactions (6.1)]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), characterized by serious skin eruptions, has been reported in patients with autoinflammatory conditions treated with ILARIS. If a severe hypersensitivity reaction occurs, immediately discontinue ILARIS; treat promptly and monitor until signs and symptoms resolve. 5.4 Immunizations Avoid administration of live vaccines concurrently with ILARIS [see Drug Interactions (7.2)]. Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, avoid administering live vaccines concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. Limited data are available on the response to vaccinations with inactivated (killed) antigens in patients receiving ILARIS [see Drug Interactions (7.2)]. Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate and if feasible, including pneumococcal vaccine and inactivated influenza vaccine. See current recommended immunization schedules at the website of the Centers for Disease Control, http://www.cdc.gov/vaccines/schedules/index.html. 5.5 Macrophage Activation Syndrome Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular Still’s disease, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of Still’s disease, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with canakinumab in clinical trials. Based on the clinical trial experience, ILARIS does not appear to increase the incidence of MAS in Still’s disease patients, but no definitive conclusion can be made. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions (5.1)] • Immunosuppression [see Warnings and Precautions (5.2)] • Hypersensitivity Reactions [see Warnings and Precautions (5.3)] • Macrophage Activation Syndrome [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trials for Treatment of Periodic Fever Syndromes: CAPS, TRAPS, HIDS/MKD, and FMF Treatment of CAPS The data described herein reflect exposure to ILARIS in 104 adult and pediatric CAPS patients, including 20 FCAS, 72 MWS, 10 MWS/NOMID (Neonatal Onset Multisystem Inflammatory Disorder) overlap, 1 non-FCAS non-MWS, and 1 misdiagnosed in placebo-controlled (35 patients) and uncontrolled trials. Sixty-two patients were exposed to ILARIS for at least 6 months, 56 for at least 1 year, and 4 for at least 3 years. A total of 9 serious adverse reactions were reported for CAPS patients. Among these were vertigo (2 patients), infections (3 patients), including intra-abdominal abscess Reference ID: 5472537 following appendectomy (1 patient). The most commonly reported adverse reactions associated with ILARIS treatment in greater than 10% of the CAPS patients were nasopharyngitis, diarrhea, influenza, rhinitis, nausea, headache, bronchitis, gastroenteritis, pharyngitis, weight increased, musculoskeletal pain, and vertigo. One patient discontinued treatment due to potential infection. CAPS Study 1 investigated the safety of ILARIS in an 8-week, open-label period (Part 1), followed by a 24-week, randomized withdrawal period (Part 2), followed by a 16-week, open-label period (Part 3). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was greater than or equal to 15 kg and less than or equal to 40 kg (see Table 1). Since all CAPS patients received ILARIS in Part 1, there are no controlled data on adverse events (AEs). Data in Table 1 are for all AEs for all CAPS patients receiving canakinumab. In CAPS Study 1, no pattern was observed for any type or frequency of adverse events throughout the 3 study periods. Table 1: Adverse Reactions in ≥ 10% of Patients in Parts 1 to 3 of the Phase 3 Trial for Patients with CAPS Adverse reactions ILARIS N = 35 n (%) n (%) of patients with adverse reactions 35 (100) Nasopharyngitis 12 (34) Diarrhea 7 (20) Influenza 6 (17) Rhinitis 6 (17) Nausea 5 (14) Headache 5 (14) Bronchitis 4 (11) Gastroenteritis 4 (11) Pharyngitis 4 (11) Weight increased 4 (11) Musculoskeletal pain 4 (11) Vertigo 4 (11) Vertigo Vertigo has been reported in 9% to 14% of patients in CAPS studies, exclusively in MWS patients, and reported as a serious adverse event in 2 cases. All events resolved with continued treatment with ILARIS. Injection-Site Reactions In CAPS Study 1, subcutaneous injection-site reactions were observed in 9% of patients in Part 1 with mild tolerability reactions; in Part 2, one patient each (7%) had a mild or a moderate tolerability reaction and, in Part 3, one patient had a mild local tolerability reaction. No severe injection-site reactions were reported, and none led to discontinuation of treatment. Treatment of TRAPS, HIDS/MKD, and FMF A Phase 3 trial (TRAPS, HIDS/MKD, and FMF Study 1) investigated the safety of ILARIS in 3 cohorts (TRAPS, HIDS/MKD, and FMF) as follows: a 12-week screening period (Part 1), followed by a 16-week, randomized, double- blind, placebo-controlled parallel-arm treatment period (Part 2), followed by a 24-week randomized withdrawal period (Part 3), followed by a 72-week, open-label treatment period (Part 4). All patients randomized to treatment with ILARIS in Part 2 received 150 mg subcutaneously every 4 weeks if body weight was greater than 40 kg (or 2 mg/kg every 4 weeks if body weight was less than or equal to 40 kg). In Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1, initially 90 patients were randomized to ILARIS treatment, and 91 patients were randomized to placebo. Of patients randomized to ILARIS, 55.6% remained on the initial dose through Week 16 with 6.7% receiving an additional ILARIS dose between Day 7 and Day 15. Of the patients randomized to placebo, 9.9% remained on placebo through Week 16 with 28.6% switching to active treatment with ILARIS by Day 15. Reference ID: 5472537 Overall, there were 43 TRAPS, 68 HIDS/MKD, and 58 FMF patients in the safety set with a cumulative canakinumab exposure of 47.61 patient-years. The cumulative exposure in the placebo group was 8.03 patient-years. In Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1, a total of 22 TRAPS patients aged 3 to 76 years of age, 37 HIDS/MKD patients aged 2 to 43 years of age, and 31 FMF patients aged 2 to 60 years of age were initially randomized to treatment with ILARIS 150 mg every four weeks in the placebo-controlled period of the clinical trial. In addition, 4 non-randomized patients (2 FMF patients of age 20 and 29 years with non-exon 10 mutations and 2 HIDS/MKD patients both of 1 year of age) received open-label treatment in Part 2. The most commonly reported adverse reactions (greater than or equal to 10%) associated with ILARIS treatment in TRAPS, HIDS/MKD, and FMF patients were injection-site reactions and nasopharyngitis. The reported adverse reactions (greater than or equal to 3%) associated with ILARIS treatment in TRAPS, HIDS/MKD, and FMF patients were injection- site reactions (10.1%), and infections, including nasopharyngitis (10.7%), upper respiratory tract infection (7.1%), rhinitis (5.3%), gastroenteritis (3.0%), and pharyngitis (3.0%). Serious infections (e.g., conjunctivitis, pneumonia, pharyngitis, pharyngotonsillitis) were observed in approximately 2.4% (0.03 per 100 patient-days) of patients receiving ILARIS in Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1. In the ILARIS treatment group, 1 TRAPS patient discontinued treatment due to adverse events, 2 HIDS/MKD patients discontinued treatment due to adverse events, and no FMF patients discontinued treatment due to an adverse event. Injection-Site Reactions In the TRAPS, HIDS/MKD, and FMF Study 1, subcutaneous injection-site reactions were observed in 10.1% of patients in Part 2 who had a mild or a moderate tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment. Adverse Reactions from Clinical Trials for Treatment of Still’s Disease: SJIA and AOSD The safety of ILARIS compared to placebo in SJIA patients was investigated in two Phase 3 studies [see Clinical Studies (14.2)]. Patients in SJIA Study 1 received a single dose of ILARIS 4 mg/kg (n = 43) or placebo (n = 41) via subcutaneous injection and were assessed at Day 15 for the efficacy endpoints and had a safety analysis up to Day 29. SJIA Study 2 was a two-part study with an open-label, single-arm active treatment period (Part I) followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (Part II). Overall, 177 patients were enrolled into the study and received ILARIS 4 mg/kg (up to 300 mg maximum) in Part I, and 100 patients received ILARIS 4 mg/kg (up to 300 mg maximum) every 4 weeks or placebo in Part II. Adverse drug reactions listed in Table 2 showed higher rates than placebo from both trials. The adverse drug reactions associated with ILARIS treatment in greater than 10% of SJIA patients were infections, abdominal pain, and injection-site reactions. Serious infections (e.g., pneumonia, varicella, gastroenteritis, measles, sepsis, otitis media, sinusitis, adenovirus, lymph node abscess, pharyngitis) were observed in approximately 4% to 5% (0.02 to 0.17 per 100 patient-days) of patients receiving ILARIS in both studies. Table 2: Tabulated Summary of Adverse Drug Reactions From Pivotal SJIA Clinical Trials SJIA Study 2 SJIA Study 1 Part I Part II ILARIS N = 177 n (%) (IR)^ ILARIS N = 50 n (%) (IR) Placebo N = 50 n (%) (IR) ILARIS N = 43 n (%) (IR) Placebo N = 41 n (%) (IR) Infections and infestations All infections (e.g., nasopharyngitis, [viral] upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, viral infection) 97 (54.8%) (0.91) 27 (54%) (0.59) 19 (38%) (0.63) 13 (30.2%) (1.26) 5 (12.2%) (1.37) Reference ID: 5472537 SJIA Study 2 SJIA Study 1 Gastrointestinal disorders Abdominal pain (upper) 25 (14.1%) (0.16) 8 (16%) (0.15) 6 (12%) (0.08) 3 (7%) (0.25) 1 (2.4%) (0.23) Skin and subcutaneous tissue disorders Injection-site reaction mild 19 (10.7%) 6 (12.0%) 2 (4.0%) 0 3 (7.3%) moderate 2 (1.1%) 1 (2.0%) 0 0 0 n = number of patients. ^IR = Exposure adjusted incidence rate per 100 patient-days. No injection-site reaction led to study discontinuation. The safety profile of ILARIS in AOSD patients in a randomized, double-blind, placebo-controlled study (GDE01T) in 36 adult patients (aged 22 to 70 years) was similar to what was observed in SJIA patients. Adverse Reactions from Clinical Trials for Treatment of Gout Flares The safety of ILARIS compared to triamcinolone acetonide in patients with gout flares was assessed in four 12-week randomized, double-blind, active-controlled Phase 3 studies [see Clinical Studies (14.4) for details of the studies supporting efficacy] and in two 12-week double-blind active-controlled extension studies. In the ILARIS treatment groups 512 patients were treated up to 12 weeks and 165 of these patients up to 24 weeks. In the triamcinolone acetonide groups, 381 patients were treated up to 12 weeks and 152 of these patients up to 24 weeks. Patients received a single dose of ILARIS 150 mg (n = 467) via subcutaneous injection or triamcinolone acetonide 40 mg (n = 279) via intramuscular injection. Upon a new flare, 85 and 152 patients received at least one additional dose of ILARIS and triamcinolone acetonide, respectively. The most commonly reported adverse drug reactions were infections and infestations (see Table 3). The most common infections reported in more than 2% of patients in the ILARIS treatment groups were nasopharyngitis, upper respiratory tract infections, and urinary tract infections. The trends observed in all infections are aligned with the overall known safety profile of canakinumab. Serious adverse events were reported in 1.4% of the ILARIS-treated patients, all of which were single events. No serious adverse events were reported in the triamcinolone acetonide-treated group. Of the ILARIS-treated patients, 17% were 65 years of age and older, including 3% who were 75 years of age and older. No new safety findings were observed between these patients compared to patients under 65 years of age [see Use in Specific Populations (8.5). Table 3: Tabulated Summary of Adverse Drug Reactions From Pivotal Gout Flare Clinical Trials System Organ Class Adverse reaction ILARIS 150 mg N = 552 n (%) (IR-w) Triamcinolone acetonide 40 mg N = 431 n (%) (IR-w) Infections and infestations All infections (e.g., nasopharyngitis, upper respiratory tract infection, urinary tract infections) 90 (16.3%) (59.0) 40 (9.3%) (32.1) Investigations Blood triglycerides increased 7 (1.3%) (3.8) 2 (0.5%) (1.3) Platelet count decreased 4 (0.7%) (2.5) 1 (0.2%) (1.0) Metabolism and nutrition disorders Hypertriglyceridemia 15 (2.7%) (9.5) 4 (0.9%) (3) Reference ID: 5472537 Musculoskeletal and connective tissue disorders Back pain 17 (3.1%) (10.9) 7 (1.6%) (6.2) Nervous system disorders Dizziness 9 (1.6%) (5.8) 2 (0.5%) (1.7) Abbreviation: SOC, system organ class. N = Number of patients at study entry. IR-w = Study size weighted incidence rate (i.e., number of patients with an event per 100 patient-years). Specific Adverse Reactions from Clinical Trials Hypersensitivity During clinical trials, no anaphylactic reactions attributable to treatment with canakinumab have been reported. In CAPS trials one patient discontinued and in TRAPS, HIDS/MKD, FMF, Still’s disease, and gout trials no patients discontinued due to hypersensitivity reactions. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS [see Contraindications (4) and Warnings and Precautions (5.3)]. Laboratory Abnormalities • Hematology TRAPS, HIDS/MKD, and FMF Overall, in the TRAPS, HIDS/MKD, and FMF Study 1, neutrophil count decreased (greater than or equal to Grade 2) was reported in 6.5% of patients and platelet count decreased (greater than or equal to Grade 2) was reported in 0.6% of patients. SJIA During clinical trials with ILARIS, mean values decreased for white blood cells, neutrophils and platelets. In the randomized, placebo-controlled portion of SJIA Study 2, decreased white blood cell counts (WBC) less than or equal to 0.8 times lower limit of normal (LLN) were reported in 5 patients (10.4%) in the ILARIS group compared to 2 patients (4.0%) in the placebo group. Transient decreases in absolute neutrophil count (ANC) to less than 1 x 109/L were reported in 3 patients (6.0%) in the ILARIS group compared to 1 patient (2.0%) in the placebo group. One case of ANC less than 0.5x109/L was observed in the ILARIS group and none in the placebo group. Mild (less than LLN and greater than 75 x 109/L) and transient decreases in platelet counts were observed in 3 (6.3%) ILARIS-treated patients versus 1 (2.0%) placebo-treated patient. Gout Flares In the pooled analysis of patients with gout flares from four 12-week randomized, double-blind, active-controlled Phase 3 studies and two 12-week active-controlled extension studies, transient cytopenias were observed. Leukopenia (WBC ≤ 0.8 x LLN) was reported in 6.4% of ILARIS-treated patients compared to 1.4% of triamcinolone acetonide-treated patients. Neutropenia (ANC < 0.9 x LLN) was reported in 15.9% of patients treated with ILARIS compared to 2.1% treated with triamcinolone acetonide. Thrombocytopenia (platelet counts < LLN) was observed in 16.3% of patients treated with ILARIS versus 12.5% of patients treated with triamcinolone acetonide. • Uric Acid Gout Flares The proportion of patients with laboratory abnormalities (from normal at baseline to >ULN or from ≤9.9 mg/dl at baseline to > 9.9 mg/dl) and/or adverse reactions of increased uric acid levels were numerically higher in the ILARIS group (43.8% for ILARIS vs. 40.1% for (triamcinolone acetonide). • Hepatic Transaminases Elevations of transaminases (ALT/AST) have been observed in patients treated with ILARIS. Reference ID: 5472537 SJIA In the randomized, placebo-controlled portion of SJIA Study 2, high ALT and/or AST ≥ 3 times upper limit of normal (ULN) were reported in 2 (4.1%) ILARIS-treated patients and 1 (2.0%) placebo patient. All patients had normal values at the next visit. Gout Flares In the randomized double-blind studies up to 24 weeks high ALT and AST ≥ 3 times upper limit of normal (ULN) were reported in 1.6% and 0.5% of ILARIS-treated patients respectively, and 2.6% and 1.9% of the triamcinolone acetonide treated patients, respectively. • Bilirubin SJIA Asymptomatic and mild elevations of serum bilirubin have been observed in patients treated with ILARIS without concomitant elevations of transaminases. • Hypertriglyceridemia Gout Flares The proportion of patients with hypertriglyceridemia events in the randomized double-blind studies up to 24 weeks was higher in the ILARIS group compared to the triamcinolone acetonide-treated group (5.6% vs. 1.9%). The majority of abnormal values were noted at a single visit. 6.2 Immunogenicity A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received ILARIS. Following treatment with ILARIS, antibodies against ILARIS were observed in approximately 1.4 %, 1.2%, and 3.5% of the patients with CAPS, SJIA, and gout flares, respectively. Neutralizing antibodies were detected in < 1% of patients with gout flares. No apparent correlation of antibody development to clinical response or adverse events was observed. The CAPS clinical studies employed the biosensor binding assay, most of the SJIA clinical studies employed the bridging assay, and the gout clinical studies used initially the biosensor assay and for later studies or extensions the bridging assay. The data obtained in an assay are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease, and the number of patients tested. For these reasons, comparison of the incidence of antibodies to canakinumab between the CAPS, SJIA, and gout flare clinical studies or with the incidence of antibodies to other products may be misleading. No TRAPS, HIDS/MKD, FMF, SJIA, or AOSD patients treated with ILARIS doses of 150 mg and 300 mg over 16 weeks of treatment tested positive for anti-canakinumab antibodies. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ILARIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.3)] DRUG INTERACTIONS Interactions between ILARIS and other medicinal products have not been investigated in formal studies. 7.1 TNF-Blocker and IL-1 Blocking Agent An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors in another patient population. Use of ILARIS with TNF inhibitors may also result in similar toxicities and is not recommended because this may increase the risk of serious infections [see Warnings and Precautions (5.1)]. Reference ID: 5472537 7 8 The concomitant administration of ILARIS with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacological interactions between ILARIS and a recombinant IL-1ra, concomitant administration of ILARIS and other agents that block IL-1 or its receptors is not recommended. 7.2 Immunization No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving ILARIS. Therefore, avoid administration of live vaccines concurrently with ILARIS. It is recommended that, if possible, pediatric and adult patients complete all immunizations in accordance with current immunization guidelines prior to initiating ILARIS therapy [see Warnings and Precautions (5.4)]. 7.3 Cytochrome P450 Substrates The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus, it is expected that for a molecule that binds to IL-1, such as canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed, and the individual dose of the medicinal product may need to be adjusted as needed. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available human data from postmarketing experience and published case reports on ILARIS use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. Canakinumab, like other monoclonal antibodies, is actively transported across the placenta mainly during the third trimester of pregnancy and may cause immunosuppression in the in utero exposed infant (see Clinical Considerations). In an animal embryo-fetal development study with marmoset monkeys, there was no evidence of embryotoxicity or fetal malformations with subcutaneous administration of canakinumab during the period of organogenesis and later in gestation at doses that produced exposures approximately 11 times the exposure at the maximum recommended human dose (MRHD) and greater. Delays in fetal skeletal development were observed in marmoset monkeys following prenatal exposure to ILARIS at concentrations approximately 11 times the MRHD and greater. Similar delays in fetal skeletal development were observed in mice administered a murine analog of ILARIS during the period of organogenesis. Delays in skeletal ossification are changes from the expected ossification state in an otherwise normal structure/bone: these findings are generally reversible or transitory and not detrimental to postnatal survival (see Animal Data). The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Because IL-1 blockade may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants who were exposed to ILARIS in utero for at least 4 to 12 months following the mother’s last dose of ILARIS. The ideal time to avoid live vaccines in infants exposed to ILARIS in utero is unknown, as there are insufficient data regarding infant serum levels of canakinumab at birth and the duration of persistence of canakinumab in infant serum after birth is also unknown. Data Animal Data In an embryo-fetal development study, pregnant marmoset monkeys received canakinumab from gestation days 25 to 109 at doses that produced exposures approximately 11 times that achieved with MRHD and greater (on a plasma area under the curve [AUC] basis with maternal subcutaneous doses of 15, 50, or 150 mg/kg twice weekly). ILARIS did not elicit any evidence of embryotoxicity or fetal malformations. There were increases in the incidence of incomplete ossification of the terminal caudal vertebra and misaligned and/or bipartite vertebra in fetuses at all dose levels when compared to Reference ID: 5472537 concurrent controls suggestive of delay in skeletal development in the marmoset. Since ILARIS does not cross-react with mouse or rat IL-1β, pregnant mice were subcutaneously administered a murine analog of ILARIS at doses of 15, 50, or 150 mg/kg during the period of organogenesis on gestation days 6, 11, and 17. The incidence of incomplete ossification of the parietal and frontal skull bones of fetuses was increased in a dose-dependent manner at all dose levels tested. 8.2 Lactation Risk Summary There is no information regarding the presence of canakinumab in human milk or the effects on milk production. There are a small number of published case reports that do not establish an association between maternal canakinumab use during lactation and adverse effects on breastfed infants. Maternal IgG is known to be present in human milk. The effects of canakinumab in breast milk and possible systemic exposure in the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ILARIS and any potential adverse effects on the breastfed infant from ILARIS or from the underlying maternal condition. 8.4 Pediatric Use The CAPS trials with ILARIS included a total of 23 pediatric patients with an age range from 4 years to 17 years (11 adolescents were treated subcutaneously with 150 mg, and 12 children were treated with 2 mg/kg based on body weight greater than or equal to 15 kg and less than or equal to 40 kg). The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A [SAA] and C-Reactive Protein). Overall, the efficacy and safety of ILARIS in pediatric and adult patients were comparable. Infections of the upper respiratory tract were the most frequently reported infection. The safety and effectiveness of ILARIS in CAPS patients less than 4 years of age has not been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The safety and effectiveness of ILARIS in SJIA patients less than 2 years of age have not been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)]. The TRAPS, HIDS/MKD, and FMF trial included a total of 102 pediatric patients (TRAPS, HIDS/MKD and FMF patients) with an age range from 2 to 17 years who received ILARIS. Overall, there were no clinically meaningful differences in the efficacy, safety and tolerability profile of ILARIS in pediatric patients compared to the overall TRAPS, HIDS/MKD, and FMF populations (comprised of adult and pediatric patients, N = 169). The majority of pediatric patients achieved improvement in clinical symptoms and objective markers of inflammation [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. The safety and effectiveness of ILARIS for the treatment of gout flares in the pediatric population have not been established. Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, pediatric patients receive all recommended vaccinations. Avoid use of live virus vaccines concurrently with ILARIS treatment in pediatric patients or in infants exposed in utero following maternal administration [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. 8.5 Geriatric Use Clinical studies of ILARIS in patients with CAPS, TRAPS, HIDS/MKD, FMF and Still’s disease, did not include sufficient numbers of patients 65 years and older to determine whether they respond differently from younger patients. In the clinical studies for gout flares, of the total number of ILARIS- treated patients (n=491), 85 (17.3 %) were 65 years of age and older, while 16 (3.3 %) were 75 years of age and older [see Clinical Studies (14.4)]. Overall, the efficacy profile of ILARIS in patients with gout flares was comparable between the age group of patients less than 65 years of age, and of patients 65 to 75 years of age. The studies did not include sufficient numbers of patients 75 years and older to determine whether they respond differently from younger patients. No new safety findings were observed in patients across these age groups [see Adverse Reactions (6.1)]. 8.6 Renal Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with renal impairment. Reference ID: 5472537 8.7 Hepatic Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with hepatic impairment. 10 OVERDOSAGE No confirmed case of overdose has been reported. In the case of overdose, it is recommended that the subject be monitored for any signs and symptoms of adverse reactions or effects, and appropriate symptomatic treatment be instituted immediately. 11 DESCRIPTION Canakinumab is a recombinant, human anti-human-IL-1β monoclonal antibody that belongs to the IgG1/κ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or 448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the protein backbone at asparagine 298 (Asn 298). The biological activity of canakinumab is measured by comparing its inhibition of IL-1β-dependent expression of the reporter gene luciferase to that of a canakinumab internal reference standard, using a stably transfected cell line. ILARIS Injection ILARIS (canakinumab) Injection is supplied as a sterile, preservative-free, clear to opalescent, colorless to slightly brownish-yellow solution for subcutaneous injection in a single-dose, glass vial with coated stopper and aluminum flip-off cap. Each vial delivers 1 mL containing 150 mg canakinumab, L-histidine (2.1 mg), L-histidine HCl monohydrate (1.3 mg), mannitol (49.2 mg), polysorbate 80 (0.4 mg), and Sterile Water for Injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to human IL 1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Autoinflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis. The NLRP3 protein is an important component of the inflammasome and regulates the protease caspase-1 and controls the activation of IL-1β. Mutations in NLRP3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Still’s disease is a severe autoinflammatory disease, driven by innate immunity by means of proinflammatory cytokines such as IL-1β. Gout flares are characterized by activation of resident macrophages and infiltrating neutrophils in the joint, and concomitant overproduction of IL-1 resulting in an acute painful inflammatory response. IL-1 production by macrophages is triggered by uric acid (monosodium urate monohydrate) crystals in the joint and surrounding tissue through activation of the NLRP3 inflammasome complex. 12.2 Pharmacodynamics C-reactive protein and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS and gout flares. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Following ILARIS treatment, CRP, and SAA levels normalize within 8 days. In patients with gout flares, CRP and SAA were rapidly reduced following ILARIS treatment. Reductions in CRP and SAA were sustained throughout the 24-week observation period. Improvement in pharmacodynamic markers may not be representative of clinical response. In SJIA the median percent reduction in CRP from baseline to Day 15 was 91%. Improvement in pharmacodynamic markers may not be representative of clinical response. Reference ID: 5472537 13 12.3 Pharmacokinetics The pharmacokinetic properties of canakinumab are typical for an IgG-type antibody and are comparable in different diseases but influenced by body weight. Absorption The peak serum canakinumab concentration (Cmax) of 16 ± 3.5 mcg/mL occurred approximately 7 days after subcutaneous administration of a single, 150 mg dose subcutaneously to adult CAPS patients. The mean terminal half-life was 26 days. The absolute bioavailability of subcutaneous canakinumab was estimated to be 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. Distribution Canakinumab binds to serum IL-1β. Canakinumab volume of distribution (Vss) varied according to body weight and was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, 3.2 liters in a SJIA patient weighing 33 kg, and 6.34 liters for a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 7.9 liters in a typical patient with gout flares of body weight 93 kg. The expected accumulation ratio was 1.3-fold for CAPS patients, 1.6-fold for SJIA patients, and 1.1-fold for patients with gout flares following 6 months of subcutaneous dosing of 150 mg ILARIS every 8 weeks, 4 mg/kg every 4 weeks, and 150 mg every 12 weeks, respectively. Elimination Clearance (CL) of canakinumab varied according to body weight and was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg, 0.11 L/day in an SJIA patient weighing 33 kg, and 0.17 L/day in a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 0.23 L/day in a typical patient with gout flares of body weight 93 kg. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender- or age-related pharmacokinetic differences were observed after correction for body weight. Specific Populations Pediatric Patients Pharmacokinetic properties are similar in Periodic Fever Syndromes (CAPS, TRAPS, HIDS/MKD, FMF) and SJIA pediatric populations. In patients less than 2 years of age (n = 7), the exposure of canakinumab were comparable to older age groups with the same weight-based dose. In CAPS patients, peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of ILARIS 150 mg or 2 mg/kg in pediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults. In SJIA, exposure parameters (such as AUC and Cmax) were comparable across age groups from 2 years of age and above following subcutaneous administration of canakinumab 4 mg/kg every 4 weeks. Across the indications, SJIA and AOSD, the pharmacokinetics of canakinumab are similar. In TRAPS, HIDS/MKD, and FMF exposure parameter trough concentrations were comparable across age groups from 2 to less than 20 years following subcutaneous administration of canakinumab 2 mg/kg every 4 weeks. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of canakinumab. As canakinumab does not cross-react with rodent IL-1β, male and female fertility were evaluated in a mouse model using a murine analog of canakinumab. Male mice were treated weekly beginning 4 weeks prior to mating and continuing through 3 weeks after mating. Female mice were treated weekly for 2 weeks prior to mating through gestation day 3 or 4. The murine analog of canakinumab did not alter either male or female fertility parameters at subcutaneous doses up to 150 mg/kg. Reference ID: 5472537 14 CLINICAL STUDIES 14.1 Treatment of CAPS The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in CAPS Study (NCT00465985), a 3-part trial in patients 9 to 74 years of age with the MWS phenotype of CAPS. Throughout the trial, patients weighing more than 40 kg received ILARIS 150 mg and patients weighing 15 to 40 kg received 2 mg/kg. Part 1 was an 8-week open-label, single-dose period where all patients received ILARIS. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part 2, a 24-week randomized, double-blind, placebo-controlled withdrawal period. Patients who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase. A complete response was defined as ratings of minimal or better for physician’s assessment of disease activity (PHY) and assessment of skin disease (SKD) and had serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. A disease flare was defined as a CRP and/or SAA values greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD. In Part 1, a complete clinical response was observed in 71% of patients one week following initiation of treatment and in 97% of patients by Week 8 (see Table 4 and Figure 1). In the randomized withdrawal period, a total of 81% of the patients randomized to placebo flared as compared to none (0%) of the patients randomized to ILARIS. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%. At the end of Part 2, all 15 patients treated with ILARIS had absent or minimal disease activity and skin disease (see Table 4). In a second trial (NCT00465985), patients 4 to 74 years of age with both MWS and FCAS phenotypes of CAPS were treated in an open-label manner. Treatment with ILARIS resulted in clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of patients within 1 week. Table 4: Physician’s Global Assessment of Auto Inflammatory Disease Activity and Assessment of Skin Disease: Frequency Table and Treatment Comparison in Part 2 (Using LOCF, ITT Population) ILARIS Placebo N = 15 N = 16 Baseline Start of Part 2 End of Part 2 Start of Part 2 End of Part 2 (Week 8) (Week 8) Physician's Global Assessment of Auto Inflammatory Disease Activity – n (%) Absent 0/31 (0) 9/15 (60) 8/15 (53) 8/16 (50) 0/16 (0) Minimal 1/31 (3) 4/15 (27) 7/15 (47) 8/16 (50) 4/16 (25) Mild 7/31 (23) 2/15 (13) 0/15 (0) 0/16 (0) 8/16 (50) Moderate 19/31 (61) 0/15 (0) 0/15 (0) 0/16 (0) 4/16 (25) Severe 4/31 (13) 0/15 (0) 0/15 (0) 0/16 (0) 0/16 (0) Assessment of skin disease – n (%) Absent 3/31 (10) 13/15 (87) 14/15 (93) 13/16 (81) 5/16 (31) Minimal 6/31 (19) 2/15 (13) 1/15 (7) 3/16 (19) 3/16 (19) Mild 9/31 (29) 0/15 (0) 0/15 (0) 0/16 (0) 5/16 (31) Moderate 12/31 (39) 0/15 (0) 0/15 (0) 0/16 (0) 3/16 (19) Severe 1/32 (3) 0/15 (0) 0/15 (0) 0/16 (0) 0/16 (0) Markers of inflammation CRP and SAA normalized within 8 days of treatment in the majority of patients. Normal mean CRP (Figure 1) and SAA values were sustained throughout CAPS Study 1 in patients continuously treated with canakinumab. After withdrawal of canakinumab in Part 2, CRP (Figure 1) and SAA values again returned to abnormal values and subsequently normalized after reintroduction of canakinumab in Part 3. The pattern of normalization of CRP and SAA was similar. Reference ID: 5472537 60 50 w 40 elO :a-;- 1::: -~ i.§. 30 'o: c.a! =~ :II!&! u 20 Haris Start of Part2 -or Placebo ., -k afler the otart of Part 1; ... - afler the otart of Part 3 ---- CIU'---llart•- - o - CIU'----- ·---- Upper 1ml of nonnal for CRP (11 m~ Stut of Part3 \ Endof Study Figure 1. Mean C-Reactive Protein Levels at the End of Parts 1, 2, and 3 of CAPS Study 1 14.2 Treatment of Periodic Fever Syndromes: TRAPS, HIDS/MKD, and FMF The efficacy and safety of ILARIS for the treatment of TRAPS, HIDS/MKD, and FMF was demonstrated in a 4-Part study (TRAPS, HIDS/MKD, and FMF Study 1) (NCT02059291) consisting of three separate, disease cohorts (TRAPS, HIDS/MKD, and FMF) which enrolled 185 patients aged greater than 28 days. Patients in each cohort entered a 12-week screening period (Part 1) during which they were evaluated for the onset of disease flare. Patients aged 2 to 76 years were then randomized at flare onset into a 16-week double-blind, placebo-controlled treatment period (Part 2) where they received either 150 mg ILARIS (2 mg/kg for patients weighing less than or equal to 40 kg) subcutaneously or placebo every 4 weeks. Part 3 and Part 4 of this study are ongoing. Randomized patients in Part 2 treated with ILARIS whose disease flare did not resolve, or who had persistent disease activity from Day 8 up to Day 14 (Physician’s Global Assessment [PGA] greater than or equal to 2 or C-reactive Protein [CRP] greater than 10 mg/L and no reduction by at least 40% from baseline) received an additional dose of 150 mg (or 2 mg/kg for patients weighing less than or equal to 40 kg). Patients treated with ILARIS whose disease flare did not resolve, or who had persistent disease activity from Day 15 up to Day 28 (PGA greater than or equal to 2 or CRP greater than 10 mg/L and no reduction by at least 70% from baseline), also received an additional dose of 150 mg (or 2 mg/kg for patients weighing less than or equal to 40 kg). On or after Day 29, patients treated with ILARIS in Part 2 with PGA greater than or equal to 2 and CRP greater than or equal to 30 mg/L were also up-titrated. All up-titrated patients remained at the increased dose of 300 mg (or 4 mg/kg for patients weighing less than or equal to 40 kg) every 4 weeks. The primary efficacy endpoint of the randomized, 16-week treatment period (Part 2) was the proportion of complete responders within each cohort as defined by patients who had resolution of their index disease flare at Day 15 and did not experience a new disease flare during the remainder of the 16-week treatment period. Resolution of the index disease flare (initial flare at the time of the randomization) was defined at the Day 15 visit as a PGA Disease Activity score less than 2 (“minimal or no disease”) and C-reactive Protein (CRP) within normal range (less than or equal to 10 mg/L) or reduction greater than or equal to 70% from baseline. The key signs and symptoms assessed in the PGA for each condition were the following: TRAPS: abdominal pain, skin rash, musculoskeletal pain, eye manifestations; HIDS/MKD: abdominal pain; lymphadenopathy, aphthous ulcers; FMF: abdominal pain, skin rash, chest pain, arthralgia/arthritis. A new flare was defined as a PGA score greater than or equal to 2 (“mild, moderate, or severe disease”) and CRP greater to or equal than 30 mg/L. In the 16-week treatment period (Part 2), patients who needed dose escalation, who crossed over from placebo to ILARIS, or who discontinued from the study due to any reason prior to Week 16 were considered as non-responders. Patients randomized in the TRAPS cohort (N = 46) were aged 2 to 76 years (median age at baseline: 15.5 years) and of this population, 57.8% did not have fever at baseline. Randomized TRAPS patients were those with chronic or recurrent disease activity defined as 6 flares per year (median number of flares per year: 9.0) with PGA greater than or equal to 2 and CRP greater than 10 mg/L (median CRP at baseline: 112.5 mg/L). In the TRAPS cohort, 11/22 (50.0%) patients Reference ID: 5472537 randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 21/24 (87.5%) patients randomized to placebo crossed over to ILARIS. Patients randomized in the HIDS/MKD cohort (N = 72) were aged 2 to 47 years (median age at baseline: 11.0 years) and of this population, 41.7% did not have fever at baseline. Randomized HIDS/MKD patients were those with a confirmed diagnosis of HIDS according to known genetic MVK/enzymatic (MKD) findings, and documented prior history of greater than or equal to 3 febrile acute flares within a 6-month period (median number of flares per year: 12.0) when not receiving prophylactic treatment and during the study, had active HIDS flares defined as PGA greater than or equal to 2 and CRP greater than 10 mg/L (median CRP at baseline: 113.5 mg/L). In the HIDS/MKD cohort, 19/37 (51.4%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 31/35 (88.6%) patients randomized to placebo crossed over to ILARIS. Patients randomized in the FMF cohort (N = 63) were aged 2 to 69 years (median age at baseline: 18.0 years) and of this population, 76.2% did not have fever at baseline. Randomized FMF patients were those with documented active disease despite colchicine therapy or documented intolerance to effective doses of colchicine. Patients had active disease defined as at least one flare per month (median number of flares per year: 18.0) and CRP greater than 10 mg/L (median CRP at baseline: 94.0 mg/L). Patients were allowed to continue their stable dose of colchicine without change. Of the 63 randomized patients, 55 (87.3%) were taking concomitant colchicine therapy on or after randomization. In the FMF cohort, 10/31 (32.3%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 27/32 (84.4%) patients randomized to placebo crossed over to ILARIS. For the primary efficacy endpoint, ILARIS was superior to placebo in the proportion of TRAPS, HIDS/MKD, and FMF patients who resolved their index disease flare at Day 15 and had no new flare over the 16 weeks of treatment from the time of the resolution of the index flare (see Table 5). Table 5: Proportion of TRAPS, HIDS/MKD, and FMF Patients Who Achieved a Complete Response (Resolution of Index Flare by Day 15 and Maintained Through Week 16) ILARIS 150 mg Placebo Treatment comparison Cohort n/N (%) n/N (%) Odds ratio 95% CI p-value TRAPS 10/22 (45.5%) 2/24 (8.3%) 9.17 (1.51, 94.61) 0.005 HIDS/MKD 13/37 (35.1%) 2/35 (5.7%) 8.94 (1.72, 86.41) 0.002 FMF 19/31 (61.3%) 2/32 (6.3%) 23.75 (4.38, 227.53) <0.0001 Abbreviation: CI, confidence interval. n = number of patients with the response. N = number of patients evaluated for that response in each cohort. At Day 15, a higher proportion of ILARIS-treated patients compared to placebo-treated patients experienced resolution of their index flare in all disease cohorts (see Table 6). Reference ID: 5472537 Table 6: Resolution of Index Flare (Full Analysis Set) Resolution at Day 15* ILARIS 150 mg every 4 weeks Placebo Variable n/N (%) n/N (%) TRAPS 14/22 (63.6%) 5/24 (20.8%) HIDS/MKD 24/37 (64.9%) 13/35 (37.1%) FMF 25/31 (80.7%) 10/32 (31.3%) n = number of patients with the response. N = number of patients evaluated for that response in each cohort. Resolution of index disease flare (PGA less than 2 and CRP less than or equal to 10 mg/L or reduction greater than or equal to 70% from baseline). There was supportive evidence of efficacy for ILARIS at Day 15, as compared to placebo, for the components of the primary endpoint, CRP and PGA Disease Activity score, as well as for the secondary endpoint SAA level (see Table 7). Table 7: Proportion of TRAPS, HIDS/MKD, and FMF Patients Achieving PGA Less Than 2, CRP Less Than or Equal to 10 mg/L and SAA Less Than or Equal to 10 mg/L at Day 15 TRAPS HIDS/MKD FMF Variable ILARIS 150 mg Placebo Treatment comparison ILARIS 150 mg Placebo Treatment comparison ILARIS 150 mg Placebo Treatment comparison n/N (%) n/N (%) Odds ratio 95% CI n/N (%) n/N (%) Odds ratio 95% CI n/N (%) n/N (%) Odds ratio 95% CI PGA less than 2 14/22 (63.6%) 8/24 (33.3%) 4.06 (1.12, 14.72) 26/37 (70.3%) 14/35 (40.0%) 3.42 (1.28, 9.16) 27/31 (87.1%) 13/32 (40.6%) 10.07 (2.78, 36.49) CRP less than or equal to 10 mg/L 13/22 (59.1%) 8/24 (33.3%) 3.88 (1.05, 14.26) 25/37 (67.6%) 9/35 (25.7%) 6.05 (2.14, 17.12) 28/31 (90.3%) 9/32 (28.1%) 22.51 (5.41, 93.62) SAA less than or equal to 10 mg/L 7/22 (31.8%) 2/24 (8.3%) 5.06 (0.92, 27.91) 10/37 (27.0%) 4/35 (11.4%) 2.94 (0.82, 10.53) 13/31 (41.9%) 5/32 (15.6%) 3.73 (1.11, 12.52) Abbreviation: CI: confidence interval. n = number of patients with the response. N = number of patients evaluated for that response in each cohort. ILARIS-treated patients who up-titrated or discontinued prior to Day 15 and placebo-treated patients who switched over to ILARIS or discontinued prior to Day 15 were classified as nonresponders. 14.3 Treatment of Still’s Disease: AOSD and SJIA SJIA The efficacy of ILARIS for the treatment of active SJIA was assessed in 2 Phase 3 studies (SJIA Study 1 and SJIA Study 2). Patients enrolled were aged 2 to less than 20 years (mean age at baseline: 8.5 years) with a confirmed diagnosis of SJIA at least 2 months before enrollment (mean disease duration at baseline: 3.5 years). Patients had active disease defined as greater than or equal to 2 joints with active arthritis (mean number of active joints at baseline: 15.4), documented spiking, intermittent fever (body temperature greater than 38°C) for at least 1 day within 1 week before study drug administration, and CRP greater than 30 mg/L (normal range less than 10 mg/L) (mean CRP at baseline: 200.5 mg/L). Patients were allowed to continue their stable dose of methotrexate, corticosteroids, and/or NSAIDs without change, except for tapering of the corticosteroid dose as per study design in SJIA Study 2 (see below). SJIA Study 1 (NCT00886769) was a randomized, double-blind, placebo-controlled, single-dose 4-week study assessing the short-term efficacy of ILARIS in 84 patients randomized to receive a single subcutaneous dose of 4 mg/kg ILARIS or placebo (43 patients received ILARIS and 41 patients received placebo). The primary objective of this study was to Reference ID: 5472537 demonstrate the superiority of ILARIS versus placebo in the proportion of patients who achieved at least 30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion which included both the pediatric ACR core set (ACR30 response) and absence of fever (temperature less than or equal to 38°C in the preceding 7 days) at Day 15. Pediatric ACR responses are defined by achieving levels of percentage improvement (30%, 50%, and 70%) from baseline in at least 3 of the 6 core outcome variables, with worsening of greater than or equal to 30% in no more than one of the remaining variables. Core outcome variables included a physician global assessment of disease activity, parent or patient global assessment of well-being, number of joints with active arthritis, number of joints with limited range of motion, CRP, and functional ability (Childhood Health Assessment Questionnaire-CHAQ). Percentages of patients by pediatric ACR response are presented in Table 8. Table 8: Pediatric ACR Response at Days 15 and 29 Day 15 Day 29 Weighted ILARIS Placebo Difference1 (95% CI)2 N = 43 N = 41 Weighted ILARIS Placebo difference1 (95% CI)2 N = 43 N = 41 ACR30 ACR50 ACR70 84% 10% 70% (56%, 84%) 67% 5% 65% (50%, 80%) 60% 2% 64% (49%, 79%) 81% 10% 70% (56%, 84%) 79% 5% 76% (63%, 88%) 67% 2% 67% (52%, 81%) 1Weighted difference is the difference between the ILARIS and placebo response rates, adjusted for the stratification factors (number of active joints, previous response to anakinra, and level of oral corticosteroid use). 2CI = confidence interval for the weighted difference. N = Number of patients. Results for the components of the pediatric ACR core set were consistent with the overall ACR response results, for systemic and arthritic components, including the reduction in the total number of active joints and joints with limited range of motion. Among the patients who returned for a Day 15 visit, the mean change in patient pain score (0 to 100 mm visual analogue scale) was -50.0 mm on ILARIS (N = 43), as compared to +4.5 mm on placebo (N = 25). The mean change in pain score among ILARIS-treated patients was consistent through Day 29. All patients treated with ILARIS had no fever at Day 3 compared to 87% of patients treated with placebo. SJIA Study 2 (NCT00889863) was a randomized, double-blind, placebo-controlled, withdrawal study of flare prevention by ILARIS in patients with active SJIA. Flare was defined by worsening of greater than or equal to 30% in at least 3 of the 6 core Pediatric ACR response variables combined with improvement of greater than or equal to 30% in no more than 1 of the 6 variables, or reappearance of fever not due to infection for at least 2 consecutive days. The study consisted of 2 major parts: 177 patients were enrolled in the study and received 4 mg/kg ILARIS subcutaneously every 4 weeks in Part I and 100 of these patients continued into Part II to receive either ILARIS 4 mg/kg or placebo subcutaneously every 4 weeks. Corticosteroid Dose Tapering Of the total 128 patients taking corticosteroids who entered the open-label portion of Study 2, 92 attempted corticosteroid tapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully taper their corticosteroid dose and 42 (46%) discontinued corticosteroids. Time to Flare Part II was a randomized withdrawal design to demonstrate that the time to flare was longer with ILARIS than with placebo. Follow-up stopped when 37 events had been observed resulting in patients being followed for different lengths of time. The probability of experiencing a flare over time in Part II was statistically lower for the ILARIS treatment group than for the placebo group (Figure 2). This corresponded to a 64% relative reduction in the risk of flare for patients in the ILARIS group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75). Reference ID: 5472537 ,,..... ~ ....... "' 0 E oi "' ... "' a:; :::::;; I C 0 a. 0 :..: 100 90 80 70 60 50 40 30 20 10 0 Number of pot,ents ct nsk ACZ885 Placebo ' -, ~~-----------~ 0 50 50 8 45 41 16 37 36 24 32 23 ' - ' 32 25 16 '-c.. 40 48 Weeks in Pod II 17 8 11 5 56 9 4 64 6 4 72 3 1 80 2 1 88 Figure 2. Kaplan-Meier Estimates of the Probability to Stay Flare-Free in Part II of SJIA Study 2 by Treatment (ILARIS (ACZ885) and Placebo groups) Very few patients were followed for more than 48 weeks. AOSD The efficacy of ILARIS in adults with AOSD is based on the pharmacokinetic exposure and extrapolation of the established efficacy of ILARIS in SJIA patients. Efficacy of ILARIS was also assessed in a randomized, double-blind, placebo-controlled study that enrolled 36 patients (22 to 70 years old) diagnosed with AOSD. The efficacy data were generally consistent with the results of a pooled efficacy analysis of SJIA patients. 14.4 Treatment of Gout Flares The efficacy of ILARIS was demonstrated in two 12-week, randomized, double-blind, active-controlled studies in patients with gout flares for whom NSAIDs and/or colchicine were contraindicated, not tolerated or ineffective, and who had experienced at least three gout flares in the previous year (Studies 1 and 2). The studies continued in 1) two 12-week, double-blind, active-controlled extensions, followed by 2) two open-label extensions and continued 3) in a third open- label extension (combined for both studies) up to a maximum of 36 months where all patients were treated with ILARIS upon a new flare. In Study 1 (NCT01029652), patients were randomized to receive ILARIS 150 mg subcutaneous (N = 115) or triamcinolone acetonide 40 mg intramuscular (N = 115) at baseline and thereafter treated upon a new flare. Two patients randomized to canakinumab were not included in the analysis as they did not receive any study medication. In Study 2 (NCT01080131), patients were randomized to receive ILARIS 150 mg subcutaneous (N =112) or triamcinolone acetonide 40 mg intramuscular (N =114) at baseline and thereafter treated upon a new flare. In Studies 1 and 2, over 85% of patients had at least one co-morbidity, including hypertension (60%), obesity (53%), diabetes (15%), and ischemic heart disease (12%). Twenty-five percent of patients had chronic kidney disease (stage ≥ 3), based on eGFR. Concomitant treatment with allopurinol or other uric acid lowering therapies was reported by 42% of patients at entry. The majority of patients (73%) reported between 3-6 flares in the year prior to study entry and the remainder reported seven or more flares. Approximately one-third of the patients enrolled [76 in the ILARIS group (33.5%) and 84 in the triamcinolone acetonide (36.7%) group] had documented inability (intolerance, contraindication or lack of response) to use both, NSAIDs and colchicine. The remainder had intolerance, contraindication or lack of response to either NSAIDs or colchicine. Reference ID: 5472537 In both studies, the co-primary endpoints were: (i) patient’s assessment of gout flare pain intensity at the most affected joint at 72 hours post-dose measured on a 0-100 mm visual analogue scale (VAS) and (ii) the time to first new gout flare. The studies aimed to determine whether ILARIS 150 mg would be superior to triamcinolone acetonide 40 mg. Study 3 (NCT01356602), an additional 12-week, randomized, double-blind, active-controlled study, enrolled 397 patients with ILARIS 150 mg subcutaneous (Pre-Filled Syringe (PFS), N=133, Lyophilizate (LYO), N=132) or triamcinolone acetonide 40 mg intramuscular (N=132). Eight patients (2 ILARIS PFS, 3 ILARIS LYO, 3 triamcinolone) were not included for efficacy assessment as they did not receive study medication. Pain intensity at the most affected joint, assessed on a 0-100 mm VAS at 72-hours post-dose was the primary endpoint, and time to first new gout flare was a secondary endpoint. Approximately 44% of patients (45.9% ILARIS PFS group, 47.4%, ILARIS LYO group and 40.6% in the triamcinolone acetonide group) were unable to use NSAIDs and colchicine (due to contraindications, intolerance, or inadequate response) in this study. Analyses of both endpoints were conducted for Studies 1, 2, and 3 for the subpopulation of patients unable to use NSAIDs and colchicine (due to contraindications, intolerance, or inadequate response) and overall population of patients unable to use NSAIDs and/or colchicine. Efficacy on Pain In all studies (Study 1, 2, and 3), pain intensity of the most affected joint (0-100 mm VAS) at 72 hours post-dose was consistently lower for patients treated with ILARIS compared with triamcinolone acetonide in the subpopulation of patients unable to use NSAIDs and colchicine as shown in Table 9, and Figure 3 (Study 3). This benefit of ILARIS on pain intensity was comparable to the overall patient populations i.e., patients unable to use NSAIDs and/or colchicine in all three studies (see Table 9). Table 9: Pain Intensity of the Most Affected Joint at 72-h post treatment Study Population ILARIS 150 mg Triamcinolone acetonide 40 mg Difference (95% CI) in Pain Intensity 72 Hours Post-dose VAS (0-100 mm): ILARIS vs. Triamcinolone acetonide N Mean (SE)* N Mean (SE)* Study 1 Patients unable to use NSAIDs and colchicine 22 21.4 (6.05) 37 38.4 (4.65) -17.0 mm (-32.3, -1.6) Patients unable to use NSAIDs and/or colchicine 113 27.9 (2.42) 115 39.7 (2.40) -11.8 mm (-18.5, -5.1) Study 2 Patients unable to use NSAIDs and colchicine 53 24.1 (3.32) 44 33.1 (3.65) -9.1 mm (-18.9, 0.8) Patients unable to use NSAIDs and/or colchicine 112 21.9 (2.31) 114 31.7 (2.29) -9.8 mm (-16.2, -3.4) Study 3 Patients unable to use NSAIDs and colchicine 62 20.8 (3.11) 51 40.3 (3.42) -19.5 mm (-28.6, -10.3) 60# 18.5 (3.16) -21.8 mm (-31.0, -12.6) Patients unable to use NSAIDs and/or colchicine 129 19.7 (2.05) 129 32.4 (2.05) -12.7 mm (-18.4, -7.0) 131# 17.0 (2.04) -15.4 mm (-21.1, -9.8) Abbreviation: CI = confidence interval; SE=Standard Error # Prefilled Syringe (PFS) formulation. Reference ID: 5472537 ➔----+---* ------- --0-------0-------e- * Adjusted mean, standard error for mean and difference between treatment groups are estimated based on analysis of covariance (ANCOVA) model with treatment, baseline VAS score and baseline BMI as covariates. For Study 3, the use of urate lowering therapy (Yes/No) at baseline is also included in the model as additional covariate. N = number of patients randomized and received at least one dose of study treatment. Figure 3. Pain Intensity Over Time in the Subpopulation of Patients Unable to Use NSAIDs and Colchicine (Study 3, ILARIS (ACZ885) 150mg) LS mean +/- SE 0 10 20 30 40 50 60 70 80 90 100 Time post-dose (hours) 6 12 24 48 72 96 120 144 168 ACZ885 150 mg (PFS) ACZ885 150 mg (LYO) Triam 40 mg Time to New Flare In the subpopulation of patients in Studies 1, 2 and 3 unable to use NSAIDs and colchicine, time to new flare over 12 weeks from randomization showed a reduction in the risk of a new flare when treated with ILARIS compared with triamcinolone acetonide 40 mg (see Table 10). This risk reduction for a new flare after ILARIS treatment versus triamcinolone acetonide was comparable to the overall patient population over 12 weeks in all 3 studies (see Table 10). Reference ID: 5472537 Table 10: Time to New Flare Over the 12 Weeks From Randomization Study Population ILARIS 150 mg Triamcinolone acetonide 40 mg Risk reduction for a new flare ILARIS vs. Triamcinolone acetonide Hazard ratio# (95% CI) N Flare rate(n) N Flare rate(n) Study 1 Patients unable to use NSAIDs and colchicine 22 14% (3) 38 46% (17) 75% 0.25 (0.07, 0.85) Patients unable to use NSAIDs and/or colchicine 113 19% (21) 115 37% (40) 55 % 0.45 (0.26 to 0.76) Study 2 Patients unable to use NSAIDs and colchicine 54 16% (8) 46 43% (19) 72% 0.28 (0.12, 0.65) Patients unable to use NSAIDs and/or colchicine 112 14% (15) 114 38% (42) 68% 0.32 (0.18 to 0.58) Study 3 Patients unable to use NSAIDs and colchicine 62 10% (6) 51 32% (15) 71% 0.29 (0.11, 0.74) 60# 3% (2) 91% 0.09 (0.02, 0.41) Patients unable to use NSAIDs and/or colchicine 129 10% (12) 129 44% (52) 82% 0.18 (0.10, 0.34) 131# 9% (12) 83% 0.17 (0.09, 0.33) Abbreviation: CI = confidence interval. # Prefilled Syringe (PFS) formulation. * Flare rates up to 12 weeks are estimated using Kaplan-Meier method; n = number of patients with new flares. The risk reduction and hazard ratio between treatment groups are estimated using Cox proportional hazard (Cox-PH) model with treatment and baseline BMI as covariates. For study 3, the use of urate lowering therapy (Yes/No) at baseline is also included in the model as additional covariate. N = number of patients randomized and received at least one dose of study treatment. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ILARIS Injection (Solution) Carton of 1 vial NDC 0078-0734-61 Each single-dose vial of ILARIS (canakinumab) Injection delivers 150 mg/mL sterile, preservative-free, clear to slightly opalescent, colorless to a slight brownish to yellow solution. Storage and Handling The unopened vial must be stored refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Store in the original carton to protect from light. Do not use beyond the date stamped on the label. ILARIS does not contain preservatives. Discard any unused portions of ILARIS or waste material in accordance with local requirements. Keep this and all drugs out of the reach of children. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Reference ID: 5472537 Advise the patient of the potential benefits and risks of ILARIS. Physicians should instruct their patients to read the Medication Guide before starting ILARIS therapy. Drug Administration Advise the patient that healthcare providers should perform administration of ILARIS by the subcutaneous injection route [see Dosage and Administration (2.1)]. Infections Caution the patient that ILARIS use has been associated with serious infections. Counsel the patient to contact their healthcare professional immediately if they develop an infection after starting ILARIS. Treatment with ILARIS should be discontinued if a patient develops a serious infection. Counsel the patient not to take any IL-1 blocking drug, including ILARIS, if they are also taking a drug that blocks TNF, such as etanercept, infliximab, or adalimumab. Use of ILARIS with other IL-1 blocking agents, such as rilonacept and anakinra is not recommended. Caution the patient not to receive ILARIS if they have a chronic or active infection, including HIV, Hepatitis B, or Hepatitis C [see Warnings and Precautions (5.1)]. Vaccinations Prior to initiation of therapy with ILARIS, physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ILARIS [see Warnings and Precautions (5.4)]. Injection-Site Reactions Physicians should explain to patients that a very small number of patients in the clinical trials experienced a reaction at the subcutaneous injection site. Injection-site reactions may include pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Healthcare providers should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician. Hypersensitivity Reactions Counsel the patient to stop taking ILARIS and contact their healthcare provider immediately if they develop serious skin reactions or signs of allergic reaction, such as difficulty breathing or swallowing, nausea, dizziness, skin rash, itching, hives, palpitations, or low blood pressure [see Warnings and Precautions (5.3)]. Pregnancy Advise female patients of the potential risk to a fetus [see Use in Specific Populations (8.1)]. Manufactured by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 US License Number 1244 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis Reference ID: 5472537 Medication Guide ILARIS® (i-LAHR-us) (canakinumab) injection, for subcutaneous use What is the most important information I should know about ILARIS? ILARIS can cause serious side effects, including: • Increased risk of serious infections. ILARIS can lower the ability of your immune system to fight infections. Your healthcare provider should: o test you for tuberculosis (TB) before you receive ILARIS. o monitor you closely for symptoms of TB during treatment with ILARIS. o check you for symptoms of any type of infection before, during, and after your treatment with ILARIS. Tell your healthcare provider right away if you have any symptoms of an infection, such as fever, sweats or chills, cough, flu-like symptoms, weight loss, shortness of breath, blood in your phlegm, sores on your body, warm or painful areas on your body, diarrhea or stomach pain, or feeling very tired. See "What are possible side effects of ILARIS?" for more information about side effects. What is ILARIS? ILARIS is a prescription medicine injected by your healthcare provider just below the skin (subcutaneous) used to treat: • The following Periodic Fever Syndromes: o Adults and children 4 years of age and older who have auto-inflammatory diseases called Cryopyrin- Associated Periodic Syndromes (CAPS), including: • Familial Cold Auto-inflammatory Syndrome (FCAS). • Muckle-Wells Syndrome (MWS). o Adults and children who have an auto-inflammatory disease called Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS). o Adults and children who have an auto-inflammatory disease called Hyperimmunoglobulin D Syndrome (HIDS) [also known as Mevalonate Kinase Deficiency (MKD)]. o Adults and children who have an auto-inflammatory disease called Familial Mediterranean Fever (FMF). • Still’s disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in children 2 years of age and older. • Gout flares in adults who: o are not able to receive or tolerate treatment with non-steroidal anti-inflammatory drugs (NSAIDS) and colchicine. o have not responded to treatment with NSAIDS and colchicine. o are not able to receive repeated treatment with steroids. It is not known if ILARIS is safe and effective when used to treat: • SJIA in children under 2 years of age. • CAPS in children under 4 years of age. • gout flares in children. Who should not receive ILARIS? • Do not receive ILARIS if you are allergic to canakinumab or any of the ingredients in ILARIS. See the end of this Medication Guide for a complete list of ingredients in ILARIS. Before you receive ILARIS, tell your healthcare provider about all your medical conditions, including if you: • think you have or are being treated for an active infection. • have symptoms of an infection. • have a history of infections that keep coming back. • have a history of low white blood cells. • have or have had HIV, Hepatitis B, or Hepatitis C. • have recently received or are scheduled to receive any vaccinations. o You should be brought up to date with all age required vaccines before starting treatment with ILARIS. o You should not receive ‘live’ vaccines while you are being treated with ILARIS and until your healthcare provider tells you that your immune system is no longer weakened. Reference ID: 5472537 • are pregnant or planning to become pregnant. It is not known if ILARIS will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while receiving ILARIS. • received ILARIS while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby within 4 to 12 months after you received your last dose of ILARIS before giving birth. • are breastfeeding or planning to breastfeed. It is not known if ILARIS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive ILARIS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: • medicines that affect your immune system. • medicines called IL-1 blocking agents, such as Kineret® (anakinra), Arcalyst® (rilonacept). • medicines called Tumor Necrosis Factor (TNF) inhibitors, such as Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), Simponi® (golimumab), or Cimzia® (certolizumab pegol). • medicines that affect enzyme metabolism. Ask your healthcare provider for a list of these medicines if you are not sure. How should I receive ILARIS? • ILARIS is given by your healthcare provider as an injection under the skin (subcutaneous injection): o every 8 weeks for CAPS. o every 4 weeks for TRAPS, HIDS/MKD, FMF, AOSD, and SJIA. o as a single dose at the time of a gout flares. If you have a new flare and need another dose of ILARIS, you must wait at least 12 weeks before receiving the next dose. What are the possible side effects of ILARIS? ILARIS can cause serious side effects, including: • See “What is the most important information I should know about ILARIS?” • decreased ability of your body to fight infections (immunosuppression). For people treated with medicines that cause immunosuppression like ILARIS, the chances of getting cancer may increase. • serious allergic reactions. Stop taking ILARIS, contact your healthcare provider, and get emergency help right away if you have any of these symptoms of a serious allergic reaction: o swelling of the lips, tongue, mouth, o skin rash, hives, redness, or swelling outside of the injection or face site area o trouble breathing o dizziness or fainting o wheezing o fast heartbeat or pounding in your chest (tachycardia) o severe itching o sweating • risk of infection with live vaccines. You should not get live vaccines if you are receiving ILARIS. Tell your healthcare provider if you are scheduled to receive any vaccines. The most common side effects of ILARIS include: When ILARIS is used for the treatment of CAPS: • cold symptoms • headache • feeling like you are spinning (vertigo) • diarrhea • cough • weight gain • flu (influenza) • body aches • injection-site reactions (such as redness, swelling, warmth, or itching) • runny nose • nausea, vomiting, and diarrhea • nausea (gastroenteritis) When ILARIS is used for the treatment of TRAPS, HIDS/MKD, and FMF: • cold symptoms • runny nose • nausea, vomiting, and diarrhea (gastroenteritis) • upper respiratory tract infection • sore throat • injection-site reactions (such as redness, swelling, warmth, or itching) When ILARIS is used for the treatment of Still’s disease (AOSD and SJIA): • cold symptoms • runny nose • nausea, vomiting, and diarrhea (gastroenteritis) • upper respiratory tract infection • sore throat • stomach pain • pneumonia • urinary tract infection • injection-site reactions (such as redness, Reference ID: 5472537 swelling, warmth, or itching) When ILARIS is used for the treatment of gout flares: • cold symptoms • urinary tract infection • upper respiratory tract infection • increased levels of triglycerides in the blood • back pain Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of ILARIS. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of ILARIS. Medicines are sometimes prescribed for purposes other than those listed in this Medication Guide. You can ask your pharmacist or healthcare provider for information about ILARIS that was written for health professionals. What are the ingredients in ILARIS? Active ingredient: canakinumab. Inactive ingredients: Solution for Injection: L-histidine, L-histidine HCl monohydrate, mannitol, polysorbate 80, sterile water for injection. What are Periodic Fever Syndromes? Periodic Fever Syndromes is the name for several different autoinflammatory diseases, including CAPS, TRAPS, HIDS/MKD, and FMF. People with these diseases cannot keep certain chemicals made by their body (interleukin-1 beta, also called IL-1β) at the correct level. All these diseases have symptoms that often come and go, with irritated body parts (inflammation) and elevated body temperature (fever). These conditions have a dysregulation of IL-1β production and share similar clinical features of recurrent episodes of inflammation and fever, such as rash, headache, pain (mostly in the joints, belly, eyes, muscles), fatigue, inflammation of other organs, such as heart, lungs, spleen, and brain. What is Still’s Disease (AOSD and SJIA)? Still’s disease (which is referred to as AOSD in adults and SJIA in children) is an autoinflammatory disorder which can be caused by having too much or being too sensitive to certain proteins, including interleukin-1 beta (IL-1β), and can lead to symptoms such as fever, rash, headache, feeling very tired (fatigue), or painful joints and muscles. What is Gout Flare? A gout flare is caused when a chemical called urate builds-up in the body, and needle-shaped crystals form in and around the joint. These crystals lead to inflammation with excessive production of certain proteins, such as interleukin-1 beta (also called IL-1β), which in turn can lead to sudden, severe pain, redness, warmth and swelling in a joint. What is Macrophage Activation Syndrome (MAS)? MAS is a syndrome associated with Still’s disease and some other autoinflammatory diseases like HIDS/MKD that can lead to death. Tell your healthcare provider right away if your AOSD or SJIA symptoms get worse or if you have any of these symptoms of an infection: • a fever lasting longer than 3 days. • a cough that does not go away. • redness in one part of your body. • warm feeling or swelling of your skin. Manufactured by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 US License Number 1244 Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 © Novartis For more information about ILARIS, call 1-888-669-6682 or visit www.ILARIS.com. Kineret® , Arcalyst® , Enbrel® , Humira® , Remicade® , Simponi® , and Cimzia® are trademarks of Amgen, Regeneron, Immunex Corporation, AbbVie Biotechnology Ltd., Centocor Ortho Biotech Inc., Janssen Biotech Inc., and the UCB Group of companies, respectively. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: November 2024 Reference ID: 5472537	custom-source	2025-02-12T15:46:30.981240	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125319s110lbl.pdf', 'application_number': 125319, 'submission_type': 'SUPPL ', 'submission_number': 110}
80,142	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OZEMPIC® safely and effectively. See full prescribing information for OZEMPIC. OZEMPIC (semaglutide) injection, for subcutaneous use Initial U.S. Approval: 2017 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Warnings and Precautions, Pulmonary During General Anesthesia or Deep Sedation (5.9) 11/2024 ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ OZEMPIC is a glucagon-like peptide 1 (GLP-1) receptor agonist indicated as: • an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1). • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1). Limitations of Use: • Has not been studied in patients with a history of pancreatitis. Consider another antidiabetic therapy (1, 5.2). • Not for treatment of type 1 diabetes mellitus (1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Administer once weekly at any time of day, with or without meals (2.1). • Start at 0.25 mg once weekly. After 4 weeks, increase the dosage to 0.5 mg once weekly (2.2). • If additional glycemic control is needed, increase the dosage to 1 mg once weekly after at least 4 weeks on the 0.5 mg dose (2.2). • If additional glycemic control is needed, increase the dosage to 2 mg once weekly after at least 4 weeks on the 1 mg dosage (2.2) • If a dose is missed administer within 5 days of missed dose (2.2). • Inject subcutaneously in the abdomen, thigh, or upper arm (2.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Injection: 2 mg/3 mL (0.68 mg/mL) available in: • Single-patient-use pen that delivers 0.25 mg or 0.5 mg per injection (3) Injection: 4 mg/3 mL (1.34 mg/mL) available in: • Single-patient-use pen that delivers 1 mg per injection (3) Injection: 8 mg/3 mL (2.68 mg/mL) available in: • Single-patient-use pen that delivers 2 mg per injection (3) ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Personal or family history of MTC or in patients with MEN 2(4). • Serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC (4). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2). • Diabetic Retinopathy Complications: Has been reported in a clinical trial. Patients with a history of diabetic retinopathy should be monitored (5.3). • Never share an OZEMPIC pen between patients, even if the needle is changed (5.4). • Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary (5.5). • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions (5.6). • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue OZEMPIC if suspected and promptly seek medical advice (5.7). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.8). • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.9). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ The most common adverse reactions, reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS---------------------------------- Oral Medications: OZEMPIC delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution (7.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Females and Males of Reproductive Potential: Discontinue OZEMPIC in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide (8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5472319 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Recommended Dosage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Pancreatitis 5.3 Diabetic Retinopathy Complications 5.4 Never Share an OZEMPIC Pen Between Patients 5.5 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin 5.6 Acute Kidney Injury 5.7 Hypersensitivity Reactions 5.8 Acute Gallbladder Disease 5.9 Pulmonary Aspiration Duringi General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Monotherapy Use of OZEMPIC in Patients with Type 2 Diabetes Mellitus 14.3 Combination Therapy Use of OZEMPIC in Patients with Type 2 Diabetes Mellitus 14.4 Cardiovascular Outcomes Trial of OZEMPIC in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5472319 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)]. • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE OZEMPIC is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease. Limitations of Use • OZEMPIC has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. • OZEMPIC is not indicated for use in patients with type 1 diabetes mellitus. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Inspect OZEMPIC visually before use. It should appear clear and colorless. Do not use OZEMPIC if particulate matter and coloration is seen. • Administer OZEMPIC once weekly, on the same day each week, at any time of the day, with or without meals. • Inject OZEMPIC subcutaneously to the abdomen, thigh, or upper arm. Instruct patients to use a different injection site each week when injecting in the same body region. • When using OZEMPIC with insulin, instruct patients to administer as separate injections and to never mix the products. It is acceptable to inject OZEMPIC and insulin in the same body region, but the injections should not be adjacent to each other. 2.2 Recommended Dosage • Initiate OZEMPIC with a dosage of 0.25 mg injected subcutaneously once weekly for 4 weeks. The 0.25 mg dosage is intended for treatment initiation and is not effective for glycemic control. • After 4 weeks on the 0.25 mg dosage, increase the dosage to 0.5 mg once weekly. Reference ID: 5472319 • If additional glycemic control is needed after at least 4 weeks on the 0.5 mg dosage, the dosage may be increased to 1 mg once weekly. • If additional glycemic control is needed after at least 4 weeks on the 1 mg dosage, the dosage may be increased to 2 mg once weekly. The maximum recommended dosage is 2 mg once weekly. • The day of weekly administration can be changed if necessary as long as the time between two doses is at least 2 days (>48 hours). • If a dose is missed, administer OZEMPIC as soon as possible within 5 days after the missed dose. If more than 5 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. 3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless solution available in 3 pre-filled, disposable, single-patient-use pens: Dose per Injection Total Strength per Total Volume Strength per mL 0.25 mg 0.5 mg 2 mg / 3 mL 0.68 mg/mL 1 mg 4 mg / 3 mL 1.34 mg/mL 2 mg 8 mg / 3 mL 2.68 mg/mL The 2 mg/1.5 mL (1.34 mg/mL) strength is not currently marketed by Novo Nordisk Inc. 4 CONTRAINDICATIONS OZEMPIC is contraindicated in patients with: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions (5.1)]. • A serious hypersensitivity reaction to semaglutide or to any of the excipients in OZEMPIC. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with OZEMPIC [see Warnings and Precautions (5.7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including MTC, in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC. Such monitoring may increase the risk of unnecessary procedures, due Reference ID: 5472319 to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). One case of chronic pancreatitis was confirmed in an OZEMPIC-treated patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8 OZEMPIC-treated patients (0.27 cases per 100 patient years) and 10 placebo- treated patients (0.33 cases per 100 patient years), both on a background of standard of care. After initiation of OZEMPIC, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, OZEMPIC should be discontinued and appropriate management initiated; if confirmed, OZEMPIC should not be restarted. 5.3 Diabetic Retinopathy Complications In a 2-year trial involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with OZEMPIC (3.0%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (OZEMPIC 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (OZEMPIC 0.7%, placebo 0.4%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.4 Never Share an OZEMPIC Pen Between Patients OZEMPIC pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.5 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.6 Acute Kidney Injury There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of OZEMPIC in patients reporting severe adverse gastrointestinal reactions. 5.7 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with OZEMPIC. If hypersensitivity reactions occur, discontinue use of OZEMPIC; treat promptly per standard of Reference ID: 5472319 care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity to OZEMPIC [see Contraindications (4) and Adverse Reactions (6.3)]. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with OZEMPIC. 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in placebo- treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation OZEMPIC delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking OZEMPIC, including whether modifying preoperative fasting recommendations or temporarily discontinuing OZEMPIC could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking OZEMPIC. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Pancreatitis [see Warnings and Precautions (5.2)] • Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.5)] • Acute Kidney Injury [see Warnings and Precautions (5.6)] • Hypersensitivity Reactions [see Warnings and Precautions (5.7)] • Acute Gallbladder Disease [see Warnings and Precautions (5.8)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies (14)]. These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA1c of Reference ID: 5472319 8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 6.9% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies (14)] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA1c of 8.2%. At baseline, 7.8% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 2.5% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC. Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5.0 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5.0 3.1 In the pool of placebo- and active-controlled trials and in the 2-year cardiovascular outcomes trial, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. In a clinical trial with 959 patients treated with OZEMPIC 1 mg or OZEMPIC 2 mg once weekly as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%, OZEMPIC 1 mg 36.4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients receiving OZEMPIC 0.5 mg (3.1%) and OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%). In the trial with OZEMPIC 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC 2 mg (34.0%) vs OZEMPIC 1 mg (30.8%). In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5% were associated with OZEMPIC (frequencies listed, respectively, as: placebo; 0.5 mg; 1 mg): dyspepsia (1.9%, Reference ID: 5472319 3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulence (0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%, 1.9%, 1.5%), and gastritis (0.8%, 0.8%, 0.4%). Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of events related to hypoglycemia by various definitions in the placebo- controlled trials. Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Monotherapy (30 weeks) N=129 N=127 N=130 Severe† 0% 0% 0% Documented symptomatic (≤70 mg/dL glucose threshold) 0% 1.6% 3.8% Severe† or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 1.6% 0% 0% Add-on to Basal Insulin with or without Metformin (30 weeks) N=132 N=132 N=131 Severe† 0% 0% 1.5% Documented symptomatic (≤70 mg/dL glucose threshold) 15.2% 16.7% 29.8% Severe† or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 5.3% 8.3% 10.7% † “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea [see Warnings and Precautions (5.5) and Clinical Studies (14)]. Severe hypoglycemia occurred in 0.8% and 1.2% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was co-administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was co-administered with a sulfonylurea. Severe or blood glucose confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was co- administered with a sulfonylurea. Injection Site Reactions In placebo-controlled trials, injection site reactions (e.g., injection-site discomfort, erythema) were reported in 0.2% of OZEMPIC-treated patients. Increases in Amylase and Lipase In placebo-controlled trials, patients exposed to OZEMPIC had a mean increase from baseline in amylase of 13% and lipase of 22%. These changes were not observed in placebo-treated patients. Cholelithiasis Reference ID: 5472319 In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in placebo-treated patients. Increases in Heart Rate In placebo-controlled trials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute. There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients. Fatigue, Dysgeusia and Dizziness Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC include fatigue, dysgeusia and dizziness. 6.2 Immunogenicity Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with OZEMPIC may develop anti-semaglutide antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to semaglutide in the studies described below cannot be directly compared with the incidence of antibodies in other studies or to other products. Across the placebo- and active-controlled glycemic control trials, 32 (1.0%) OZEMPIC-treated patients developed anti-drug antibodies (ADAs) to the active ingredient in OZEMPIC (i.e., semaglutide). Of the 32 semaglutide-treated patients that developed semaglutide ADAs, 19 patients (0.6% of the overall population) developed antibodies cross-reacting with native GLP-1. The in vitro neutralizing activity of the antibodies is uncertain at this time. 6.3 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of OZEMPIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Ileus Hypersensitivity: anaphylaxis, angioedema, rash, urticaria. Hepatobiliary: cholecystitis, cholecystectomy Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5) and Adverse Reactions (6)]. 7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology Reference ID: 5472319 8 (12.3)]. Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited data with semaglutide use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to semaglutide during pregnancy. OZEMPIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal clinical exposure based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses or structural abnormalities were observed at clinical exposure (rabbit) and ≥2-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.06-, 0.2-, and 0.6-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure. In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.02-, 0.2-, and 1.2-fold the MRHD) were administered throughout organogenesis from Gestation Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures. In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (0.5-, 3-, and 8-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (≥3X human exposure). Reference ID: 5472319 In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (0.3-, 2-, and 4-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg twice weekly (≥2X human exposure). 8.2 Lactation Risk Summary There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats, however, due to species- specific differences in lactation physiology, the clinical relevance of these data are not clear (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OZEMPIC and any potential adverse effects on the breastfed infant from OZEMPIC or from the underlying maternal condition. Data In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in maternal plasma. 8.3 Females and Males of Reproductive Potential Discontinue OZEMPIC in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use Safety and efficacy of OZEMPIC have not been established in pediatric patients (younger than 18 years). 8.5 Geriatric Use In the pool of placebo- and active-controlled glycemic control trials, 744 (23.6%) OZEMPIC-treated patients were 65 years of age and over and 102 OZEMPIC-treated patients (3.2%) patients were 75 years of age and over. In SUSTAIN 6, the cardiovascular outcome trial, 788 (48.0%) OZEMPIC-treated patients were 65 years of age and over and 157 OZEMPIC-treated patients (9.6%) patients were 75 years of age and over. No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dose adjustment of OZEMPIC is recommended for patients with renal impairment. In subjects with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment of OZEMPIC is recommended for patients with hepatic impairment. In a study in subjects with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of OZEMPIC of approximately 1 week. Reference ID: 5472319 1 0 10 20 0 "& ~, JL-s,~%~~&~&&-~J--©L-,9;:! "A , \ 0 'yi~,~~'~"" ~•--CNH OH 30 37 OH 0 0 11 DESCRIPTION OZEMPIC (semaglutide) injection, for subcutaneous use, contains semaglutide, a human GLP-1 receptor agonist (or GLP-1 analog). The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. Structural formula: OZEMPIC is a sterile, aqueous, clear, colorless solution. Each 3 mL pre-filled single-patient use pen contains semaglutide 2 mg (0.68 mg/mL), 4 mg (1.34 mg/mL), or 8 mg (2.68 mg/mL). Each 1 mL of OZEMPIC solution also contains the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14.0 mg; phenol, 5.50 mg; and water for injections. OZEMPIC has a pH of approximately 7.4. Hydrochloric acid or sodium hydroxide may be added to adjust pH. The 2 mg/1.5 mL (1.34 mg/mL) strength is not currently marketed by Novo Nordisk Inc. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is Reference ID: 5472319 250 200 150 100 0 2 4 6 8 10 12 14 16 18 20 22 24 - -0--- - - -B- ---------- stimulated, and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. 12.2 Pharmacodynamics Semaglutide lowers fasting and postprandial blood glucose and reduces body weight. All pharmacodynamic evaluations were performed after 12 weeks of treatment (including dose escalation) at steady state with semaglutide 1 mg. Fasting and Postprandial Glucose Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes, treatment with semaglutide 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative reduction compared to placebo of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2-hour postprandial glucose, and 30 mg/dL (22%) for mean 24-hour glucose concentration (see Figure 1). Figure 1. Mean 24-hour plasma glucose profiles (standardized meals) in patients with type 2 diabetes before (baseline) and after 12 weeks of treatment with semaglutide or placebo Time since start of breakfast meal (hours) Plasma glucose (mg/dL) OZEMPIC - baseline (n=37) OZEMPIC 1 mg - end of treatment (n=36) Placebo - baseline (n=38) Placebo - end of treatment (n=37) Insulin Secretion Both first-and second-phase insulin secretion are increased in patients with type 2 diabetes treated with OZEMPIC compared with placebo. Glucagon Secretion Semaglutide lowers the fasting and postprandial glucagon concentrations. In patients with type 2 diabetes, treatment with semaglutide resulted in the following relative reductions in glucagon compared to placebo, fasting glucagon (8%), postprandial glucagon response (14-15%), and mean 24 hour glucagon concentration (12%). Glucose dependent insulin and glucagon secretion Semaglutide lowers high blood glucose concentrations by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner. With semaglutide, the insulin secretion rate in patients with type 2 diabetes was similar to that of healthy subjects (see Figure 2). Figure 2. Mean insulin secretion rate versus glucose concentration in patients with type 2 diabetes during graded glucose infusion before (baseline) and after 12 weeks of treatment with semaglutide or placebo and in untreated healthy subjects Reference ID: 5472319 14 12 10 8 6 4 2 OL.,-------------------------~ 90 100 110 120 130 140 150 160 170 180 190 200 210 ------ Plasma glucose (mg/dL) Insulin secretion rate (pmol/kg/min) OZEMPIC - baseline (n=37) OZEMPIC 1 mg - end of treatment (n=36) Placebo - baseline (n=38) Placebo - end of treatment (n=37) Healthy subjects (n=12) During induced hypoglycemia, semaglutide did not alter the counter regulatory responses of increased glucagon compared to placebo and did not impair the decrease of C-peptide in patients with type 2 diabetes. Gastric emptying Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially. Cardiac electrophysiology (QTc) The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. Semaglutide does not prolong QTc intervals at doses up to 1.5 mg at steady-state. 12.3 Pharmacokinetics Absorption Absolute bioavailability of semaglutide is 89%. Maximum concentration of semaglutide is reached 1 to 3 days post dose. Similar exposure is achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm. In patients with type 2 diabetes, semaglutide exposure increases in a dose-proportional manner for once-weekly doses of 0.5 mg, 1 mg and 2 mg. Steady-state exposure is achieved following 4-5 weeks of once-weekly administration. In patients with type 2 diabetes, the mean population-PK estimated steady-state concentrations following once weekly subcutaneous administration of 0.5 mg and 1 mg semaglutide were approximately 65.0 ng/mL and 123.0 ng/mL, respectively. In the trial comparing semaglutide 1 mg and 2 mg, the mean steady state concentrations were 111.1 ng/mL and 222.1 ng/mL, respectively. Distribution The mean apparent volume of distribution of semaglutide following subcutaneous administration in patients with type 2 diabetes is approximately 12.5L. Semaglutide is extensively bound to plasma albumin (>99%). Elimination The apparent clearance of semaglutide in patients with type 2 diabetes is approximately 0.05 L/h. With an elimination half-life of approximately 1 week, semaglutide will be present in the circulation for about 5 weeks after the last dose. Metabolism Reference ID: 5472319 1--+-i 0.5 2 The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain. Excretion The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the dose is excreted in the urine as intact semaglutide. Specific Populations Based on a population pharmacokinetic analysis, age, sex, race, and ethnicity, and renal impairment do not have a clinically meaningful effect on the pharmacokinetics of semaglutide. The exposure of semaglutide decreases with an increase in body weight. However, semaglutide doses of 0.5 mg and 1 mg provide adequate systemic exposure over the body weight range of 40-198 kg evaluated in the clinical trials. The effects of intrinsic factors on the pharmacokinetics of semaglutide are shown in Figure 3. Figure 3. Impact of intrinsic factors on semaglutide exposure Intrinsic factor Sex Male Relative exposure (Cavg) Ratio and 90% CI Age 65-74 years >74 years Body weight 55 kg 127 kg Race Black or African American Asian Ethnicity Hispanic or Latino Renal impairment Moderate Mild Severe Semaglutide exposure (Cavg) relative to reference subject profile: non-Hispanic/non-Latino, White, female below 65 years, body weight 85 kg, with normal renal function. Population PK model also included maintenance dose and injection site as covariates. Body weight test categories (55 and 127 kg) represent the 5% and 95% percentiles in the dataset. Abbreviations: Cavg: average semaglutide concentration. CI: Confidence interval. Patients with Renal impairment - Renal impairment does not impact the pharmacokinetics of semaglutide in a clinically relevant manner. This was shown in a study with a single dose of 0.5 mg semaglutide in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function. This was also shown for subjects with both type 2 diabetes and renal impairment based on data from clinical studies (Figure 3). Patients with Hepatic impairment - Hepatic impairment does not have any impact on the exposure of semaglutide. The pharmacokinetics of semaglutide were evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function in a study with a single-dose of 0.5 mg semaglutide. Pediatric Patients- Semaglutide has not been studied in pediatric patients. Drug Interaction Studies In vitro studies have shown very low potential for semaglutide to inhibit or induce CYP enzymes, and to inhibit drug transporters. Reference ID: 5472319 The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral medicinal products [see Drug Interactions (7.2)]. The potential effect of semaglutide on the absorption of co-administered oral medications was studied in trials at semaglutide 1 mg steady-state exposure. No clinically relevant drug-drug interaction with semaglutide (Figure 4) was observed based on the evaluated medications; therefore, no dose adjustment is required when co-administered with semaglutide. In a separate study, no apparent effect on the rate of gastric emptying was observed with semaglutide 2.4 mg. Figure 4. Impact of semaglutide on the exposure of co-administered oral medications Co-administered medication Metformin S-warfarin R-warfarin Digoxin Atorvastatin Ethinylestradiol Levonorgestrel AUC0-12h Cmax AUC0-168h Cmax AUC0-168h Cmax AUC0-120h Cmax AUC0-72h Cmax AUC0-24h Cmax AUC0-24h Cmax 0.5 1 2 Relative exposure Ratio and 90% CI Recommendation No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment Relative exposure in terms of AUC and Cmax for each medication when given with semaglutide compared to without semaglutide. Metformin and oral contraceptive drug (ethinylestradiol/levonorgestrel) were assessed at steady state. Warfarin (S-warfarin/R warfarin), digoxin and atorvastatin were assessed after a single dose. Abbreviations: AUC: area under the curve. Cmax: maximum concentration. CI: confidence interval. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day [2-, 11-, and 30 fold the maximum recommended human dose (MRHD) of 2 mg/week, based on AUC] were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (1-, 2-, and 7-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at clinically relevant exposures. In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.2-, 0.5-, and 3-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at ≥0.01 mg/kg/day, at clinically relevant exposures. Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)]. Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, rat bone marrow micronucleus). In a combined fertility and embryo-fetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.06-, 0.2-, and 0.6-fold the MRHD) were administered to male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length Reference ID: 5472319 was observed at all dose levels, together with a small reduction in numbers of corpora lutea at ≥0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies OZEMPIC has been studied as monotherapy and in combination with metformin, metformin and sulfonylureas, metformin and/or thiazolidinedione, and basal insulin in patients with type 2 diabetes mellitus. The efficacy of OZEMPIC was compared with placebo, sitagliptin, exenatide extended-release (ER), and insulin glargine. Most trials evaluated the use of OZEMPIC 0.5 mg, and 1 mg, with the exception of the trial comparing OZEMPIC and exenatide ER where only the 1 mg dose was studied. One trial evaluated the use of OZEMPIC 2 mg once weekly. In patients with type 2 diabetes mellitus, OZEMPIC produced clinically relevant reduction from baseline in HbA1c compared with placebo. The efficacy of OZEMPIC was not impacted by age, gender, race, ethnicity, BMI at baseline, body weight (kg) at baseline, diabetes duration and level of renal function impairment. 14.2 Monotherapy Use of OZEMPIC in Patients with Type 2 Diabetes Mellitus In a 30-week double-blind trial (NCT02054897), 388 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to OZEMPIC 0.5 mg or OZEMPIC 1 mg once weekly or placebo. Patients had a mean age of 54 years and 54% were men. The mean duration of type 2 diabetes was 4.2 years, and the mean BMI was 33 kg/m2. Overall, 64% were White, 8% were Black or African American, and 21% were Asian; 30% identified as Hispanic or Latino ethnicity. Monotherapy with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3). Table 3. Results at Week 30 in a Trial of OZEMPIC as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Intent-to-Treat (ITT) Population (N)a 129 128 130 HbA1c (%) Baseline (mean) 8.0 8.1 8.1 Change at week 30b -0.1 -1.4 -1.6 Difference from placebob [95% CI] -1.2 [-1.5, -0.9]c -1.4 [-1.7, -1.1]c Patients (%) achieving HbA1c <7% 28 73 70 FPG (mg/dL) Baseline (mean) 174 174 179 Change at week 30b -15 -41 -44 aThe intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA1c endpoint was missing for 10%, 7% and 7% of patients and during the trial rescue medication was initiated by 20%, 5% and 4% of patients randomized to Reference ID: 5472319 c placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. bIntent-to-treat analysis using ANCOVA adjusted for baseline value and country. p<0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.1 kg, 89.8 kg, 96.9 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.8 kg and -4.7 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.6 kg (-3.8, -1.5), and for OZEMPIC 1 mg was -3.5 kg (-4.8, -2.2). 14.3 Combination Therapy Use of OZEMPIC in Patients with Type 2 Diabetes Mellitus Combination with metformin and/or thiazolidinediones In a 56-week, double-blind trial (NCT01930188), 1231 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or sitagliptin 100 mg once daily, all in combination with metformin (94%) and/or thiazolidinediones (6%). Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes was 6.6 years, and the mean BMI was 32 kg/m2. Overall, 68% were White, 5% were Black or African American, and 25% were Asian; 17% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin (see Table 4 and Figure 5). Table 4. Results at Week 56 in a Trial of OZEMPIC Compared to Sitagliptin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin and/or Thiazolidinediones OZEMPIC 0.5 mg OZEMPIC 1 mg Sitagliptin Intent-to-Treat (ITT) Population (N)a 409 409 407 HbA1c (%) Baseline (mean) 8.0 8.0 8.2 Change at week 56b -1.3 -1.5 -0.7 Difference from sitagliptinb [95% CI] -0.6 [-0.7, -0.4]c -0.8 [-0.9, -0.6]c Patients (%) achieving HbA1c <7% 66 73 40 FPG (mg/dL) Baseline (mean) 168 167 173 Change at week 56b -35 -43 -23 aThe intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA1c endpoint was missing for 7%, 5% and 6% of patients and during the trial rescue medication was initiated by 5%, 2% and 19% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and sitagliptin, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. bIntent-to-treat analysis using ANCOVA adjusted for baseline value and country. p<0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.9 kg, 89.2 kg, 89.3 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The mean changes from baseline to week 56 were -4.2 kg, -5.5 kg, and -1.7 kg for the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The difference from sitagliptin (95% CI) for OZEMPIC 0.5 mg was -2.5 kg (-3.2, -1.8), and for OZEMPIC 1 mg was -3.8 kg (-4.5, -3.1). Reference ID: 5472319 c 8.5 ♦ ► 1--,- 0 4 8 12 16 23 30 40 56 56 (Ml) Figure 5. Mean HbA1c (%) over time - baseline to week 56 OZEMPIC 1 mg OZEMPIC 0.5 mg Sitagliptin HbA1c (%) Week post randomization Number of patients OZEMPIC 0.5 mg OZEMPIC 1 mg Sitagliptin 409 409 407 383 378 387 382 387 384 409 409 407 Observed mean HbA1c at scheduled visits and retrieved dropout multiple imputation (MI) based estimate at week 56 with standard error Combination with metformin or metformin with sulfonylurea In a 56-week, open-label trial (NCT01885208), 813 patients with type 2 diabetes mellitus on metformin alone (49%), metformin with sulfonylurea (45%), or other (6%) were randomized to OZEMPIC 1 mg once weekly or exenatide 2 mg once weekly. Patients had a mean age of 57 years and 55% were men. The mean duration of type 2 diabetes was 9 years, and the mean BMI was 34 kg/m2. Overall, 84% were White, 7% were Black or African American, and 2% were Asian; 24% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to exenatide 2 mg once weekly (see Table 5). Table 5. Results at Week 56 in a Trial of OZEMPIC Compared to Exenatide 2 mg Once Weekly in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea OZEMPIC 1 mg Exenatide ER 2 mg Intent-to-Treat (ITT) Population (N)a 404 405 HbA1c (%) Baseline (mean) 8.4 8.3 Change at week 56b -1.4 -0.9 Difference from exenatideb [95% CI] -0.5 [-0.7, -0.3]c Patients (%) achieving HbA1c <7% 62 40 FPG (mg/dL) Baseline (mean) 191 188 Change at week 56b -44 -34 aThe intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA1c endpoint was missing for 9% and 11% of patients and during the trial rescue medication was initiated by 5% and 10% of patients randomized to OZEMPIC 1 mg and exenatide ER 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. bIntent-to-treat analysis using ANCOVA adjusted for baseline value and country. p<0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 96.2 kg and 95.4 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The mean changes from baseline to week 56 were -4.8 kg and -2.0 kg in the OZEMPIC 1 mg and Reference ID: 5472319 c exenatide ER arms, respectively. The difference from exenatide ER (95% CI) for OZEMPIC 1 mg was -2.9 kg (-3.6, -2.1). Combination with metformin or metformin with sulfonylurea In a 30-week, open-label trial (NCT02128932), 1089 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or insulin glargine once daily on a background of metformin (48%) or metformin and sulfonylurea (51%). Patients had a mean age of 57 years and 53% were men. The mean duration of type 2 diabetes was 8.6 years, and the mean BMI was 33 kg/m2. Overall, 77% were White, 9% were Black or African American, and 11% were Asian; 20% identified as Hispanic or Latino ethnicity. Patients assigned to insulin glargine had a baseline mean HbA1c of 8.1% and were started on a dose of 10 U once daily. Insulin glargine dose adjustments occurred throughout the trial period based on self-measured fasting plasma glucose before breakfast, targeting 71 to <100 mg/dL. In addition, investigators could titrate insulin glargine at their discretion between study visits. Only 26% of patients had been titrated to goal by the primary endpoint at week 30, at which time the mean daily insulin dose was 29 U per day. Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with the insulin glargine titration implemented in this study protocol (see Table 6). Table 6. Results at Week 30 in a Trial of OZEMPIC Compared to Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea OZEMPIC 0.5 mg OZEMPIC 1 mg Insulin Glargine Intent-to-Treat (ITT) Population (N)a 362 360 360 HbA1c (%) Baseline (mean) 8.1 8.2 8.1 Change at week 30b -1.2 -1.5 -0.9 Difference from insulin glargineb [95% CI] -0.3 [-0.5, -0.1]c -0.6 [-0.8, -0.4]c Patients (%) achieving HbA1c <7% 55 66 40 FPG (mg/dL) Baseline (mean) 172 179 174 Change at week 30b -35 -46 -37 aThe intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA1c endpoint was missing for 8%, 6% and 6% of patients and during the trial rescue medication was initiated by 4%, 3% and 1% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and insulin glargine, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. bIntent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors. cp<0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 93.7 kg, 94.0 kg, 92.6 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The mean changes from baseline to week 30 were -3.2 kg, -4.7 kg and 0.9 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The difference from insulin glargine (95% CI) for OZEMPIC 0.5 mg was -4.1 kg (-4.9, -3.3) and for OZEMPIC 1 mg was -5.6 kg (-6.4, -4.8). Combination with metformin or metformin with sulfonylurea In a 40-week, double-blind trial (NCT03989232), 961 patients with type 2 diabetes currently treated with metformin with or without sulfonylurea treatment were randomized to OZEMPIC 2 mg or OZEMPIC 1 mg once weekly. Patients had a mean age of 58.0 years and 58.6% were men. The mean duration of type 2 diabetes Reference ID: 5472319 was 9.5 years and the mean BMI was 34.6 kg/m2 . At randomization, 53.3% of patients were treated with sulfonylurea and metformin. Overall, 88.1% were White, 4.5% were Black or African American, and 7.2% were Asian; 11.6% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 2 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with OZEMPIC 1 mg (see Table 7). Patients were stratified by region (Japan/outside Japan) at randomization. Table 7. Results at Week 40 in a Trial of OZEMPIC 2 mg Compared to OZEMPIC 1 mg in Adult Patients with Type 2 Diabetes Mellitus in Combination With Metformin or Metformin with Sulfonylurea OZEMPIC 1 mg OZEMPIC 2 mg Intent-to-Treat (ITT) Population (N)a 481 480 HbA1c (%) Baseline (mean) 8.8 8.9 Change at week 40b -1.9 -2.1 Difference from OZEMPIC 1 mg [95% CI] -0.2 [-0.31 ; -0.04]c Patients (%) achieving HbA1c <7%a 56 64 FPG (mg/dL) Baseline (mean) 196 193 Change at week 40b -55 -59 a The intent-to-treat population includes all randomized subjects. At week 40 the primary HbA1c endpoint was missing for 3% and 5% of patients randomized to OZEMPIC 1 mg and OZEMPIC 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. For calculation of proportions, imputed values are dichotomized and the denominator is the number of all randomized subjects. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and stratification factor. c p<0.01 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 98.6 kg and 100.1 kg in the OZEMPIC 1 mg and OZEMPIC 2 mg arms, respectively. The mean changes from baseline to week 40 were -5.6 kg and -6.4 kg in the OZEMPIC 1 mg and OZEMPIC 2 mg arms, respectively. The difference between treatment arms in body weight change from baseline at week 40 was not statistically significant. Combination with basal insulin In a 30-week, double-blind trial (NCT02305381), 397 patients with type 2 diabetes mellitus inadequately controlled with basal insulin, with or without metformin, were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or placebo. Patients with HbA1c ≤ 8.0% at screening reduced their insulin dose by 20% at start of the trial to reduce the risk of hypoglycemia. Patients had a mean age of 59 years and 56% were men. The mean duration of type 2 diabetes was 13 years, and the mean BMI was 32 kg/m2. Overall, 78% were White, 5% were Black or African American, and 17% were Asian; 12% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC resulted in a statistically significant reduction in HbA1c after 30 weeks of treatment compared to placebo (see Table 8). Table 8. Results at Week 30 in a Trial of OZEMPIC in Adult Patients with Type 2 Diabetes Mellitus in Combination with Basal Insulin with or without Metformin Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Intent-to-Treat (ITT) Population (N)a 133 132 131 HbA1c (%) Baseline (mean) 8.4 8.4 8.3 Change at week 30b -0.2 -1.3 -1.7 Difference from placebob -1.1 -1.6 Reference ID: 5472319 c [95% CI] [-1.4, -0.8]c [-1.8, -1.3]c Patients (%) achieving HbA1c <7% 13 56 73 FPG (mg/dL) Baseline (mean) 154 161 153 Change at week 30b -8 -28 -39 aThe intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA1c endpoint was missing for 7%, 5% and 5% of patients and during the trial rescue medication was initiated by 14%, 2% and 1% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. bIntent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors. p<0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.9 kg, 92.7 kg, and 92.5 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.5 kg, and -6.0 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.2 kg (-3.4, -1.1), and for OZEMPIC 1 mg was -4.7 kg (-5.8, -3.6). 14.4 Cardiovascular Outcomes Trial of OZEMPIC in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease SUSTAIN 6 (NCT01720446) was a multi-center, multi-national, placebo-controlled, double-blind cardiovascular outcomes trial. In this trial, 3,297 patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to OZEMPIC (0.5 mg or 1 mg) once weekly or placebo for a minimum observation time of 2 years. The trial compared the risk of Major Adverse Cardiovascular Event (MACE) between semaglutide and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Patients eligible to enter the trial were; 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for cardiovascular disease. In total, 1,940 patients (58.8%) had established cardiovascular disease without chronic kidney disease, 353 (10.7%) had chronic kidney disease only, and 442 (13.4%) had both cardiovascular disease and kidney disease; 562 patients (17%) had cardiovascular risk factors without established cardiovascular disease or chronic kidney disease. In the trial 453 patients (13.7%) had peripheral artery disease. The mean age at baseline was 65 years, and 61% were men. The mean duration of diabetes was 13.9 years, and mean BMI was 33 kg/m2 . Overall, 83% were White, 7% were Black or African American, and 8% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (24%), hypertension (93%), history of ischemic stroke (12%) and history of a myocardial infarction (33%). In total, 98.0% of the patients completed the trial and the vital status was known at the end of the trial for 99.6%. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of OZEMPIC to placebo for time to first MACE using a risk margin of 1.3. The statistical analysis plan pre specified that the 0.5 mg and 1 mg doses would be combined. Type-1 error was controlled across multiple tests using a hierarchical testing strategy. OZEMPIC significantly reduced the occurrence of MACE. The estimated hazard ratio for time to first MACE was 0.74 (95% CI: 0.58, 0.95). Refer to Figure 6 and Table 9. Reference ID: 5472319 10 8 6 0 1648 1649 8 16 1619 1616 24 32 1601 1586 40 48 1584 1567 r f 1 56 ---' ,, ,.. 64 72 1568 1534 ..,, ..,. 80 1543 1508 _,, .,,. _, 88 ,r _; ,,. 96 104109 1524 1479 1505 1460 Figure 6. Kaplan-Meier: Time to First Occurrence of a MACE in the SUSTAIN 6 Trial Placebo Patients with Event (%) OZEMPIC HR: 0.74 95% CI [0.58 - 0.95] Time from Randomization (Weeks) Patients at risk OZEMPIC Placebo The treatment effect for the primary composite endpoint and its components in the SUSTAIN 6 trial is shown in Table 9. Table 9. Treatment Effect for MACE and its Components, Median Study Observation Time of 2.1 Years Placebo N=1649 (%) OZEMPIC N=1648 (%) Hazard ratio vs Placebo (95% CI)a Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) 146 (8.9) 108 (6.6) 0.74 (0.58, 0.95) Non-fatal Myocardial Infarction 64 (3.9) 47 (2.9) 0.74 (0.51, 1.08) Non-fatal Stroke 44 (2.7) 27 (1.6) 0.61 (0.38, 0.99) Cardiovascular Death 46 (2.8) 44 (2.7) 0.98 (0.65, 1.48) Fatal or Non-fatal Myocardial Infarction 67 (4.1) 54 (3.3) 0.81 (0.57, 1.16) Fatal or Non-fatal Stroke 46 (2.8) 30 (1.8) 0.65 (0.41, 1.03) a Cox-proportional hazards models with treatment as factor and stratified by evidence of cardiovascular disease, insulin treatment and renal impairment. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Injection: clear, colorless solution of 0.68 mg/mL, 1.34 mg/mL or 2.68 mg/mL of semaglutide available in pre filled, disposable, single-patient-use pens in the following packaging configurations: Dose per Injection Use For Total Strength per Total Volume Doses per Pen Carton Contents NDC 0.25 mg Initiation 2 mg / 3 mL 4 doses of 0.25 mg and 2 doses of 0.5 mg or 1 pen 6 NovoFine® Plus needles 0169-4181-13 Reference ID: 5472319 0.5 mg Maintenance 4 doses of 0.5 mg 1 mg Maintenance 4 mg / 3 mL 4 doses of 1 mg 1 pen 4 NovoFine® Plus needles 0169-4130-13 2 mg Maintenance 8 mg / 3 mL 4 doses of 2 mg 1 pen 4 NovoFine® Plus needles 0169-4772-12 The 2 mg/1.5 mL (1.34 mg/mL) strength (NDC 0169-4132-12) is not currently marketed by Novo Nordisk Inc. Each OZEMPIC pen is for use by a single patient. An OZEMPIC pen must never be shared between patients, even if the needle is changed [see Warnings and Precautions (5.4)]. Recommended Storage Prior to first use, OZEMPIC should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) (Table 10). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze OZEMPIC and do not use OZEMPIC if it has been frozen. After first use of the OZEMPIC pen, the pen can be stored for 56 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Do not freeze. Keep the pen cap on when not in use. OZEMPIC should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the OZEMPIC pen without an injection needle attached. Always use a new needle for each injection. The storage conditions are summarized in Table 10: Table 10. Recommended Storage Conditions for the OZEMPIC Pen Prior to first use After first use Refrigerated 36°F to 46°F (2°C to 8°C) Room Temperature 59°F to 86°F (15°C to 30°C) Refrigerated 36°F to 46°F (2°C to 8°C) Until expiration date 56 days 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Risk of Thyroid C-cell Tumors Inform patients that semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1)]. Pancreatitis Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue OZEMPIC promptly and contact their physician if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting) [see Warnings and Precautions (5.2)]. Diabetic Retinopathy Complications Inform patients to contact their physician if changes in vision are experienced during treatment with OZEMPIC [see Warnings and Precautions (5.3)]. Reference ID: 5472319 Never Share an OZEMPIC Pen Between Patients Advise patients that they must never share an OZEMPIC pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.4)]. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Inform patients that the risk of hypoglycemia is increased when OZEMPIC is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5)]. Acute Kidney Injury Advise patients treated with OZEMPIC of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if acute kidney injury occurs [see Warnings and Precautions (5.6)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of OZEMPIC. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking OZEMPIC and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.7)]. Acute Gallbladder Disease Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.8)]. Pulmonary Aspiration During General Anesthesia or Deep Sedation Inform patients that OZEMPIC may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking OZEMPIC [see Warnings and Precautions (5.9)]. Pregnancy Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1), (8.3)]. Missed doses Inform patients if a dose is missed, it should be administered as soon as possible within 5 days after the missed dose. If more than 5 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once weekly dosing schedule [see Dosage and Administration (2.2)]. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For information about OZEMPIC contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-888-693-6742 Reference ID: 5472319 ~ nO'\IO nor<lisk Version: 10 OZEMPIC® and NovoFine® are registered trademarks of Novo Nordisk A/S. PATENT INFORMATION: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk COVER PAGE INFORMATION OZEMPIC® (semaglutide) injection 2 mg/3 mL (0.68 mg/ml) Prefilled pen and 4 mg/3 mL (1.34 mg/mL) Prefilled pen and 8 mg/3 mL (2.68 mg/mL) Prefilled pen Reference ID: 5472319 Medication Guide OZEMPIC® (oh-ZEM-pick) (semaglutide) injection, for subcutaneous use Do not share your OZEMPIC pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. Read this Medication Guide before you start using OZEMPIC and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about OZEMPIC? OZEMPIC may cause serious side effects, including: • Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, OZEMPIC and medicines that work like OZEMPIC caused thyroid tumors, including thyroid cancer. It is not known if OZEMPIC will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people. • Do not use OZEMPIC if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is OZEMPIC? OZEMPIC is an injectable prescription medicine used: • along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes mellitus. • to reduce the risk of major cardiovascular events such as heart attack, stroke or death in adults with type 2 diabetes mellitus with known heart disease. It is not known if OZEMPIC can be used in people who have had pancreatitis. OZEMPIC is not for use in people with type 1 diabetes. It is not known if OZEMPIC is safe and effective for use in children under 18 years of age. Do not use OZEMPIC if: • you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). • you have had a serious allergic reaction to semaglutide or any of the ingredients in OZEMPIC. See the end of this Medication Guide for a complete list of ingredients in OZEMPIC. Symptoms of a serious allergic reaction include: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat Before using OZEMPIC, tell your healthcare provider if you have any other medical conditions, including if you: • have or have had problems with your pancreas or kidneys. • have a history of diabetic retinopathy. • are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). • are pregnant or plan to become pregnant. It is not known if OZEMPIC will harm your unborn baby. You should stop using OZEMPIC 2 months before you plan to become pregnant. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant. • are breastfeeding or plan to breastfeed. It is not known if OZEMPIC passes into your breast milk. You should talk with your healthcare provider about the best way to feed your baby while using OZEMPIC. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. OZEMPIC may affect the way some medicines work and some medicines may affect the way OZEMPIC works. Before using OZEMPIC, talk to your healthcare provider about low blood sugar and how to manage it. Tell your healthcare provider if you are taking other medicines to treat diabetes, including insulin or sulfonylureas. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use OZEMPIC? • Read the Instructions for Use that comes with OZEMPIC. • Use OZEMPIC exactly as your healthcare provider tells you to. Reference ID: 5472319 • Your healthcare provider should show you how to use OZEMPIC before you use it for the first time. • OZEMPIC is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Do not inject OZEMPIC into a muscle (intramuscularly) or vein (intravenously). • Use OZEMPIC 1 time each week, on the same day each week, at any time of the day. • You may change the day of the week you use OZEMPIC as long as your last dose was given 2 or more days before. • If you miss a dose of OZEMPIC, take the missed dose as soon as possible within 5 days after the missed dose. If more than 5 days have passed, skip the missed dose and take your next dose on the regularly scheduled day. • OZEMPIC may be taken with or without food. • Do not mix insulin and OZEMPIC together in the same injection. • You may give an injection of OZEMPIC and insulin in the same body area (such as your stomach area), but not right next to each other. • Change (rotate) your injection site with each injection. Do not use the same site for each injection. • Check your blood sugar as your healthcare provider tells you to. • Stay on your prescribed diet and exercise program while using OZEMPIC. • Talk to your healthcare provider about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes. • Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. • Do not share your OZEMPIC pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. Your dose of OZEMPIC and other diabetes medicines may need to change because of: • change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, fever, trauma, infection, surgery or because of other medicines you take. • If you take too much OZEMPIC, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of OZEMPIC? OZEMPIC may cause serious side effects, including: • See “What is the most important information I should know about OZEMPIC?” • inflammation of your pancreas (pancreatitis). Stop using OZEMPIC and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. • changes in vision. Tell your healthcare provider if you have changes in vision during treatment with OZEMPIC. • low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use OZEMPIC with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: o dizziness or light-headedness o blurred vision o anxiety, irritability, or mood changes o sweating o slurred speech o hunger o confusion or drowsiness o shakiness o weakness o headache o fast heartbeat o feeling jittery • kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration. • serious allergic reactions. Stop using OZEMPIC and get medical help right away, if you have any symptoms of a serious allergic reaction including: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat • gallbladder problems. Gallbladder problems have happened in some people who take OZEMPIC. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include: opain in your upper stomach (abdomen) o yellowing of skin or eyes (jaundice) ofever o clay-colored stools Reference ID: 5472319 • food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). OZEMPIC may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking OZEMPIC before you are scheduled to have surgery or other procedures. The most common side effects of OZEMPIC may include nausea, vomiting, diarrhea, stomach (abdominal) pain, and constipation. Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of OZEMPIC. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of OZEMPIC. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use OZEMPIC for a condition for which it was not prescribed. Do not give OZEMPIC to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about OZEMPIC that is written for health professionals. For more information, go to OZEMPIC.com or call 1-888-693-6742. What are the ingredients in OZEMPIC? Active Ingredient: semaglutide Inactive Ingredients: disodium phosphate dihydrate, propylene glycol, phenol and water for injection Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark OZEMPIC® is a registered trademark of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5472319 -- ,-- - 0 I ,, -· INSTRUCTIONS FOR USE OZEMPIC® [oh-ZEM-pick] (semaglutide) injection, for subcutaneous use 0.25 mg or 0.5 mg doses (pen delivers doses in 0.25 mg or 0.5 mg increments only) • Read these instructions carefully before using your OZEMPIC® pen. • Do not use your pen without proper training from your healthcare provider. Make sure that you know how to give yourself an injection with the pen before you start your treatment. • Do not share your OZEMPIC pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use this pen without help. Get help from a person with good eyesight who is trained to use the OZEMPIC pen. • Start by checking your pen to make sure that it contains OZEMPIC, then look at the pictures below to get to know the different parts of your pen and needle. • Your pen is a prefilled, single-patient-use, dial-a dose pen. It contains 2 mg of semaglutide, and you can select doses of 0.25 mg or 0.5 mg. Each prefilled pen contains 4 doses of 0.25 mg and 2 doses of 0.5 mg or contains 4 doses of 0.5 mg. • Your pen is made to be used with NovoFine® Plus or NovoFine® disposable needles up to a length of 8 mm. • NovoFine® Plus 32G 4 mm disposable needles are included with your OZEMPIC pen. • Always use a new needle for each injection. Supplies you will need to give your OZEMPIC injection: • OZEMPIC pen • a new NovoFine Plus or NovoFine needle • 1 alcohol swab • 1 gauze pad or cotton ball • 1 sharps disposal container for throwing away used OZEMPIC pens and needles. See “Disposing of used OZEMPIC pens and needles” at the end of these instructions. OZEMPIC® pen and NovoFine® Plus needle (example) Pen cap Outer needle cap Inner needle cap Needle Paper tab Pen window Expiration date (EXP) on back of pen label Dose counter Dose pointer Dose selector Dose button Flow check symbol Dashed line (used to guide to your dose) (semaglutide) injection Reference ID: 5472319 Step 1. Prepare your pen with a new needle • Wash your hands with soap and water. • Check the name and colored label of your pen, to make sure that it contains OZEMPIC. This is especially important if you take more than 1 type of medicine. • Pull off the pen cap. A • Check that the OZEMPIC medicine in your pen is clear and colorless. Look through the pen window. If OZEMPIC looks cloudy or contains particles, do not use the pen. B • Take a new needle, and tear off the paper tab. Do not attach a new needle to your pen until you are ready to give your injection. C • Push the needle straight onto the pen. Turn until it is on tight. D • The needle is covered by 2 caps. You must remove both caps. If you forget to remove both caps, you will not inject any medicine. • Pull off the outer needle cap. Do not throw it away. E • Pull off the inner needle cap and throw it away. A drop of OZEMPIC may appear at the needle tip. This is normal, but you must still check the OZEMPIC flow if you use a new pen for the first time. F • A Always use a new needle for each injection. This will reduce the risk of contamination, infection, leakage of OZEMPIC, and blocked needles leading to the wrong dose. Do not reuse or share your needles with other people. You may give other people a serious infection, or get a serious infection from them. Never use a bent or damaged needle. Reference ID: 5472319 Step 2. First Time Use for Each New Pen: Check the OZEMPIC flow • Check the OZEMPIC flow before the first injection with each new pen only. If your OZEMPIC pen is already in use, go to Step 3 “Select your dose”. • Turn the dose selector until the dose counter shows the flow check symbol ( ). G Flow check symbol selected • Hold the pen with the needle pointing up. Press and hold in the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. A drop of OZEMPIC will appear at the needle tip. • If no drop appears, repeat Step 2 above as shown in Figure G and Figure H up to 6 times. If there is still no drop, change the needle and repeat Step 2 as shown in Figure G and Figure H 1 more time. Do not use the pen if a drop of OZEMPIC still does not appear. Contact Novo Nordisk at 1-888-693-6742. H < ! ) Always make sure that a drop appears at the needle tip before you use a new pen for the first time. This makes sure that OZEMPIC flows. If no drop appears, you will not inject any OZEMPIC, even though the dose counter may move. This may mean that there is a blocked or damaged needle. A small drop may remain at the needle tip, but it will not be injected. Only check the OZEMPIC flow before your first injection with each new pen. Step 3. Select your dose • Turn the dose selector until the dose counter stops and shows your dose (0.25 mg or 0.5 mg). The dashed line in the dose counter will guide you to your dose. Make sure you know the dose of OZEMPIC you should use. If you select the wrong dose, you can turn the dose selector forward or backwards to the correct dose. Reference ID: 5472319 r---~ Dos~ counter stopped: 0.25 mg left Always use the dose counter and the dose pointer to see how many mg you select. You will hear a “click” every time you turn the dose selector. Do not set the dose by counting the number of clicks you hear. Only doses of 0.25 mg or 0.5 mg can be selected with the dose selector. The selected dose must line up exactly with the dose pointer to make sure that you get a correct dose. The dose selector changes the dose. Only the dose counter and dose pointer will show how many mg you select for each dose. You can select 0.25 mg or 0.5 mg for each dose. When your pen contains less than 0.5 or 0.25 mg, the dose counter stops before 0.5 mg or 0.25 mg is shown. The dose selector clicks differently when turned forward or backward. Do not count the pen clicks. How much OZEMPIC is left? • To see how much OZEMPIC is left in your pen, use the dose counter: Turn the dose selector until the dose counter stops. • If it shows 0.5, at least 0.5 mg is left in your pen. If the dose counter stops before 0.5 mg, there is not enough OZEMPIC left for a full dose of 0.5 mg. • If it shows 0.25, at least 0.25 mg is left in your pen. If the dose counter stops before 0.25 mg, there is not enough OZEMPIC left for a full dose of 0.25 mg. If there is not enough OZEMPIC left in your pen for a full dose, do not use it. Use a new OZEMPIC pen. Step 4. Inject your dose • Choose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure K). K • Insert the needle into your skin as your healthcare provider has shown you. • Make sure you can see the dose counter. Do not cover it with your fingers. This could stop the injection. L • Press and hold down the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. You may then hear or feel a click. Continue pressing the dose button while keeping the needle in your skin. M Reference ID: 5472319 • Count 6 seconds while keeping the dose button pressed. • If the needle is removed earlier, you may see a stream of OZEMPIC coming from the needle tip. If this happens, the full dose will not be delivered. N Count slowly: 1-2-3-4-5-6 • Remove the needle from your skin. You can then release the dose button. If blood appears at the injection site, press lightly with a gauze pad or cotton ball. Do not rub the area. O Always watch the dose counter to make sure you have injected your complete dose. Hold the dose button down until the dose counter shows 0. How to identify a blocked or damaged needle? • If 0 does not appear in the dose counter after continuously pressing the dose button, you may have used a blocked or damaged needle. • If this happens you have not received any OZEMPIC even though the dose counter has moved from the original dose that you have set. How to handle a blocked needle? Change the needle as described in Step 5, and repeat all steps starting with Step 1: “Prepare your pen with a new needle”. Never touch the dose counter when you inject. This can stop the injection. You may see a drop of OZEMPIC at the needle tip after injecting. This is normal and does not affect your dose. Step 5. After your injection • Carefully remove the needle from the pen. Do not put the needle caps back on the needle to avoid needle sticks. P • • Place the needle in a sharps disposal container right away to reduce the risk of needle sticks. See “Disposing of used OZEMPIC pens and needles” below for more information about how to dispose of used pens and needles the right way. Q Reference ID: 5472319 • Put the pen cap on your pen after each use to protect OZEMPIC from light. R • If you do not have a sharps disposal container, follow a 1-handed needle recapping method. Carefully slip the needle into the outer needle cap. Dispose of the needle in a sharps disposal container as soon as possible. S Never try to put the inner needle cap back on the needle. You may stick yourself with the needle. Always remove the needle from your pen. This will reduce the risk of contamination, infection, leakage of OZEMPIC, and blocked needles leading to the wrong dose. If the needle is blocked, you will not inject any OZEMPIC. Always dispose of the needle after each injection. Disposing of used OZEMPIC pens and needles: • Put your used OZEMPIC pen and needle in a FDA-cleared sharps disposal container right away after use. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright and stable during use o leak-resistant o properly labeled to warn of hazardous waste inside the container • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. • Safely dispose of OZEMPIC that is out of date or no longer needed. Important • Caregivers must be very careful when handling used needles to prevent accidental needle stick injuries and prevent passing (transmission) of infection. • Never use a syringe to withdraw OZEMPIC from your pen. • Always carry an extra pen and new needles with you, in case of loss or damage. • Always keep your pen and needles out of reach of others, especially children. • Always keep your pen with you. Do not leave it in a car or other place where it can get too hot or too cold. Caring for your pen • Do not drop your pen or knock it against hard surfaces. If you drop it or suspect a problem, attach a new needle and check the OZEMPIC flow before you inject. • Do not try to repair your pen or pull it apart. Reference ID: 5472319 • Do not expose your pen to dust, dirt or liquid. • Do not wash, soak, or lubricate your pen. If necessary, clean it with mild detergent on a moistened cloth. How should I store my OZEMPIC pen? • Store your new, unused OZEMPIC pens in the refrigerator between 36°F to 46°F (2°C to 8°C). • Store your pen in use for 56 days at room temperature between 59ºF to 86ºF (15ºC to 30ºC) or in a refrigerator between 36°F to 46°F (2°C to 8°C). • The OZEMPIC pen you are using should be disposed of (thrown away) after 56 days, even if it still has OZEMPIC left in it. Write the disposal date on your calendar. • Do not freeze OZEMPIC. Do not use OZEMPIC if it has been frozen. • Unused OZEMPIC pens may be used until the expiration date (“EXP”) printed on the label, if kept in the refrigerator. • When stored in the refrigerator, do not store OZEMPIC pens directly next to the cooling element. • Keep OZEMPIC away from heat and out of the light. • Keep the pen cap on when not in use. • Keep OZEMPIC and all medicines out of the reach of children. For more information go to www.OZEMPIC.com Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For information about OZEMPIC contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-888-693-6742 Version: 2 OZEMPIC® and NovoFine® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html © 2023 Novo Nordisk This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: September/2023 Reference ID: 5472319 COVER PAGE INFORMATION OZEMPIC® (semaglutide) injection 2 mg/3 mL (0.68 mg/mL) Prefilled pen Pen delivers doses in 0.25 mg or 0.5 mg increments only Reference ID: 5472319 -- ,-- - 0 I ,, -· INSTRUCTIONS FOR USE OZEMPIC® [oh-ZEM-pick] (semaglutide) injection, for subcutaneous use 2 mg dose (pen delivers doses in 2 mg increments only) • Read these instructions carefully before using your OZEMPIC® pen. • Do not use your pen without proper training from your healthcare provider. Make sure that you know how to give yourself an injection with the pen before you start your treatment. • Do not share your OZEMPIC pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use this pen without help. Get help from a person with good eyesight who is trained to use the OZEMPIC pen. • Start by checking your pen to make sure that it contains OZEMPIC, then look at the pictures below to get to know the different parts of your pen and needle. • Your pen is a prefilled, single-patient-use, dial-a dose pen. It contains 8 mg of semaglutide, and you can only select doses of 2 mg. Each prefilled pen contains 4 doses of 2 mg. • Your pen is made to be used with NovoFine® Plus or NovoFine® disposable needles up to a length of 8 mm. • NovoFine® Plus 32G 4 mm disposable needles are included with your OZEMPIC pen. • Always use a new needle for each injection. Supplies you will need to give your OZEMPIC injection: • OZEMPIC pen 2 mg dose • a new NovoFine Plus or NovoFine needle • 1 alcohol swab • 1 gauze pad or cotton ball • 1 sharps disposal container for throwing away used OZEMPIC pens and needles. See “Disposing of used OZEMPIC pens and needles” at the end of these instructions. OZEMPIC® pen and NovoFine® Plus needle (example) Pen cap Outer needle cap Inner needle cap Needle Paper tab Pen window Expiration date (EXP) on back of pen label Dose counter Dose pointer Dose selector Dose button Flow check symbol Dashed line (used to guide to your dose) (semaglutide) injection Reference ID: 5472319 Step 1. Prepare your pen with a new needle • Wash your hands with soap and water. • Check the name and colored label of your pen, to make sure that it contains OZEMPIC. This is especially important if you take more than 1 type of medicine. • Pull off the pen cap. A • Check that the OZEMPIC medicine in your pen is clear and colorless. Look through the pen window. If OZEMPIC looks cloudy or contains particles, do not use the pen. B • Take a new needle, and tear off the paper tab. Do not attach a new needle to your pen until you are ready to give your injection. C • Push the needle straight onto the pen. Turn until it is on tight. D • A • The needle is covered by 2 caps. You must remove both caps. If you forget to remove both caps, you will not inject any medicine. • Pull off the outer needle cap. Do not throw it away. E • Pull off the inner needle cap and throw it away. A drop of OZEMPIC may appear at the needle tip. This is normal, but you must still check the OZEMPIC flow if you use a new pen for the first time. F Always use a new needle for each injection. This will reduce the risk of contamination, infection, leakage of OZEMPIC, and blocked needles leading to the wrong dose. Do not reuse or share your needles with other people. You may give other people a serious infection, or get a serious infection from them. Never use a bent or damaged needle. Reference ID: 5472319 Step 2. First Time Use for Each New Pen: Check the OZEMPIC flow • Check the OZEMPIC flow before the first injection with each new pen only. If your OZEMPIC pen is already in use, go to Step 3 “Select your dose”. • Turn the dose selector until the dose counter shows the flow check symbol ( ). G Flow check symbol selected • Hold the pen with the needle pointing up. Press and hold in the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. A drop of OZEMPIC will appear at the needle tip. • If no drop appears, repeat Step 2 above as shown in Figure G and Figure H up to 6 times. If there is still no drop, change the needle and repeat Step 2 as shown in Figure G and Figure H 1 more time. Do not use the pen if a drop of OZEMPIC still does not appear. Contact Novo Nordisk at 1-888-693-6742. H Always make sure that a drop appears at the needle tip before you use a new pen for the first time. This makes sure that OZEMPIC flows. If no drop appears, you will not inject any OZEMPIC, even though the dose counter may move. This may mean that there is a blocked or damaged needle. A small drop may remain at the needle tip, but it will not be injected. Only check the OZEMPIC flow before your first injection with each new pen. Step 3. Select your dose • Turn the dose selector until the dose counter stops and shows your 2 mg dose. The dashed line in the dose counter will guide you to 2 mg. I Dashed line 2 mg selected ( i ) Reference ID: 5472319 Always use the dose counter and the dose pointer to see that 2 mg has been selected. You will hear a “click” every time you turn the dose selector. Do not set the dose by counting the number of clicks you hear. Only doses of 2 mg can be selected with the dose selector. 2 mg must line up exactly with the dose pointer to make sure that you get a correct dose. The dose selector changes the dose. Only the dose counter and dose pointer will show that 2 mg has been selected. You can only select 2 mg for each dose. When your pen contains less than 2 mg, the dose counter stops before 2 mg is shown. The dose selector clicks differently when turned forward or backward. Do not count the pen clicks. How much OZEMPIC is left? • To see how much OZEMPIC is left in your pen, use the dose counter: Turn the dose selector until the dose counter stops. • If it shows 2, at least 2 mg is left in your pen. If the dose counter stops before 2 mg, there is not enough OZEMPIC left for a full dose of 2 mg. If there is not enough OZEMPIC left in your pen for a full dose, do not use it. Use a new OZEMPIC pen. J Dose counter stopped: 2 mg left Step 4. Inject your dose • Choose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure K). K • Insert the needle into your skin as your healthcare provider has shown you. • Make sure you can see the dose counter. Do not cover it with your fingers. This could stop the injection. L • Press and hold down the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. You may then hear or feel a click. Continue pressing the dose button while keeping the needle in your skin. M Reference ID: 5472319 • Count 6 seconds while keeping the dose button pressed. • If the needle is removed earlier, you may see a stream of OZEMPIC coming from the needle tip. If this happens, the full dose will not be delivered. N Count slowly: 1-2-3-4-5-6 • Remove the needle from your skin. You can then release the dose button. If blood appears at the injection site, press lightly with a gauze pad or cotton ball. Do not rub the area. O Always watch the dose counter to make sure you have injected your complete dose. Hold the dose button down until the dose counter shows 0. How to identify a blocked or damaged needle? • If 0 does not appear in the dose counter after continuously pressing the dose button, you may have used a blocked or damaged needle. • If this happens you have not received any OZEMPIC even though the dose counter has moved from the original dose that you have set. How to handle a blocked needle? Change the needle as described in Step 5, and repeat all steps starting with Step 1: “Prepare your pen with a new needle”. Never touch the dose counter when you inject. This can stop the injection. You may see a drop of OZEMPIC at the needle tip after injecting. This is normal and does not affect your dose. Step 5. After your injection • Carefully remove the needle from the pen. Do not put the needle caps back on the needle to avoid needle sticks. P ■ • Place the needle in a sharps disposal container right away to reduce the risk of needle sticks. See “Disposing of used OZEMPIC pens and needles” below for more information about how to dispose of used pens and needles the right way. Q Reference ID: 5472319 • Put the pen cap on your pen after each use to protect OZEMPIC from light. R • If you do not have a sharps disposal container, follow a 1-handed needle recapping method. Carefully slip the needle into the outer needle cap. Dispose of the needle in a sharps disposal container as soon as possible. S Never try to put the inner needle cap back on the needle. You may stick yourself with the needle. Always remove the needle from your pen. This will reduce the risk of contamination, infection, leakage of OZEMPIC, and blocked needles leading to the wrong dose. If the needle is blocked, you will not inject any OZEMPIC. Always dispose of the needle after each injection. Disposing of used OZEMPIC pens and needles: • Put your used OZEMPIC pen and needle in a FDA-cleared sharps disposal container right away after use. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright and stable during use o leak-resistant o properly labeled to warn of hazardous waste inside the container • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. • Safely dispose of OZEMPIC that is out of date or no longer needed. Important • Caregivers must be very careful when handling used needles to prevent accidental needle stick injuries and prevent passing (transmission) of infection. • Never use a syringe to withdraw OZEMPIC from your pen. • Always carry an extra pen and new needles with you, in case of loss or damage. • Always keep your pen and needles out of reach of others, especially children. • Always keep your pen with you. Do not leave it in a car or other place where it can get too hot or too cold. Caring for your pen • Do not drop your pen or knock it against hard surfaces. If you drop it or suspect a problem, attach a new needle and check the OZEMPIC flow before you inject. • Do not try to repair your pen or pull it apart. Reference ID: 5472319 • Do not expose your pen to dust, dirt or liquid. • Do not wash, soak, or lubricate your pen. If necessary, clean it with mild detergent on a moistened cloth. How should I store my OZEMPIC pen? • Store your new, unused OZEMPIC pens in the refrigerator between 36°F to 46°F (2°C to 8°C). • Store your pen in use for 56 days at room temperature between 59ºF to 86ºF (15ºC to 30ºC) or in a refrigerator between 36°F to 46°F (2°C to 8°C). • The OZEMPIC pen you are using should be disposed of (thrown away) after 56 days, even if it still has OZEMPIC left in it. Write the disposal date on your calendar. • Do not freeze OZEMPIC. Do not use OZEMPIC if it has been frozen. • Unused OZEMPIC pens may be used until the expiration date (“EXP”) printed on the label, if kept in the refrigerator. • When stored in the refrigerator, do not store OZEMPIC pens directly next to the cooling element. • Keep OZEMPIC away from heat and out of the light. • Keep the pen cap on when not in use. • Keep OZEMPIC and all medicines out of the reach of children. For more information go to www.OZEMPIC.com Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For information about OZEMPIC contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-888-693-6742 Version: 2 OZEMPIC® and NovoFine® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html © 2023 Novo Nordisk This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: September/2023 Reference ID: 5472319 COVER PAGE INFORMATION OZEMPIC® (semaglutide) injection 8 mg/3 mL (2.68 mg/mL) Prefilled pen Pen delivers doses in 2 mg increments only Reference ID: 5472319 -- ,-- - 0 I ,, -· INSTRUCTIONS FOR USE OZEMPIC® [oh-ZEM-pick] (semaglutide) injection, for subcutaneous use 1 mg dose (pen delivers doses in 1 mg increments only) • Read these instructions carefully before using your OZEMPIC® pen. • Do not use your pen without proper training from your healthcare provider. Make sure that you know how to give yourself an injection with the pen before you start your treatment. • Do not share your OZEMPIC pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use this pen without help. Get help from a person with good eyesight who is trained to use the OZEMPIC pen. • Start by checking your pen to make sure that it contains OZEMPIC, then look at the pictures below to get to know the different parts of your pen and needle. • Your pen is a prefilled, single-patient-use, dial-a dose pen. It contains 4 mg of semaglutide, and you can only select doses of 1 mg. Each prefilled pen contains 4 doses of 1 mg. • Your pen is made to be used with NovoFine® Plus or NovoFine® disposable needles up to a length of 8 mm. • NovoFine® Plus 32G 4 mm disposable needles are included with your OZEMPIC pen. • Always use a new needle for each injection. Supplies you will need to give your OZEMPIC injection: • OZEMPIC pen 1 mg dose • a new NovoFine Plus or NovoFine needle • 1 alcohol swab • 1 gauze pad or cotton ball • 1 sharps disposal container for throwing away used OZEMPIC pens and needles. See “Disposing of used OZEMPIC pens and needles” at the end of these instructions. OZEMPIC® pen and NovoFine® Plus needle (example) Pen cap Outer needle cap Inner needle cap Needle Paper tab Pen window Expiration date (EXP) on back of pen label Dose counter Dose pointer Dose selector Dose button Flow check symbol Dashed line (used to guide to your dose) (semaglutide) injection Reference ID: 5472319 Step 1. Prepare your pen with a new needle • Wash your hands with soap and water. • Check the name and colored label of your pen, to make sure that it contains OZEMPIC. This is especially important if you take more than 1 type of medicine. • Pull off the pen cap. A • Check that the OZEMPIC medicine in your pen is clear and colorless. Look through the pen window. If OZEMPIC looks cloudy or contains particles, do not use the pen. B • Take a new needle, and tear off the paper tab. Do not attach a new needle to your pen until you are ready to give your injection. C • Push the needle straight onto the pen. Turn until it is on tight. D • The needle is covered by 2 caps. You must remove both caps. If you forget to remove both caps, you will not inject any medicine. • Pull off the outer needle cap. Do not throw it away. E • Pull off the inner needle cap and throw it away. A drop of OZEMPIC may appear at the needle tip. This is normal, but you must still check the OZEMPIC flow if you use a new pen for the first time. F • A Always use a new needle for each injection. This will reduce the risk of contamination, infection, leakage of OZEMPIC, and blocked needles leading to the wrong dose. Do not reuse or share your needles with other people. You may give other people a serious infection, or get a serious infection from them. Never use a bent or damaged needle. Reference ID: 5472319 Step 2. First Time Use for Each New Pen: Check the OZEMPIC flow • Check the OZEMPIC flow before the first injection with each new pen only. If your OZEMPIC pen is already in use, go to Step 3 “Select your dose”. • Turn the dose selector until the dose counter shows the flow check symbol ( ). G Flow check symbol selected • Hold the pen with the needle pointing up. Press and hold in the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. A drop of OZEMPIC will appear at the needle tip. • If no drop appears, repeat Step 2 above as shown in Figure G and Figure H up to 6 times. If there is still no drop, change the needle and repeat Step 2 as shown in Figure G and Figure H 1 more time. Do not use the pen if a drop of OZEMPIC still does not appear. Contact Novo Nordisk at 1-888-693-6742. H < ! ) Dashed L---r line 1 mg selected Always make sure that a drop appears at the needle tip before you use a new pen for the first time. This makes sure that OZEMPIC flows. If no drop appears, you will not inject any OZEMPIC, even though the dose counter may move. This may mean that there is a blocked or damaged needle. A small drop may remain at the needle tip, but it will not be injected. Only check the OZEMPIC flow before your first injection with each new pen. Step 3. Select your dose • Turn the dose selector until the dose counter stops and shows your 1 mg dose. The dashed line in the dose counter will guide you to 1 mg. Reference ID: 5472319 Always use the dose counter and the dose pointer to see that 1 mg has been selected. You will hear a “click” every time you turn the dose selector. Do not set the dose by counting the number of clicks you hear. Only doses of 1 mg can be selected with the dose selector. 1 mg must line up exactly with the dose pointer to make sure that you get a correct dose. The dose selector changes the dose. Only the dose counter and dose pointer will show that 1 mg has been selected. You can only select 1 mg for each dose. When your pen contains less than 1 mg, the dose counter stops before 1 mg is shown. The dose selector clicks differently when turned forward or backward. Do not count the pen clicks. How much OZEMPIC is left? • To see how much OZEMPIC is left in your pen, use the dose counter: Turn the dose selector until the dose counter stops. • If it shows 1, at least 1 mg is left in your pen. If the dose counter stops before 1 mg, there is not enough OZEMPIC left for a full dose of 1 mg. If there is not enough OZEMPIC left in your pen for a full dose, do not use it. Use a new OZEMPIC pen. Step 4. Inject your dose • Choose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure K). K • Insert the needle into your skin as your healthcare provider has shown you. • Make sure you can see the dose counter. Do not cover it with your fingers. This could stop the injection. L • Press and hold down the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. You may then hear or feel a click. Continue pressing the dose button while keeping the needle in your skin. M Reference ID: 5472319 • Count 6 seconds while keeping the dose button pressed. • If the needle is removed earlier, you may see a stream of OZEMPIC coming from the needle tip. If this happens, the full dose will not be delivered. N Count slowly: 1-2-3-4-5-6 • Remove the needle from your skin. You can then release the dose button. If blood appears at the injection site, press lightly with a gauze pad or cotton ball. Do not rub the area. O Always watch the dose counter to make sure you have injected your complete dose. Hold the dose button down until the dose counter shows 0. How to identify a blocked or damaged needle? • If 0 does not appear in the dose counter after continuously pressing the dose button, you may have used a blocked or damaged needle. • If this happens you have not received any OZEMPIC even though the dose counter has moved from the original dose that you have set. How to handle a blocked needle? Change the needle as described in Step 5, and repeat all steps starting with Step 1: “Prepare your pen with a new needle”. Never touch the dose counter when you inject. This can stop the injection. You may see a drop of OZEMPIC at the needle tip after injecting. This is normal and does not affect your dose. Step 5. After your injection • Carefully remove the needle from the pen. Do not put the needle caps back on the needle to avoid needle sticks. P ■ ■ • Place the needle in a sharps disposal container right away to reduce the risk of needle sticks. See “Disposing of used OZEMPIC pens and needles” below for more information about how to dispose of used pens and needles the right way. Q Reference ID: 5472319 • Put the pen cap on your pen after each use to protect OZEMPIC from light. R • If you do not have a sharps disposal container, follow a 1-handed needle recapping method. Carefully slip the needle into the outer needle cap. Dispose of the needle in a sharps disposal container as soon as possible. S Never try to put the inner needle cap back on the needle. You may stick yourself with the needle. Always remove the needle from your pen. This will reduce the risk of contamination, infection, leakage of OZEMPIC, and blocked needles leading to the wrong dose. If the needle is blocked, you will not inject any OZEMPIC. Always dispose of the needle after each injection. Disposing of used OZEMPIC pens and needles: • Put your used OZEMPIC pen and needle in a FDA-cleared sharps disposal container right away after use. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright and stable during use o leak-resistant o properly labeled to warn of hazardous waste inside the container • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. • Safely dispose of OZEMPIC that is out of date or no longer needed. Important • Caregivers must be very careful when handling used needles to prevent accidental needle stick injuries and prevent passing (transmission) of infection. • Never use a syringe to withdraw OZEMPIC from your pen. • Always carry an extra pen and new needles with you, in case of loss or damage. • Always keep your pen and needles out of reach of others, especially children. • Always keep your pen with you. Do not leave it in a car or other place where it can get too hot or too cold. Caring for your pen • Do not drop your pen or knock it against hard surfaces. If you drop it or suspect a problem, attach a new needle and check the OZEMPIC flow before you inject. • Do not try to repair your pen or pull it apart. Reference ID: 5472319 • Do not expose your pen to dust, dirt or liquid. • Do not wash, soak, or lubricate your pen. If necessary, clean it with mild detergent on a moistened cloth. How should I store my OZEMPIC pen? • Store your new, unused OZEMPIC pens in the refrigerator between 36°F to 46°F (2°C to 8°C). • Store your pen in use for 56 days at room temperature between 59ºF to 86ºF (15ºC to 30ºC) or in a refrigerator between 36°F to 46°F (2°C to 8°C). • The OZEMPIC pen you are using should be disposed of (thrown away) after 56 days, even if it still has OZEMPIC left in it. Write the disposal date on your calendar. • Do not freeze OZEMPIC. Do not use OZEMPIC if it has been frozen. • Unused OZEMPIC pens may be used until the expiration date (“EXP”) printed on the label, if kept in the refrigerator. • When stored in the refrigerator, do not store OZEMPIC pens directly next to the cooling element. • Keep OZEMPIC away from heat and out of the light. • Keep the pen cap on when not in use. • Keep OZEMPIC and all medicines out of the reach of children. For more information go to www.OZEMPIC.com Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For information about OZEMPIC contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-888-693-6742 Version: 4 OZEMPIC® and NovoFine® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html © 2023 Novo Nordisk This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: September/2023 Reference ID: 5472319 COVER PAGE INFORMATION OZEMPIC® (semaglutide) injection 4 mg/3 mL (1.34 mg/mL) Prefilled pen Pen delivers doses in 1 mg increments only Reference ID: 5472319	custom-source	2025-02-12T15:46:31.412510	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/209637s032lbl.pdf', 'application_number': 209637, 'submission_type': 'SUPPL ', 'submission_number': 32}
80,146	_________________ ______________ _____________ ______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EMROSI safely and effectively. See full prescribing information for EMROSI. EMROSI (minocycline hydrochloride) extended-release capsules, for oral use Initial U.S. Approval: 1971 __________________INDICATIONS AND USAGE EMROSI is a tetracycline-class drug indicated to treat inflammatory lesions (papules and pustules) of rosacea in adults. (1) Limitations of Use This formulation of minocycline has not been evaluated in the treatment or prevention of infections. To reduce the development of drug-resistant bacteria and to maintain the effectiveness of other antibacterial drugs, use EMROSI only as indicated. (1) _______________DOSAGE AND ADMINISTRATION ______________ The recommended dosage of EMROSI is 40 mg orally, once daily. (2) DOSAGE FORMS AND STRENGTHS Extended-release capsules: 40 mg. (3) ___________________ CONTRAINDICATIONS ___________________ Known hypersensitivity to any of the tetracyclines. (4) _______________ WARNINGS AND PRECAUTIONS_______________ • Serious Skin/Hypersensitivity Reactions: Minocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Discontinue EMROSI immediately if symptoms occur. (5.1) • Tooth Discoloration and Enamel Hypoplasia: The use of EMROSI during tooth development (second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.2) • Inhibition of Bone Growth: Use during the second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years may cause reversible inhibition of bone growth. (5.3) • Clostridioides difficile-Associated Diarrhea (Antibiotic-Associated Colitis): Discontinue if Clostridioides difficile-associated diarrhea (antibiotic associated colitis) occurs. (5.4) • Hepatotoxicity: Discontinue EMROSI if liver injury is suspected. (5.5) • Central Nervous System Effects: May cause central nervous system side effects including light-headedness, dizziness, or vertigo. (5.6) • Idiopathic Intracranial Hypertension: May cause idiopathic intracranial hypertension in adults and adolescents. Discontinue EMROSI if symptoms occur. (5.7) • Autoimmune Syndromes: Minocycline has been associated with autoimmune syndromes; discontinue EMROSI immediately if symptoms occur. (5.8) • Metabolic Effects: If renal impairment exists, monitor serum levels of EMROSI during treatment, discontinue EMROSI if necessary. (5.9) ___________________ ADVERSE REACTIONS ___________________ The most commonly observed adverse reaction (incidence ≥1%) is dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Journey Medical Corporation at 1-855-531-1859 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ___________________ DRUG INTERACTIONS____________________ Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. (7.1) USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reaction and Serious Skin Reactions 5.2 Tooth Discoloration and Enamel Hypoplasia 5.3 Inhibition of Bone Growth 5.4 Clostridioides difficile-Associated Diarrhea (Antibiotic- Associated Colitis) 5.5 Hepatotoxicity 5.6 Central Nervous System Effects 5.7 Idiopathic Intracranial Hypertension 5.8 Autoimmune Syndromes 5.9 Metabolic Effects 5.10 Photosensitivity 5.11 Tissue Hyperpigmentation 5.12 Development of Drug-Resistant Bacteria 5.13 Superinfection 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Anticoagulants 7.2 Penicillin 7.3 Antacids and Iron Preparations 7.4 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not 6.2 Postmarketing Experience listed. 1 Reference ID: 5472966 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE EMROSI is indicated to treat inflammatory lesions (papules and pustules) of rosacea in adults. Limitations of Use • This formulation of minocycline has not been evaluated in the treatment or prevention of infections. • To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, use EMROSI only as indicated. 2 DOSAGE AND ADMINISTRATION The recommended dosage of EMROSI is one capsule taken orally, once daily. Higher doses have not shown to be of additional benefit in the treatment of rosacea. EMROSI may be taken with or without food [see Clinical Pharmacology (12.3)]. Ingestion of food along with EMROSI may help to reduce the risk of esophageal irritation and ulceration. Swallow the capsule whole. Do not crush or chew the extended-release capsule. 3 DOSAGE FORMS AND STRENGTHS Extended-release capsules: 40mg 4 CONTRAINDICATIONS EMROSI is contraindicated in patients with a history of hypersensitivity to any of the tetracyclines [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reaction and Serious Skin Reactions Cases of anaphylaxis, serious skin reactions (e.g., Stevens-Johnson syndrome), erythema multiforme, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported postmarketing with minocycline use in patients with acne. DRESS syndrome consists of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following visceral complications such as: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. Fever and lymphadenopathy may be present. In some cases, death has been reported. If this syndrome is recognized, discontinue EMROSI immediately. 5.2 Tooth Discoloration and Enamel Hypoplasia The use of tetracycline class drugs, including EMROSI during tooth development (second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Permanent discoloration of the teeth is more common during long-term use of tetracycline-class drugs but has been observed 2 Reference ID: 5472966 following repeated short-term courses. Enamel hypoplasia has also been reported. Use of EMROSI is not recommended during tooth development. Advise the patient of the potential risk to the fetus if EMROSI is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)]. 5.3 Inhibition of Bone Growth The use of tetracycline-class drugs, including EMROSI, during the second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines, including EMROSI, form a stable calcium complex in any bone- forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if EMROSI is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)]. 5.4 Clostridioides difficile-Associated Diarrhea (Antibiotic-Associated Colitis) Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including minocycline, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, discontinue EMROSI. 5.5 Hepatotoxicity Postmarketing cases of serious liver injury, including irreversible drug-induced hepatitis and fulminant hepatic failure (sometimes fatal) have been reported with minocycline use in the treatment of acne. Discontinue EMROSI if liver injury is suspected. 5.6 Central Nervous System Effects Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with minocycline therapy. Caution patients who experience these symptoms about driving vehicles or using hazardous machinery while on EMROSI. These symptoms may disappear during therapy and usually rapidly disappear when the drug is discontinued. 5.7 Idiopathic Intracranial Hypertension Idiopathic Intracranial hypertension has been associated with the use of tetracyclines. Clinical manifestations of idiopathic intracranial hypertension include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are 3 Reference ID: 5472966 overweight or have a history of idiopathic intracranial hypertension are at a greater risk for developing idiopathic intracranial hypertension. Avoid concomitant use of isotretinoin and EMROSI because isotretinoin, a systemic retinoid, is also known to cause idiopathic intracranial hypertension. Permanent visual loss may exist, even after the medication is discontinued. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Because intracranial pressure can remain elevated for weeks after drug cessation, monitor patients until they stabilize. 5.8 Autoimmune Syndromes Tetracyclines have been associated with the development of autoimmune syndromes. The long term use of minocycline in the treatment of acne has been associated with drug-induced lupus- like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness have presented shortly after minocycline use. Symptoms may be manifested by fever, rash, arthralgia, and malaise. Evaluate symptomatic patients. If symptoms occur, immediately discontinue EMROSI. 5.9 Metabolic Effects The anti-anabolic action of the tetracyclines, including EMROSI, may cause an increase in blood urea nitrogen (BUN). In patients with significantly impaired renal function, higher serum levels of EMROSI may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists monitor serum levels of EMROSI during treatment, discontinue EMROSI if necessary. 5.10 Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including minocycline. Advise patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using EMROSI. Instruct patients to use sunscreen products and wear protective apparel (e.g., hat) when exposure to sun cannot be avoided. 5.11 Tissue Hyperpigmentation Tetracycline-class antibiotics are known to cause hyperpigmentation. EMROSI may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been reported to occur independently of time or amount of drug administration, whereas other tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury. 5.12 Development of Drug-Resistant Bacteria Bacterial resistance to the tetracyclines may develop in patients using EMROSI, Because of the potential for drug-resistant bacteria to develop during the use of EMROSI, use EMROSI only as indicated. 4 Reference ID: 5472966 5.13 Superinfection Use of EMROSI may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue EMROSI and institute appropriate therapy. 5.14 Laboratory Monitoring Perform periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Skin/Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Clostridioides difficile-Associated Diarrhea (Antibiotic-Associated Colitis) [see Warnings and Precautions (5.4)] • Hepatotoxicity [see Warnings and Precautions (5.5)] • Central Nervous System Effects [see Warnings and Precautions (5.6)] • Idiopathic Intracranial Hypertension [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In two clinical trials, MVOR-1 and MVOR-2, a total of 638 adult subjects were analyzed under the safety population with 243 subjects in EMROSI group, 237 subjects in doxycycline (40 mg) group and 158 subjects in placebo group [see Clinical Studies (14)]. The most common adverse reaction reported by ≥1% of subjects treated with EMROSI and more frequently than in subjects receiving placebo was dyspepsia, which was reported in 2% of subjects treated with EMROSI and none of the subjects receiving placebo. 6.2 Postmarketing Experience The following adverse reactions have been reported with post-approval use of minocycline hydrochloride in a variety of indications. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and hypersensitivity reactions: anaphylaxis, angioedema, DRESS syndrome, erythema multiforme, Stevens-Johnson syndrome, acute febrile neutrophilic dermatosis (Sweet’s syndrome), fixed drug eruptions, balanitis, anaphylactoid purpura photosensitivity, pigmentation of skin and mucous membranes. Autoimmune conditions: polyarthralgia, pericarditis, exacerbation of systemic lupus, pulmonary infiltrates with eosinophilia, lupus-like syndrome. 5 Reference ID: 5472966 Central nervous system: idiopathic intracranial hypertension, bulging fontanels in infants, decreased hearing. Endocrine: brown-black microscopic thyroid discoloration, abnormal thyroid function. Oncology: thyroid cancer. Oral: glossitis, dysphagia, tooth discoloration. Gastrointestinal: enterocolitis, pancreatitis, hepatitis, liver failure. Renal: acute renal failure. Hematology: hemolytic anemia, thrombocytopenia, eosinophilia. 7 DRUG INTERACTIONS 7.1 Anticoagulants Because tetracyclines have been shown to decrease plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 7.2 Penicillin Because bacteriostatic drugs may interfere with the bactericidal action of penicillin, avoid giving EMROSI in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and iron-containing preparations. 7.4 Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Tetracycline-class drugs, including EMROSI, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.4)]. A few postmarketing cases of limb reductions have been reported over decades of use; however, the association is unclear. The limited data from postmarketing reports are not sufficient to inform a drug-associated risk for birth defects or miscarriage. In animal reproduction studies conducted in pregnant rats and rabbits, bent limb bones were observed following oral administration of minocycline hydrochloride during organogenesis at 6 Reference ID: 5472966 systemic exposure of approximately 7.1 and 4.8 times, respectively, the maximum recommended human dose (MRHD) based on AUC exposures (see Data). If the patient becomes pregnant while taking this drug, advise the patient of the risk to the fetus and discontinue treatment. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data The use of tetracycline class drugs, including EMROSI, during tooth development (second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of deciduous teeth (yellow-gray-brown). Permanent discoloration of the teeth is more common during long-term use of the drug but has been observed following repeated short-term courses [see Warnings and Precautions (5.2)]. Animal Data Results of animal studies indicate that minocycline hydrochloride crosses the placenta, are found in fetal tissues, and can cause delayed skeletal development in the developing fetus. Evidence of embryotoxicity has been noted in animals treated early in pregnancy [see Warnings and Precautions (5.3)]. Minocycline hydrochloride induced skeletal malformations (bent limb bones) in fetuses when administered to pregnant rats and rabbits during the period of organogenesis at doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (7.1 and 4.8 times, respectively, the MRHD based on AUC comparison). Reduced mean fetal body weight was observed in studies in which minocycline hydrochloride was administered to pregnant rats at an oral dose of 10 mg/kg/day (2.4 times the MRHD based on AUC comparison). Minocycline hydrochloride was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at doses of 5, 10, or 50 mg/kg/day. In this study, body weight gain was significantly reduced in pregnant females that received 50 mg/kg/day (6 times the MRHD based on AUC comparison). No effects of treatment on the duration of the gestation period or the number of live pups born per litter were observed. Gross external anomalies observed in offspring of animals that received minocycline hydrochloride at 50 mg/kg/day included reduced body size, improperly rotated forelimbs, and reduced size of extremities. No effects were observed on the physical development, behavior, learning ability, or reproduction of the offspring of animals that received minocycline hydrochloride. 8.2 Lactation Risk Summary Tetracycline-class antibiotics, including minocycline, are present in breast milk following oral administration. There are no data on the effects of minocycline on milk production. Because of the 7 Reference ID: 5472966 • HCI potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during EMROSI therapy and for 4 days after the final dose [see Warnings and Precautions (5.2, 5.3)]. 8.4 Pediatric Use The safety and effectiveness of EMROSI have not been established in pediatric patients. Tooth discoloration and inhibition of bone growth have been observed in pediatric patients with the use of tetracycline class antibiotics [see Warnings and Precaution (5.2, 5.3)]. 8.5 Geriatric Use Of the 653 subjects in the phase 3 clinical trials of EMROSI, 101 (15.5%) subjects were 65 years of age and older and 25 (3.8%) were 75 years of age and older. No overall differences in safety or effectiveness of EMROSI have been observed between subjects 65 years of age and older and younger adult subjects. 10 OVERDOSAGE Minocycline is not removed in significant quantities by hemodialysis or peritoneal dialysis. In case of overdosage, discontinue EMROSI, treat symptomatically and institute supportive measures. Call Poison Control Center at 1-800-222-1222 for the latest recommendations. 11 DESCRIPTION Minocycline hydrochloride, a semi synthetic derivative of tetracycline, is [4S (4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide mono hydrochloride. Its molecular formula is C23H27N3O7•HCl with a molecular weight of 493.95. Minocycline hydrochloride has the following structure: Minocycline hydrochloride is a yellow, hygroscopic, crystalline powder. It is sparingly soluble in water, slightly soluble in ethanol (96%). In 1% w/v solution in water has pH between 3.5 and 4.5. Each EMROSI extended-release capsule contains 40 mg of minocycline (equivalent to 43.19 mg of minocycline hydrochloride) as 10 mg immediate-release and 30 mg extended-release beads and the following inactive ingredients: ethyl cellulose, hypromellose, isopropyl alcohol, microcrystalline cellulose, Opadry clear, polyethylene glycol 400, triethyl citrate and talc. Opadry clear contains: hydroxypropyl cellulose and hypromellose. Capsule shell contains gelatin, iron oxide red and titanium dioxide. White ink contains ammonia, butyl alcohol, 8 Reference ID: 5472966 dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, titanium dioxide and shellac. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of EMROSI for the treatment of rosacea is unknown. 12.2 Pharmacodynamics The pharmacodynamics of EMROSI for the treatment of rosacea are unknown. 12.3 Pharmacokinetics EMROSI is not bioequivalent to any other minocycline products. The pharmacokinetics of minocycline following administration of EMROSI was investigated in two studies that enrolled 32 healthy, adult subjects. In Study 1, the plasma pharmacokinetic parameters for EMROSI following single dose administration under fasting and fed states are presented in Table 1. Table 1: Plasma Pharmacokinetic Parameters [Mean (%CV)] for EMROSI (40 mg) N Cmax (ng/mL) Tmax (hr) AUCinf (ng.hr/mL) t1/2 (hr) EMROSI (Fasting) 23 243.9 (37.3) 1.50 (1.00 – 4.17) 3933.6 (31.2) 14.67 (26.7) EMROSI (Fed) 23 225.0 (16.7) 4.50 (3.00 – 8.00) 4404.1 (21.0) 14.93 (21.5) Note: * Median (Range) In Study 2, minocycline plasma PK following EMROSI single (Day 1) and after repeated (Day 21) once daily administrations in eight (8) subjects were found to be similar with overlapping ranges. The mean Cmax was 382.83 ng/mL versus 337.74 ng/mL and AUC0-24 was 3549.64 nghr/mL versus 3957.62 nghr/mL, respectively on Day 1 versus Day 21. Absorption: In Study 1, the median plasma Tmax of minocycline from EMROSI was 1.50 hours (1.00 – 4.17). In Study 2, the median plasma Tmax values of minocycline from EMROSI on Day 1 and Day 21 were 1.75 and 1.5 hours, respectively. Effect of Food: Following administration of EMROSI with a high-fat meal (1011 Kcal, 53% fat), Tmax was delayed by approximately 3 hours. The high fat meal did not impact the Cmax however, the AUCinf was increased by 15.26% (Table 1) [see Dosage and Administration (2)]. Distribution: Minocycline is lipid soluble and distributes into the skin and sebum. In Study 1, the mean apparent volume of distribution (Vz/F) values of minocycline following oral administration of EMROSI at fasting and fed condition were 229.61 (±67.83) L and 199.83 (±43.71) L, respectively. Elimination: The mean apparent elimination half-life (t½) of minocycline from EMROSI was approximately 15 hours independent of fasting and fed dosing condition. 9 Reference ID: 5472966 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In an oral carcinogenicity study in rats in which minocycline hydrochloride was administered once daily for up to 104 weeks at doses up to 200 mg/kg/day, minocycline hydrochloride increased incidences of follicular cell tumors of the thyroid gland in both sexes, including adenomas, carcinomas, and the combined incidence of adenomas and carcinomas in males and adenomas and the combined incidence of adenomas and carcinomas in females. In an oral carcinogenicity study in mice in which minocycline hydrochloride was administered once daily for up to 104 weeks at doses up to 150 mg/kg/day, minocycline hydrochloride did not increase tumor incidence. Minocycline hydrochloride was not mutagenic in vitro in a bacterial reverse mutation assay (Ames test) or CHO/HGPRT mammalian cell assay in the presence or absence of metabolic activation. Minocycline hydrochloride was not clastogenic in vitro using human peripheral blood lymphocytes or in vivo in a mouse micronucleus test. Male and female reproductive performance in rats was unaffected by oral doses of minocycline hydrochloride up to 300 mg/kg/day (95 times the MRHD based on AUC comparison). However, doses of 100 mg/kg/day (36 times the MRHD based on AUC comparison) and higher to male rats adversely affected spermatogenesis. At 100 mg/kg/day, minocycline increased morphological abnormalities, including absent heads, misshapen heads, and abnormal flagella. At 300 mg/kg/day, minocycline also reduced the number of sperm cells per gram of epididymis and reduced the percentage of motile sperm. 14 CLINICAL STUDIES The safety and efficacy of EMROSI in the treatment of inflammatory lesions and erythema of rosacea was assessed in two 16-week, multi-center, randomized, double-blind, active- and placebo-controlled trials (MVOR-1 [NCT05296629] and MVOR-2 [NCT05343455]) in adults. In the two trials, a total of 653 subjects with papulopustular rosacea received EMROSI or doxycycline capsules 40 mg or placebo for up to 16 weeks. Subjects were required to have an inflammatory lesion count (papules and pustules) in the range 15-60 lesions and an Investigator’s Global Assessment (IGA) score of 3 (“moderate”) or 4 (“severe”) at baseline. The mean age of subjects was 49 years and subjects were from the following racial groups: White (93%), Asian (4%), Black or African American (2%), and Other (1%); for ethnicity, 38% of subjects identified as Hispanic or Latino. At baseline, subjects had a mean inflammatory lesion count of 25 (ranged 15 to 58), 88% were scored as moderate (IGA=3), and 12% were scored as severe (IGA=4). The co-primary efficacy endpoints were the proportion of subjects with IGA ‛treatment success’ at Week 16 (defined as an IGA score of 0 [“clear”] or 1 [“near clear”] with at least a 2-grade reduction from baseline) and the absolute change from baseline in total inflammatory lesion counts at Week 16, in the EMROSI group compared to the placebo group. The efficacy results are presented in Table 2. 10 Reference ID: 5472966 Table 2: Efficacy Results at Week 16 in Trials MVOR-1 and MVOR-2 Endpoint Trial MVOR-1 Trial MVOR-2 EMROSI (N=122) Doxycycline (N=121) Placebo (N=80) EMROSI (N=123) Doxycycline (N=125) Placebo (N=82) IGA Treatment Success1 65% 46% 31% 60% 31% 27% Difference from Placebo (95% CI) 33% (20%, 46%) 34% (21%, 47%) Difference from Doxycycline (95% CI) 18% (5%, 31%) 28% (17%, 39%) Inflammatory Lesion Counts Mean2 Absolute Change from Baseline -20.6 -15.6 -11.4 -18.1 -14.6 -11.2 Difference from Placebo (95% CI) -9.3 (-11.6, -6.9) -6.9 (-9.1, -4.6) Difference from Doxycycline (95% CI) -5.1 (-7.2, -2.9) -3.4 (-5.4, -1.5) Mean2 Percent Change from Baseline -79% -63% -47% -75% -60% -46% Difference from Placebo (95% CI) -33% (-41%, -24%) -30% (-39%, -20%) Difference from Doxycycline (95% CI) -16% (-24%, -8%) -15% (-23%, -7%) 1 Investigator’s Global Assessment (IGA) treatment success was defined as an IGA score of 0 or 1 with at least a 2-grade from baseline. 2 Means presented in table are Least Square (LS) means. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied EMROSI is an opaque, brownish-red colored, hard gelatin capsule, imprinted “MEC” on both cap and body with white ink. Bottles of 30 capsules with child-resistant closure, NDC 69489-131-30. Storage and Handling Store at room temperature 20°C to 25°C (68°F to77°F); excursions are permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Protect from light, moisture, and excessive heat. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise patients taking EMROSI extended-release capsules of the following information and instructions: Administration Instructions • EMROSI should be taken exactly as directed. 11 Reference ID: 5472966 • Advise patients to swallow EMROSI capsule whole and not to chew or crush the capsule [see Dosage and Administration (2)]. Serious Skin/Hypersensitivity Reactions • Inform patients that serious skin reactions have occurred with the minocycline use in patients with acne. Advise patients to discontinue use of EMROSI and contact their healthcare provider immediately at the first evidence of skin erythema [see Warnings and Precautions (5.1)]. Tooth Discoloration and Enamel Hypoplasia • Advise patients that EMROSI use in pregnancy may cause permanent tooth discoloration of deciduous teeth. Advise patients to discontinue EMROSI during pregnancy and to inform their healthcare provider right away if they become pregnant during treatment [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. Inhibition of Bone Growth • Advise patients that EMROSI use in pregnancy may cause inhibition of fetal bone growth. Advise patients to discontinue EMROSI during pregnancy and to inform their healthcare provider right away if they become pregnant during treatment [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]. Clostridioides difficile-Associated Diarrhea (Antibiotic-Associated Colitis) • Advise patients that Clostridioides difficile-associated diarrhea (antibiotic-associated colitis) can occur with minocycline therapy, including EMROSI. If patients develop watery or bloody stools, advise patients to seek medical attention [see Warnings and Precautions (5.4)]. Hepatotoxicity • Inform patients about the possibility of hepatotoxicity. Advise patients to seek medical advice if they experience signs or symptoms of hepatotoxicity, including loss of appetite, tiredness, diarrhea, jaundice, bleeding easily, confusion, and sleepiness [see Warnings and Precautions (5.5)]. Central Nervous System Effects • Inform patients that central nervous system adverse reactions including dizziness or vertigo have been reported with oral minocycline therapy. Caution patients about driving vehicles or using hazardous machinery if they experience such symptoms while on EMROSI [see Warnings and Precautions (5.6)]. Idiopathic Intracranial Hypertension • Inform patients that idiopathic intracranial hypertension can occur with minocycline therapy. Advise patients to seek medical attention if they develop unusual headache, visual symptoms, such as blurred vision, diplopia, and vision loss [see Warnings and Precautions (5.7)]. Autoimmune Syndromes • Inform patients that autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis, and serum sickness have been observed with tetracycline 12 Reference ID: 5472966 class drugs, including minocycline. Symptoms may be manifested by arthralgia, fever, rash, and malaise. Advise patients who experience such symptoms to immediately discontinue EMROSI and seek medical help [see Warnings and Precautions (5.8)]. Photosensitivity • Inform patients that photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including minocycline. Advise patients to minimize or avoid exposure to natural or artificial sunlight (i.e., tanning beds or UVA/B treatment) while using EMROSI. Instruct patients to use sunscreen and wear protective clothing (e.g., hat) over treated areas when exposure to sun cannot be avoided [see Warnings and Precautions (5.10)]. Tissue Hyperpigmentation • Inform patients that EMROSI may cause discoloration of skin, scars, teeth, or gums [see Warnings and Precautions (5.11)]. Lactation • Advise patients that EMROSI therapy is not recommended during breast feeding for 4 days after the final dose [see Use in Specific Populations (8.2)]. Manufactured for: Journey Medical Corporation Scottsdale, AZ 85258. 13 Reference ID: 5472966 PATIENT INFORMATION EMROSI (em-ROH-see) (minocycline hydrochloride) extended-release capsules, for oral use What is EMROSI? EMROSI is a prescription medicine used to treat adults with pimples and bumps (inflammatory lesions) caused by a condition called rosacea. It is not known if EMROSI is: • safe and effective for the treatment of infections. • safe and effective in children under the age of 18 years. Who should not take EMROSI? Do not take EMROSI if you are allergic to any tetracycline medicines. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Before taking EMROSI, tell your healthcare provider about all of your medical conditions, including if you: • have diarrhea or watery stools • have liver problems • have kidney problems • have had increased pressure around your brain that may have cause vision problems • are pregnant or plan to become pregnant. EMROSI may harm your unborn baby. Taking EMROSI while you are pregnant may cause serious side effects on the growth of bone and teeth of your baby. Stop taking EMROSI and call your healthcare provider right away if you become pregnant during treatment with EMROSI. • are breastfeeding or plan to breastfeed. EMROSI passes into your milk and may harm your baby. Do not breastfeed during treatment with EMROSI and for 4 days after your final dose. Tell your healthcare provider about all the other medicines you take, including prescription and over-the counter medicines, vitamins and herbal supplements. EMROSI and other medicines may affect each other and cause serious side effects. EMROSI may affect the way other medicines work, and other medicines may affect how EMROSI works. Especially tell your healthcare provider if you take: • a blood thinner medicine • penicillin antibiotic medicine • antacids that contain aluminum, calcium, or magnesium or iron-containing medicines • an acne medicine that contains isotretinoin Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist. How should I take EMROSI? • Take EMROSI exactly as your healthcare provider tells you. • Take EMROSI 1 time per day with or without food. Taking EMROSI with food may lower your chances of getting irritation or ulcers in your esophagus. Your esophagus is the tube that connects your mouth to your stomach. • Swallow EMROSI whole. Do not chew or crush the capsules. If you take too much EMROSI, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room away. What should I avoid while taking EMROSI? • You should not drive or operate dangerous machinery until you know how EMROSI affects you. EMROSI may cause you to feel dizzy or lightheaded or have a spinning feeling (vertigo). • Avoid sunlight or artificial sunlight, such as sunlamps and tanning beds during treatment with EMROSI. EMROSI can make your skin sensitive to the sun and artificial sunlight and you could get severe sunburn during treatment. Use sunscreen and wear a hat and protective clothing that covers your skin while out in the sunlight during treatment with EMROSI. Reference ID: 5472966 What are the possible side effects of EMROSI? EMROSI may cause serious side effects, including: • Serious skin and allergic reactions have happened during treatment with minocycline. EMROSI may cause serious skin or allergic reactions that may also affect parts of your body such as your liver, lungs, kidneys, and heart. Sometimes these reactions can lead to death. Stop taking EMROSI and call your healthcare provider right away or go to the nearest hospital emergency room if you have any of the following signs or symptoms, including: o skin redness, rash, hives, sores in your mouth, or your skin blisters and peels o swelling of your face, eyes, lips, tongue, or throat o trouble swallowing or breathing o blood in your urine o fever, yellowing of the skin or the whites of your eyes (jaundice), dark colored urine o pain on the right side of the stomach area (abdominal pain) o chest pain or abnormal heartbeats o swelling in your legs, ankles, and feet • Permanent tooth discoloration and problems with tooth enamel. EMROSI may permanently turn a baby or child's teeth yellow-grey-brown during tooth development. EMROSI may cause tooth enamel to not develop properly. You should not use EMROSI during tooth development. Tooth development happens in the second and third trimesters of pregnancy, and in children from birth to 8 years of age. See “Before taking EMROSI, tell your healthcare provider about all your medical conditions, including if you:” • Slow bone growth. EMROSI may cause slow bone growth if it is used during the second and third trimesters of pregnancy and if it is used in infants and children up to 8 years of age. Slow bone growth is reversible after stopping treatment with EMROSI. • Diarrhea (antibiotic associated colitis). Antibiotic associated colitis can happen with most antibiotics, including EMROSI. This type of diarrhea may be caused by an infection (Clostridioides difficile) in your intestines and can be severe and lead to death. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. • Liver problems. EMROSI may cause serious liver problems that can lead to death. Stop taking EMROSI and call your healthcare provider right away if you get any of the following symptoms of liver problems: o loss of appetite o tiredness o diarrhea o yellowing of your skin or the whites of your eyes o unexplained bleeding or bleeding easily than normal o confusion o sleepiness • Central nervous system effects. See “What should I avoid while taking EMROSI?” Central nervous system effects such as light headedness, dizziness, and a spinning feeling (vertigo) may go away during your treatment with EMROSI or if treatment is stopped. • Increased pressure around the brain (idiopathic intracranial hypertension). This condition may lead to vision changes and permanent vision loss. You are more likely to get intracranial hypertension if you are a female who can have children, are overweight, and have already had intracranial hypertension. Stop taking EMROSI and tell your healthcare provider right away if you have unusual headaches, blurred vision, double vision, and vision loss. • Immune system reactions including a lupus-like syndrome, hepatitis, and inflammation of blood or lymph vessels (vasculitis). Using EMROSI for a long time to treat acne may cause immune system reactions. Stop taking EMROSI and tell your healthcare provider right away if you get a fever, rash, joint pain, or body weakness. • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking EMROSI?” • Discoloration (tissue hyperpigmentation). EMROSI may cause darkening of your nails, bone, skin, eyes, teeth, gums, scars, and internal organs. The most common side effects of EMROSI include stomach upset or burning (dyspepsia) after eating or drinking. Your healthcare provider may do blood tests and check you for side effects during treatment with EMROSI and may stop treatment if you develop certain side effects. Reference ID: 5472966 These are not all the side effects with EMROSI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Journey Medical Corporation at 1-855-531-1859. How should I store EMROSI? • Store EMROSI at room temperature between 68°F to 77°F (20°C to 25°C). • EMROSI comes in a child-resistant package. • Keep EMROSI container tightly closed. • Keep EMROSI away from light, moisture, and excessive heat. • Do not eat desiccant. Keep EMROSI out of the reach of children. General information about the safe and effective use of EMROSI. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use EMROSI for a condition for which it was not prescribed. Do not give EMROSI to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about EMROSI that is written for health professionals. What are the ingredients in EMROSI? Active ingredient: minocycline hydrochloride Inactive ingredients: ethyl cellulose, hypromellose, isopropyl alcohol, microcrystalline cellulose, Opadry clear, polyethylene glycol, triethyl citrate, and talc Manufactured for: Journey Medical Corporation Scottsdale, AZ 85258 For more information, go to www.journeymedicalcorp.com or call 1-855-521-1859 This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5472966	custom-source	2025-02-12T15:46:31.522028	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219015s000lbl.pdf', 'application_number': 219015, 'submission_type': 'ORIG ', 'submission_number': 1}
80,147	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VOXZOGO safely and effectively. See full prescribing information for VOXZOGO. VOXZOGO (vosoritide) for injection, for subcutaneous use Initial U.S. Approval: 2021 ---------------------------INDICATIONS AND USAGE--------------------------- VOXZOGO is a C type natriuretic peptide (CNP) analog indicated to increase linear growth in pediatric patients with achondroplasia with open epiphyses. This indication is approved under accelerated approval based on an improvement in annualized growth velocity. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1) -----------------------DOSAGE AND ADMINISTRATION---------------------- • Ensure adequate food and fluid intake prior to administration. (2.1) • Recommended dosage is based on patient’s actual body weight. Administer VOXZOGO subcutaneously once daily. (2.2) • Reconstitute prior to use. Injection volume is based on both patient’s weight and concentration of reconstituted VOXZOGO. (2.2) • Monitor growth and adjust dosage according to actual body weight. Permanently discontinue upon closure of epiphyses. (2.3) • See full prescribing information for reconstitution, dilution, and administration instructions. (2.4) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- For injection: 0.4 mg, 0.56 mg, or 1.2 mg of vosoritide as a lyophilized powder in a single-dose vial for reconstitution. (3) ------------------------------CONTRAINDICATIONS------------------------------ None. (4) ------------------------WARNINGS AND PRECAUTIONS--------------------- Risk of Low Blood Pressure: Transient decreases in blood pressure have been reported. Instruct patients to be well-hydrated and have adequate food intake prior to administration of VOXZOGO (5.1) ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions (>10%) are injection site erythema, injection site swelling, rash, vomiting, injection site urticaria, arthralgia, decreased blood pressure, and gastroenteritis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------USE IN SPECIFIC POPULATIONS---------------------- Renal Impairment: Not recommended in patients with eGFR < 60 mL/min/1.73 m2. (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Instructions Prior to Administration of VOXZOGO 2.2 Recommended Dosage and Administration 2.3 Growth Monitoring 2.4 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Low Blood Pressure 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.6 Renal Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Pediatric Patients 5 Years of Age and Older 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5473427 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE VOXZOGO is indicated to increase linear growth in pediatric patients with achondroplasia with open epiphyses. This indication is approved under accelerated approval based on an improvement in annualized growth velocity [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 2 DOSAGE AND ADMINISTRATION 2.1 Important Instructions Prior to Administration of VOXZOGO To reduce the risk of low blood pressure and its associated signs and symptoms, instruct the caregiver and patient that the patient should [see Warnings and Precautions (5.1)]: • Have adequate food intake prior to VOXZOGO administration. • Drink approximately 240 to 300 mL of fluid in the hour prior to VOXZOGO administration. 2.2 Recommended Dosage and Administration The recommended dosage of VOXZOGO is based on the patient’s actual body weight (see Table 1). VOXZOGO is administered by subcutaneous injection once daily [see Dosage and Administration (2.4)]. Inject VOXZOGO at approximately the same time each day, if possible. The volume of VOXZOGO to be administered (injection volume) is based on the patient's actual body weight and the concentration of VOXZOGO must be reconstituted reconstituted VOXZOGO (0.8 mg/mL or 2 mg/mL) (see Table 1). prior to use [see Dosage and Administration (2.4)]. Reference ID: 5473427 Table 1: Recommended VOXZOGO Daily Dosage and Injection Volume Actual Body Weight* Dose Injection Volume Vial Strength for Reconstitution** 3 kg 0.096 mg 0.12 mL 0.4 mg 4 kg 0.12 mg 0.15 mL 0.4 mg 5 kg 0.16 mg 0.2 mL 0.4 mg 6 to 7 kg 0.2 mg 0.25 mL 0.4 mg 8 to 11 kg 0.24 mg 0.3 mL 0.4 mg 12 to 16 kg 0.28 mg 0.35 mL 0.56 mg 17 to 21 kg 0.32 mg 0.4 mL 0.56 mg 22 to 32 kg 0.4 mg 0.5 mL 0.56 mg 33 to 43 kg 0.5 mg 0.25 mL 1.2 mg 44 to 59 kg 0.6 mg 0.3 mL 1.2 mg 60 to 89 kg 0.7 mg 0.35 mL 1.2 mg ≥ 90 kg 0.8 mg 0.4 mL 1.2 mg * Intermediate body weights that fall within these weight bands should be rounded to the nearest whole number. *The concentration of vosoritide in reconstituted 0.4 mg vial and 0.56 mg vial is 0.8 mg/mL. The concentration of vosoritide in reconstituted 1.2 mg vial is 2 mg/mL. Missed dose If a dose of VOXZOGO is missed, it can be administered within 12 hours of the scheduled time of administration. Beyond 12 hours, skip the missed dose and administer the next daily dose according to the usual dosing schedule. 2.3 Growth Monitoring Monitor and assess patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust the dosage according to the patient’s actual body weight [see Dosage and Administration (2.2)]. Permanently discontinue VOXZOGO upon confirmation of no further growth potential, indicated by closure of epiphyses. 2.4 Preparation and Administration Reconstitute VOXZOGO before administration using the provided diluent syringe containing Sterile Water for Injection, USP (see Reconstitution Instructions below). Caregivers may inject VOXZOGO subcutaneously after proper training by a healthcare professional on the preparation and administration of VOXZOGO [see Instructions for Use]. Reference ID: 5473427 Reconstitution Instructions • Select the correct VOXZOGO vial strength (co-packaged with prefilled syringe with Sterile Water for Injection diluent) based on the patient’s actual body weight [see Dosage and Administration (2.2)]. • Remove VOXZOGO vial and prefilled diluent syringe from the refrigerator and allow the vial and prefilled diluent syringe to reach room temperature before reconstituting VOXZOGO. • Attach the diluent needle provided with ancillary supplies to the diluent prefilled syringe. • Inject the entire diluent prefilled syringe volume into the vial (see Table 2). • Gently swirl the diluent in the vial until the white powder is completely dissolved. Do not shake. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Once reconstituted VOXZOGO is a clear, colorless to yellow liquid. The solution should not be used if discolored or cloudy, or if particles are present. The concentration of reconstituted solution is 0.8 mg/mL or 2.0 mg/mL (see Table 2). • After reconstitution, VOXZOGO can be held in the vial at a room temperature 20°C to 25°C (68°F to 77°F) for a maximum of 3 hours. • For administration, extract the required dose volume from the vial using the supplied administration syringe [see Dosage and Administration (2.2)]. Table 2: Dilution Requirements for VOXZOGO Prior to Administration Vial Strength Reconstitution Volume Reconstituted Concentration 0.4 mg 0.5 mL 0.8 mg/mL 0.56 mg 0.7 mL 0.8 mg/mL 1.2 mg 0.6 mL 2 mg/mL Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. Do not mix with other medications. Instructions for Subcutaneous Administration See the Instructions for Use document for detailed, illustrated instructions. • Ensure patients have had adequate food and fluid intake prior to VOXZOGO administration [see Dosage and Administration (2.1)]. Slowly withdraw the dosing volume of the reconstituted VOXZOGO solution from the single-dose vial into a syringe. • Rotate sites for subcutaneous injections. • The recommended injection sites for VOXZOGO are: the front middle of the thighs, the lower part of the abdomen at least 2 inches (5 centimeters) away from the navel, top of the buttocks or the back of the upper arms. The same injection area should not be used on two consecutive days. Do not inject VOXZOGO into sites that are red, swollen, or tender. 3 DOSAGE FORMS AND STRENGTHS For Injection: 0.4 mg, 0.56 mg, or 1.2 mg of vosoritide as a white to yellow lyophilized powder in a single-dose vial for reconstitution. Reference ID: 5473427 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Low Blood Pressure Transient decreases in blood pressure were observed in clinical studies of VOXZOGO. Subjects with significant cardiac or vascular disease and patients on anti-hypertensive medicinal products were excluded from participation in VOXZOGO clinical trials. To reduce the risk of a decrease in blood pressure and associated symptoms (dizziness, fatigue and/or nausea), instruct patients to be well hydrated and have adequate food intake prior to administration of VOXZOGO [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risk of Low Blood Pressure [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pediatric Patients 5 Years of Age and Older VOXZOGO was studied in a 52-week, randomized, double-blind, placebo-controlled trial in 121 subjects with achondroplasia (Study 1) [see Clinical Studies (14)]. The subjects’ ages ranged from 5.1 to 14.9 years with a mean of 8.7 years. Sixty four (53%) subjects were male and 57 (47%) were female. Overall, 86 (71%) subjects were White, 23 (19%) were Asian, 5 (4%) were Black or African American, and 7 (6%) were classified as “multiple” race. The demographic and baseline characteristics were balanced between treatment groups. The subjects received either VOXZOGO 15 mcg/kg, or placebo administered subcutaneously once daily. Table 3 shows adverse reactions that occurred in ≥5% of patients treated with VOXZOGO and at a percentage greater than placebo. Reference ID: 5473427 Table 3: Adverse Reactions that Occurred in ≥5% of Patients Treated with VOXZOGO and at a Percentage Greater than Placebo in Study 1 Adverse Reaction Placebo (N=61) n (%) VOXZOGO (N=60) n (%) Injection site erythema 42 (69%) 45 (75%) Injection site swelling 22 (36%) 37 (62%) Vomiting 12 (20%) 16 (27%) Injection site urticaria 6 (10%) 15 (25%) Arthralgia 4 (7%) 9 (15%) Decreased blood pressure 3 (5%) 8 (13%) Gastroenteritisa 5 (8%) 8 (13%) Diarrhea 2 (3%) 6 (10%) Dizzinessb 2 (3%) 6 (10%) Ear pain 3 (5%) 6 (10%) Influenza 3 (5%) 6 (10%) Fatiguec 2 (3%) 5 (8%) Seasonal allergy 1 (2%) 4 (7%) Dry skin 0 3 (5%) Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects with the adverse reaction; %, percent of subjects with the adverse reaction. * Includes adverse reactions occurring more frequently in the vosoritide arm and with a risk difference of ≥5% (i.e., difference of >2 subjects) between treatment arms a Includes the preferred terms: gastroenteritis and gastroenteritis, viral b Includes the preferred terms: dizziness, presyncope, procedural dizziness, vertigo c Includes the preferred terms: fatigue, lethargy, malaise Laboratory Abnormalities Increase in Alkaline Phosphatase More VOXZOGO-treated patients had an increase in alkaline phosphatase levels during the study compared to placebo (17% vs 7%). Discussion of Selected Adverse Reactions Decreased blood pressure Eight (13%) of 60 subjects treated with VOXZOGO had a total of 11 events of transient decrease in blood pressure compared to 3 (5%) of 61 subjects on placebo, identified predominantly during periods of frequent monitoring at clinical visits after dosing over a 52-week treatment period. The median time to onset from injection was 31 (18 to 120) minutes with resolution within 31 (5 to 90) minutes in VOXZOGO-treated subjects. Two out of 60 (3%) VOXZOGO-treated subjects each had one symptomatic episode of decreased blood pressure with vomiting and/or dizziness compared to 0 of 61 (0%) subjects on placebo. Reference ID: 5473427 Injection site reactions Injection site reactions occurred in 51 (85%) subjects receiving VOXZOGO and 50 (82%) subjects receiving placebo over a 52 week period of treatment. Injection site reactions included the preferred terms injection site erythema, injection site reaction, injection site swelling, injection site urticaria, injection site pain, injection site bruising, injection site pruritus, injection site hemorrhage, injection site discoloration, and injection site induration. Over a 52 week period, 51 (85%) of 60 subjects receiving VOXZOGO experienced a total of 6983 events of injection site reactions, while 50 (82%) of 61 subjects receiving placebo experienced a total of 1776 events of injections site reactions, representing 120.4 events per person/year exposure and 29.2 per person/year exposure, respectively. One injection site reaction event could have been associated with one or more injection site reaction symptoms (e.g., injection site swelling, injection site erythema, injection site urticaria, etc.). Two subjects in the VOXZOGO arm discontinued treatment due to adverse reactions of pain and anxiety with injections. Pediatric Patients <5 Years The safety of VOXZOGO in pediatric patients <5 years with achondroplasia was evaluated in a 52-week randomized, double blind, placebo-controlled study (Study 2). In this study, 64 patients from 4.4 months to <5 years of age were randomized to receive either a daily vosoritide dose with similar exposure to that characterized to be safe and effective in children with ACH aged ≥5 years old, or placebo. An additional 11 patients received open-label treatment as part of this study. Subjects received 30 mcg/kg while they were <2 years of age. The daily dose for subjects was adjusted to 15 mcg/kg immediately following their 2 year birthday. The most common adverse reactions (>10%) reported in pediatric patients <5 years were injection site reactions (86%) and rash (28%). The overall safety profile of VOXZOGO in pediatric patients <5 years was similar to that seen in older pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of VOXZOGO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: hypertrichosis (includes the preferred terms: hair growth abnormal and hypertrichosis). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on vosoritide use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of embryo-fetal toxicity or congenital malformations when pregnant rats and rabbits were administered vosoritide subcutaneously at doses equivalent to 14-times and 200-times, respectively, the exposure at the maximum recommended human dose (MRHD) (see Data). The estimated background risk of major birth defects for the indicated population is higher than the general population. The estimated background risk of miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the Reference ID: 5473427 U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal developmental toxicity study in rats, vosoritide was administered at 90, 270, 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis from gestation day (GD) 6 – 17. There were no effects on maternal animals or on embryofetal development at the highest dose administered (14-times the exposure at the MRHD). In an embryofetal developmental toxicity study in rabbits, vosoritide was administered at 45, 135, 240 mcg/kg once daily by subcutaneous injection during the period of major organogenesis (GD 7 – 19). No effects were observed in maternal animals or on embryofetal development at the highest dose administered (200-times the exposure at the MRHD). In a pre- and postnatal toxicity study in rats, vosoritide was administered at 90, 270, and 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis and continuing to weaning (GD 6 through postpartum day 20). There were no effects on maternal animals, including maintenance of pregnancy, parturition, or care of offspring, and no effects were noted on offspring growth and development or ability to reproduce at the highest dose (14-times the exposure at the MRHD). 8.2 Lactation Risk Summary There is no information regarding the presence of vosoritide in human milk, the effects on the breastfed infant, or the effects on milk production. Vosoritide is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VOXZOGO and any potential adverse effects on the breastfed child from VOXZOGO or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of VOXZOGO have been established in pediatric patients for the improvement in linear growth in patients with achondroplasia with open epiphyses. Use of VOXZOGO for this indication is supported by evidence from an adequate and well-controlled study in 121 pediatric patients aged 5 to 15 years with achondroplasia, pharmacokinetic data in pediatric patients aged 4.5 months to 15 years, and additional safety data in pediatric patients aged 4.4 months to <5 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of VOXZOGO has not been evaluated. No dosage adjustment is needed for patients with eGFR ≥ 60 mL/min/1.73 m2. VOXZOGO is not recommended for patients with eGFR < 60 mL/min/1.73 m2. 11 DESCRIPTION Reference ID: 5473427 H O N O NH2 HN N OH NH2 NH2 O OH N NH NH H OH NH NH H2 O O O 2 O 2 O S O HN O O H O O O O O O O S H H H H H H H H NH H N H N N N N N N N N N N O N N N N N N N N N N N HN O H H H H H H H H H H O O O O O O O O NH OH HO S O O NH O VOXZOGO contains vosoritide, a human C type natriuretic peptide (CNP) analog. Vosoritide is a 39 amino acid peptide. Its amino acid sequence includes the 37 C terminal amino acids of the human CNP53 sequence plus Pro Gly on the N terminus to convey resistance to neutral endopeptidase (NEP) degradation. Vosoritide is manufactured from Escherichia coli using recombinant DNA technology. Vosoritide has a chemical formula of C176H290N56O51S3 with a molecular weight of 4.1 kDa. Vosoritide has the structural formula shown in Figure 1. Figure 1 H N O HN NH2 O N NH2 NH2 OH N O NH OH NH H NH OH NH NOC H2NOC O O O CONH CONH O CONH2 CONH2 O S HN O O H O O O O O O O O S H H H H H H H H NH H H N N N N N N N N N N N O N N N N N N N N N N N HN H O H H H H H H H H H O O O O O O O O NH COOH OH HO O S O NH O COOH HN HN OO NH2 NH2 NH2 O NH H NH O N O H N NH HN O H N O O HN NH2 COOH NH2 HN VOXZOGO (vosoritide) for injection, is a sterile, preservative-free white-to-yellow lyophilized powder, for subcutaneous administration after reconstitution with Sterile Water for Injection, USP. VOXZOGO is provided as a single-dose vial containing 0.4 mg, 0.56 mg, or 1.2 mg of vosoritide per vial. A pre-filled syringe containing Sterile Water for Injection, USP for use as a diluent is also provided. The contents of each single dose vial are summarized by strength in Table 4. The product contains no preservative. Table 4: Contents of VOXZOGO O Strength Inactive Ingredients per Vial VOXZOGO 0.4 mg Citric acid monohydrate (0.14 mg), mannitol (7.5 mg), methionine (0.36 mg), polysorbate 80 (0.025 mg), sodium citrate dihydrate (0.54 mg) and trehalose dihydrate (29.01 mg). After reconstitution with 0.5 mL Sterile Water for Injection USP, the resulting concentration is 0.4 mg/0.5 mL of vosoritide and the nominal deliverable volume is 0.4 mL. VOXZOGO 0.56 mg Citric acid monohydrate (0.20 mg), mannitol (10.50 mg), methionine (0.51 mg), polysorbate 80 (0.035 mg), sodium citrate dihydrate (0.76 mg) and trehalose dihydrate (40.61 mg). After reconstitution with 0.7 mL Sterile Water for Injection USP, the resulting concentration is 0.56 mg/0.7 mL of vosoritide and the nominal deliverable volume is 0.6 mL. VOXZOGO 1.2 mg Citric acid monohydrate (0.17 mg), mannitol (9 mg), methionine (0.44 mg), polysorbate 80 (0.030 mg), sodium citrate dihydrate (0.65 mg) and trehalose dihydrate (34.81 mg). After reconstitution with 0.6 mL Sterile Water for Injection USP, the resulting Reference ID: 5473427 concentration is 1.2 mg/0.6 mL of vosoritide and the nominal deliverable volume is 0.5 mL. Trehalose dihydrate and D-Mannitol are used as isotonic agent. Citric acid monohydrate and sodium citrate dihydrate are used as buffering agent. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action In patients with achondroplasia, endochondral bone growth is negatively regulated due to a gain of function mutation in fibroblast growth factor receptor 3 (FGFR3). Binding of vosoritide to natriuretic peptide receptor-B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) pathway at the level of rapidly accelerating fibrosarcoma serine/threonine protein kinase (RAF-1). As a result, vosoritide, like CNP, acts as a positive regulator of endochondral bone growth as it promotes chondrocyte proliferation and differentiation. In animal models with open growth plates, vosoritide administration resulted in the promotion of chondrocyte proliferation and differentiation that led to a widening of the growth plate and subsequent increase in skeletal growth. In the mouse models of FGFR3-related chondrodysplasia, a partial or complete normalization of the dwarfism phenotype was observed. 12.2 Pharmacodynamics NPR-B Binding Activity Biomarker and Bone Metabolism Biomarker An increase in urinary cyclic guanosine monophosphate (cGMP) concentrations from pre-dose baseline were observed within the first four hours post-dose, with a maximum level at 2 hours post-dose, after VOXZOGO administration to pediatric patients with achondroplasia. Daily administration of VOXZOGO also led to the increase from baseline in serum collagen type X marker (CXM), an endochondral ossification biomarker and remains elevated beyond 24 months. In subjects aged 5 - 14 years old at screening, exposure-response analyses showed that vosoritide activity measured by urinary cGMP was near saturation at the dose of 15 mcg/kg once daily, while maximal increase in growth plate activity indicated by CXM was achieved at this dose. Cardiac Electrophysiology At the maximum approved recommended dose, VOXZOGO does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics The area under the concentration-time curve (AUC) and peak concentration (Cmax) of vosoritide increased greater than proportionally following subcutaneous administration to pediatric subjects with achondroplasia in the dose range of 7.5 to 30.0 mcg/kg. The pharmacokinetics of vosoritide were evaluated in 58 subjects aged 5 to 13 years with achondroplasia who received subcutaneous injections of vosoritide 15 mcg/kg once daily for 52 weeks. The mean (± SD) Cmax and area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) observed across 52 weeks of treatment ranged from 4.71 (± 2.32) to 7.18 (± 9.65) ng/mL, and 161 (± 98.1) to 290 (± 235) ng-min/mL, respectively. No drug accumulation was observed following 15 mcg/kg once daily Reference ID: 5473427 dosing. The exposure of vosoritide increased with the duration of treatment. The mean AUC0-t at week 52 increased approximately 20% compared to that at day 1. Absorption Absolute bioavailability for vosoritide following subcutaneous injection was not determined. Vosoritide was absorbed with a median Tmax of 15 minutes after dosing. Distribution The mean (± SD) apparent volume of distribution of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 2880 (± 2450) to 3020 (± 1980) mL/kg. Elimination The mean (± SD) apparent clearance of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 79.4 (± 53.0) to 104 (± 98.8) mL/min/kg. The mean (± SD) half-life ranged from 21.0 (± 4.7) to 27.9 (± 9.9) minutes. Metabolism The metabolism of vosoritide is expected to occur via catabolic pathways with degradation into small peptide fragments and amino acids. Specific Populations No clinically significant differences in the vosoritide pharmacokinetics were observed based on age (0.4 to 15 years), sex or race. The effect of hepatic or renal impairment on the pharmacokinetics of vosoritide is unknown. Body weight Population pharmacokinetic analyses indicated that body weight is a significant covariate for vosoritide clearance and volume of distribution. The apparent clearance and volume of distribution of vosoritide increased with increasing body weight in patients with achondroplasia (5 to 74.5 kg). Drug Interaction Studies In vitro assessment of drug-drug interactions In vitro studies showed that vosoritide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Based on in vitro studies, vosoritide is considered unlikely to inhibit the human drug uptake or efflux transporters such as OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP at clinically relevant concentrations and therefore, no effect of vosoritide is anticipated on concomitantly administered drugs that are substrates of these transporters. In vivo assessment of drug-drug interactions No clinical studies evaluating the drug-drug interaction potential of vosoritide have been conducted. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug Reference ID: 5473427 antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of vosoritide. Of 131 subjects aged 5 years and older who were treated with VOXZOGO 15 mcg/kg/day and evaluable for the presence of anti-drug antibodies (ADA) for up to 240 weeks, ADA were detected in 35% (46/131). The earliest time to ADA development was day 85. All ADA-positive subjects tested negative for anti-vosoritide neutralizing antibodies. There was no correlation between the number, duration, or severity of hypersensitivity adverse reactions or injection site reactions and ADA positivity or mean ADA titer. There was no association between ADA positivity or mean ADA titer and change from baseline in annual growth velocity (AGV) or height Z-score at month 12. There was no impact of serum ADA detected on the plasma PK measurements of vosoritide. In subjects under 5 years of age, 33% (20/61) of vosoritide-treated subjects tested positive for ADA and all placebo-treated subjects tested negative for ADA for up to 44 months. The earliest time to ADA development was week 26. All of the ADA-positive subjects tested negative for neutralizing antibodies at all time points. There was no impact of ADA development on safety, efficacy or PK of vosoritide up to Month 12. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term carcinogenicity studies and genotoxicity studies with vosoritide have not been performed. In a fertility and reproductive study in male and female rats at doses up to 540 mcg/kg/day (15-times the exposure at the MRHD), vosoritide had no effect on mating performance, fertility, or litter characteristics. 14 CLINICAL STUDIES 14.1 Pediatric Patients 5 Years of Age and Older The safety and effectiveness of VOXZOGO in patients with achondroplasia were assessed in one 52-week, multi-center, randomized, double-blind, placebo-controlled, phase 3 study - Study 1 (NCT03197766). Study 1 was conducted in 121 subjects with genetically-confirmed achondroplasia, who were randomized to either VOXZOGO (N=60) or placebo (N=61). The dosage of VOXZOGO was 15 mcg/kg administered subcutaneously once daily. Baseline standing height, weight Z-score, body mass index (BMI) Z-score, and upper to lower body ratio were collected for at least 6 months prior to randomization. Subjects with limb-lengthening surgery in the prior 18 months or who planned to have limb-lengthening surgery during the study period were excluded. The study included a 52-week placebo-controlled treatment phase followed by an open-label treatment extension study period in which all subjects received VOXZOGO. The primary efficacy endpoint was the change from baseline in annualized growth velocity (AGV) at Week 52 compared with placebo. The subjects’ ages ranged from 5.1 to 14.9 years with a mean of 8.7 years. Sixty four (53%) subjects were male and 57 (47%) were female. Overall, 86 (71%) subjects were White, 23 (19%) were Asian, 5 (4%) were Black or African American, and 7 (6%) were classified as “multiple” race. The subjects had a mean baseline height standard deviation score (SDS) of -5.13. Reference ID: 5473427 Treatment with VOXZOGO for 52 weeks resulted in a treatment difference in the change from baseline in AGV of 1.57 cm/year after 52 weeks of treatment (Table 5). Table 5: Annualized Growth Velocity (cm/year) at Week 52 in Subjects 5 Years of Age and Older with Achondroplasia - Study 1 Placebo (N=61a) VOXZOGO 15 mcg/kg Daily (N=60a) Baseline mean (SD)b 4.06 (1.20) 4.26 (1.53) Change from baselinec -0.17 1.40 Difference in change of VOXZOGO – Placeboc (95% CI) 1.57 (1.22, 1.93)d Abbreviations: AGV, annualized growth velocity; 95% CI, 95% confidence interval; LS, least-square; SD, standard deviation a All randomized subjects. Two patients in the VOXZOGO group discontinued from the study before Week 52. The values for these 2 patients were imputed assuming baseline growth rate for the period with missing data. b Baseline AGV was based on standing height at least 6 months prior to enrollment into the study. c LS means were estimated from the ANCOVA (analysis of covariance) model, which included treatment, stratum defined by sex and Tanner stage, baseline age, baseline AGV and baseline height Z-score. d 2-sided p-value <0.0001 for superiority. The improvement in AGV in favor of VOXZOGO was consistent across all predefined subgroups analyzed including sex, age group, Tanner stage, baseline height Z-score, and baseline AGV. Height Standard Deviation Score (SDS) The LS mean change from baseline to Week 52 in height SDS was -0.02 in the placebo group and 0.26 in the VOXZOGO group. The difference in LS mean change from baseline was 0.28 (95% CI 0.17, 0.39; p<0.0001) in favor of VOXZOGO. The LS mean change from baseline to Week 52 in upper to lower body segment ratio was -0.02 in the placebo group and -0.03 in the VOXZOGO group. The difference in LS mean change from baseline was -0.01 (95% CI -0.05, 0.02; p=0.5). Open-label extension After the 52 week double blind, placebo-controlled, phase 3 study, Study 1, 58 subjects initially randomized to VOXZOGO enrolled into an open-label extension. Among the subjects who had 2 years of follow-up since randomization, the improvement in AGV was maintained. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied VOXZOGO for injection is a white to yellow lyophilized powder for reconstitution and is provided as a co-pack which includes ten: • Sterile, single-dose 2 mL glass vials containing VOXZOGO • Diluent (Sterile Water for Injection, USP) in a single-dose prefilled syringe • Diluent transfer needles (23 gauge) • Single-dose administration syringes (30 gauge) both with needle retraction safety devices Strength (mg) Diluent (mL) Co-pack NDC Number Flip Cap Color 0.4 0.5 NDC 68135-082-36 White Reference ID: 5473427 0.56 0.7 NDC 68135-119-66 Magenta 1.2 0.6 NDC 68135-181-93 Grey The following items to be obtained separately; alcohol aseptic wipes, gauze, bandages and sharps container. Storage Refrigerate VOXZOGO vials and prefilled diluent syringes at 2°C to 8°C (36°F to 46°F). Do not freeze. VOXZOGO can be stored at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) for 90 days. Do not return VOXZOGO to the refrigerator once stored at room temperature. After reconstitution, VOXZOGO can be held in the vial at room temperature 20°C to 25°C (68°F to 77°F) for a maximum of 3 hours [see Dosage and Administration (2.4)]. Record the starting date of room-temperature storage clearly on the unopened product carton. Do not use beyond expiration date on the label. Store in the original package to protect from light. Handling Reconstituted VOXZOGO must be administered within 3 hours of reconstitution [see Dosage and Administration (2.4)]. 17 PATIENT COUNSELING INFORMATION Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Preparation and Administration Instruct caregivers on proper preparation and administration of VOXZOGO. Ensure caregivers have demonstrated the ability to perform a subcutaneous injection [see Dosage and Administration (2.4)]. Instruct caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct caregivers to dispose needles and syringes in a puncture-resistant container. Risk of Low Blood Pressure Inform caregivers and patients that VOXZOGO may lower blood pressure after administration. Instruct caregivers and patients that prior to VOXZOGO administration, the patient should have adequate food intake and within the hour prior to administration, the patient should drink approximately 8-10 ounces (240-300 mL) of fluid [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. Manufactured for: BioMarin Pharmaceutical Inc. 105 Digital Drive, Novato, CA 94949 Reference ID: 5473427 PATIENT INFORMATION VOXZOGO (vox zoeʹ goe) (vosoritide) for injection, for subcutaneous use What is VOXZOGO? VOXZOGO is a prescription medicine used to increase linear growth in children with achondroplasia with open bone growth plates (epiphyses). Before you give your child VOXZOGO, tell your child’s healthcare provider about all your child’s medical conditions, including if they: • have kidney problems. • are pregnant or plan to become pregnant. It is not known if VOXZOGO will harm your child’s unborn baby. • are breastfeeding or plan to breastfeed. It is not known if VOXZOGO passes into your child’s breast milk. Talk to your child’s healthcare provider about the best way to feed your child’s baby if your child takes VOXZOGO. Tell your child’s healthcare provider about all the medicines your child takes, including prescription and over-the counter medicines, vitamins, and herbal supplements. Know the medicines your child takes. Keep a list of them to show your child’s healthcare provider and pharmacist when your child gets a new medicine. How should I give VOXZOGO? • See the detailed Instructions for Use that comes with this Patient Information leaflet for instructions about the right way to store, prepare, and give VOXZOGO injections at home. • VOXZOGO is given as an injection under the skin (subcutaneous or SC). Inject VOXZOGO 1 time every day, at about the same time each day. • If your child’s healthcare provider decides a caregiver can give the injections of VOXZOGO at home, your child’s caregiver should receive training on the right way to prepare and inject VOXZOGO. Do not try to inject VOXZOGO until you have been shown the right way by your child’s healthcare provider or nurse. • Your child’s healthcare provider will tell you how often you should give VOXZOGO. If your child misses a dose of VOXZOGO, it can be given within 12 hours of the scheduled time of injection. If more than 12 hours have passed, do not give the missed dose. Give the next daily dose according to your child’s usual schedule. • Your child should eat a meal and drink about 8 to 10 ounces of fluid within 1 hour before injection. • In case you are not sure when to inject VOXZOGO, call your child’s healthcare provider or pharmacist. Do not give VOXZOGO more often than as directed by your child’s healthcare provider. • Your child’s dose of VOXZOGO depends on his or her body weight. Your child’s healthcare provider will tell you which strength of VOXZOGO to use and how much to give your child. • Your child’s healthcare provider will monitor your child’s growth and instruct you on when your child should stop VOXZOGO if they determine that your child is no longer able to grow. Stop giving VOXZOGO to your child if instructed by your child’s healthcare provider. What are the possible side effects of VOXZOGO? VOXZOGO may cause serious side effects, including: • risk of low blood pressure. VOXZOGO may temporarily lower blood pressure in some people. To help reduce the risk of low blood pressure and its symptoms (dizziness, feeling tired, or nausea), your child should eat a meal and drink about 8 to 10 ounces of fluid within 1 hour before receiving VOXZOGO. The most common side effects of VOXZOGO include: • injection site reactions (redness, itching, swelling, bruising, rash, hives, pain) • high levels of blood alkaline phosphatase (shown in blood tests) • vomiting • joint pain • decreased blood pressure Reference ID: 5473427 BiOMARIN" • stomach ache These are not all the possible side effects of VOXZOGO. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VOXZOGO? • Store the VOXZOGO vial and prefilled diluent syringe in the refrigerator between 36°F to 46°F (2°C to 8°C). • You may store VOXZOGO (before mixing) at room temperature between 68°F to 77°F (20°C to 25°C) for 90 days. • Record the date you started storing VOXZOGO at room temperature on the carton to keep track of the 90 days. • Do not return VOXZOGO to the refrigerator after it has been stored at room temperature. Throw VOXZOGO away if unused within 90 days of storing at room temperature. • Do not use VOXZOGO past the expiration date. • Do not freeze VOXZOGO. • Store VOXZOGO out of direct sunlight. Keep VOXZOGO and all medicines out of the reach of children. General information about the safe and effective use of VOXZOGO. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VOXZOGO for a condition for which it was not prescribed. Do not give VOXZOGO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VOXZOGO that is written for health professionals. What are the ingredients in VOXZOGO? Active ingredient: vosoritide Inactive ingredients: trehalose dihydrate, mannitol, sodium citrate dihydrate, methionine, citric acid monohydrate, and polysorbate 80 BioMarin Pharmaceutical Inc. Novato, CA 94949 © BioMarin Pharmaceutical Inc. All rights reserved. VOXZOGO is a registered trademark of BioMarin Pharmaceutical Inc. For more information, go to www.VOXZOGO.com or call 1-877-695-8826. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 10/2023 Reference ID: 5473427 INSTRUCTIONS FOR USE VOXZOGO™ [Vox zoeʹ goe] (vosoritide) for injection, for subcutaneous use Single-Use This Instructions for Use contains information for caregivers on how to inject VOXZOGO. Read this Instructions for Use before you start using VOXZOGO and each time you get a refill. There may be new information. This information does not take the place of talking to your child’s healthcare provider about your child’s medical condition and their treatment. Before you use VOXZOGO for the first time, make sure your child’s healthcare provider shows you the right way to use it. Contact your child’s healthcare provider if you or your child have any questions. Important Information You Need to Know Before Injecting VOXZOGO • Wash your hands with soap and water. • Do not drop VOXZOGO or put opened items down on surfaces that are not clean. • VOXZOGO is available in more than 1 strength. Make sure the strength matches your prescription strength. Do not open packaging until ready to use. • Take the VOXZOGO vial and prefilled diluent syringe out of the refrigerator and allow them to reach room temperature before mixing. • Inspect the vial and supplies for any signs of damage or contamination. Do not use if damaged or contaminated. • Check the expiration date. The expiration date can be found on the carton, vial and prefilled diluent syringe. Do not use if expired. • Your child should eat a meal and drink a glass (about 8 to 10 ounces) of fluid (such as water, milk, or juice) within 1 hour before injection. • VOXZOGO should be given at about the same time every day. • Do not mix VOXZOGO with other medicines. • After mixing the VOXZOGO, use it right away. Do not use the mixed VOXZOGO if it has been sitting at room temperature for more than 3 hours. Throw it away (dispose of) in a sharps container. See step 18 and “How to Throw Away (Dispose of) VOXZOGO” for more information. • Do not reuse any of the supplies. After the injection, throw away (dispose of) the used vial even if there is VOXZOGO remaining. See step 18 and “How to Throw Away (Dispose of) VOXZOGO” for more information. How to Store VOXZOGO • Store the VOXZOGO vial and prefilled diluent syringe in the refrigerator between 36°F to 46°F (2°C to 8°C). • You may store VOXZOGO (before mixing) at room temperature between 68°F to 77°F (20°C to 25°C) for 90 days. Record the date you started storing VOXZOGO at room temperature on the carton to keep track of the 90 days. Do not return VOXZOGO to the refrigerator after it has been stored at room temperature. Throw VOXZOGO away if unused within 90 days of storing at room temperature. • Do not freeze VOXZOGO. • Store VOXZOGO out of direct sunlight. Keep VOXZOGO and all other medicines out of the reach of children. Reference ID: 5473427 Diluent Needle 1(4 Needle Cap Blue Tab r ) Safety Shield Needle inside to retract needle Prefilled Diluent Syringe ~ Cap Diluent Plunger Rod Sterile water for reconstitution of BMN-111 Injection Syringe :::::=~f Jl:ll:Jl]j,,1:g,..;~,.~of&+ ~iil~ct+1l:::l~M:[::J~ Needle Cap Needle inside Plunger Rod Alcohol Pads ALCOHOL PAD Sharps Container Gauze or Bandage Supplies Needed to Inject VOXZOGO Gather all of these supplies on a clean, flat surface before injecting. Items supplied Items not supplied If you do not have these items, ask your pharmacist. VOXZOGO Reference ID: 5473427 ~t t A Be careful notlDrxJSh toobluelab until Step 5 Do not touch the vial stopper with your fingers after wiping it with an alcohol pad. t Be careful not to touch the needle tip \,\ Press blue tab I to retract needle ~ - Preparing VOXZOGO for Injection ► Step 1 On a clean flat surface, flip off the vial cap and wipe the top with an alcohol pad. ► Step 2 Gently bend to snap off the cap from the prefilled diluent syringe. ► Step 3 Twist the diluent needle onto the prefilled diluent syringe until you can no longer twist it. Do not use the prefilled diluent syringe to give the injection. ► Step 4 Pull off the needle cap and insert the needle through the middle of the vial stopper. Slowly push the plunger rod down to inject all of the liquid. ► Step 5 Remove the needle from the vial, then press the blue tab for the needle to pull back (retract). Throw away the needle and syringe in a sharps container. See step 18 and “How to Throw Away (Dispose of) VOXZOGO.” Do not use the prefilled diluent syringe to give the injection. Reference ID: 5473427 Make sure medicine is clear to yellow, not cloudy and does not have particles. Be careful not ,.--:=;::::::::~11--' to bend needle 0,... ,I ► Step 6 Gently swirl the vial until the powder has completely dissolved and the solution is clear. Do not shake. ► Step 7 Take the injection syringe out of the carton. Pull off the needle cap from the injection syringe and insert the needle straight through the middle of the vial stopper. Be careful not to bend the needle. ► Step 8 Carefully hold the vial and syringe and turn the vial upside down with the needle still inserted. The vial should be on top. Be careful not to bend the needle. Reference ID: 5473427 Removing Bubbles A Remove any large bubbles 1 or 2 small bubbles are acceptable Measuring Prescribed Dose Make sure the dose in the syringe matches ~ the prescribed dose t~ A Make sure the dose in the syringe matches the prescribed dose before removing the vial Preparing VOXZOGO for Injection (continued) ► Step 9 Keep the needle tip in the medicine and slowly pull the plunger rod back to draw up the prescribed dose in the syringe. Check the prescription label for how much to draw up. ► Step 10 Remove large air bubbles in the syringe by gently tapping the syringe. Then push the bubbles back into the vial. ► Step 11 Repeat steps 9 and 10 until you have the correct prescribed dose in the syringe and no large bubbles. ► Step 12 Make sure you have the prescribed dose in the syringe, then remove the vial and prepare to give the dose. Reference ID: 5473427 A Do not inject through clothes. Do not inject into skin that is swollen, sore, bruised, red, hard, or scarred. The following sites are recommended for injection: • Thighs or • Abdomen (2 inches from belly button) or • Buttocks • Healthcare providers and caregivers may also inject V0XZ0G0 into the back of the upper arms. 0 'A' T A Do not touch the area again before injecting. Select and Prepare Injection Site ► Step 13 VOXZOGO should be injected into the fatty layer under the skin (subcutaneous) only. Do not inject into the same site 2 times in a row. ► Step 14 Wipe the injection site with an alcohol pad and let the skin air dry. Reference ID: 5473427 Giving VOXZOGO Injection ► Step 15 After wiping the site with an alcohol pad, pinch the skin up around the selected injection site. ► Step 16 Quickly insert the needle all the way into the skin at a 45-degree angle. ► Step 17 Release the pinch and slowly push the plunger rod all the way down. Continue pressing the plunger rod until the needle retracts into the syringe. ► Step 18 Throw away the used vial, syringes and needles in a sharps container. See “How to Throw Away (Dispose of) VOXZOGO” for more information. How to Throw Away (Dispose of) VOXZOGO Put your used or expired vials, needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the vials, loose needles and syringes in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that: • is made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture-resistant lid without sharps being able to come out, • is upright and stable during use, • is leak-resistant, and • is properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Reference ID: 5473427 After the Injection • Inspect the injection site. If a small amount of bleeding occurs from the injection site, gently press a gauze pad on it for a few seconds or apply a bandage. Do not rub the injection site. • Monitor for signs of low blood pressure, such as dizziness, tiredness, and nausea. If your child experiences these symptoms you should call your child’s healthcare provider, then get your child to lay back with legs raised. For Help or More Information • Call your healthcare provider • Call BioMarin at 1-800-123-4567 • Visit www.VOXZOGO.com Manufactured for: BioMarin Pharmaceutical Inc., Novato, CA 94949 REP-5233-C10 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: November 2021 Reference ID: 5473427 This page is intended to be blank. Turn page over for Instructions for Use. Reference ID: 5473427	custom-source	2025-02-12T15:46:31.691833	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214938s004lbl.pdf', 'application_number': 214938, 'submission_type': 'SUPPL ', 'submission_number': 4}
80,148	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CADUET safely and effectively. See full prescribing information for CADUET. CADUET® (amlodipine and atorvastatin) tablets, for oral use Initial U.S. Approval: 2004 ----------------------------RECENT MAJOR CHANGES------------------------- Contraindications, Pregnancy and Lactation (4) Removed 05/2024 Warnings and Precautions, CNS Toxicity (5.7) Removed 05/2024 -------------------------INDICATIONS AND USAGE----------------------------- CADUET is a combination of amlodipine besylate, a calcium channel blocker, and atorvastatin calcium, a HMG-CoA-reductase inhibitor (statin), indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate (1). Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Amlodipine is indicated for the treatment of Coronary Artery Disease (1). Atorvastatin is indicated (1):  To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD.  As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).  As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia.  As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia. -----------------------DOSAGE AND ADMINISTRATION---------------------- Usual starting dose (mg daily) Maximum dose (mg daily) Amlodipine 5a 10 Atorvastatin 10-20b 80 a Start small adults or children, fragile, or elderly patients, or patients with hepatic insufficiency on 2.5 mg once daily (2). b Start patients requiring large LDL-C reduction (> 45%) at 40 mg once daily (2). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets contain amlodipine besylate equivalent to amlodipine 5 or 10 mg and atorvastatin calcium equivalent to atorvastatin 10, 20, 40, or 80 mg (3). ----------------------------CONTRAINDICATIONS-------------------------------- • Acute liver failure or decompensated cirrhosis (4). • Hypersensitivity to amlodipine, atorvastatin or any excipient in CADUET (4). -----------------------WARNINGS AND PRECAUTIONS----------------------- • Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher CADUET dosage. Discontinue CADUET if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue CADUET in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing CADUET dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever (2, 5.1, 7.3, 8.5, 8.6). • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue CADUET if IMNM is suspected (5.2). • Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue CADUET (5.3). • Angina or myocardial infarction may occur with initiation or dose increase (5.4) • Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, acute hypotension is unlikely (5.5). ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reaction to amlodipine is edema which occurred in a dose related manner (6.1). Most common adverse reactions (incidence ≥ 5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection to atorvastatin (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------------DRUG INTERACTIONS------------------------------ • See full prescribing information for details regarding concomitant use of CADUET with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis (2.5, 7.3). • Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin (7.4). • Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive (7.5). • Digoxin: May increase digoxin plasma levels; monitor patients appropriately (7.5). -----------------------USE IN SPECIFIC POPULATIONS-----------------------  Pregnancy: May cause fetal harm (8.1).  Lactation: Breastfeeding not recommended during treatment with CADUET (8.2). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 1 Reference ID: 5473667 ______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myopathy and Rhabdomyolysis 5.2 Immune-Mediated Necrotizing Myopathy 5.3 Hepatic Dysfunction 5.4 Increased Angina and Myocardial Infarction 5.5 Hypotension 5.6 Increases in HbA1c and Fasting Serum Glucose Levels 5.7 Increased Risk of Hemorrhagic Stroke in Patients on Atorvastatin 80 mg with Recent Hemorrhagic Stroke 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Impact of Other Drugs on Amlodipine 7.2 Impact of Amlodipine on Other Drugs 7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin 7.4 Drug Interactions that may Decrease Exposure to Atorvastatin 7.5 Atorvastatin Effects on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Amlodipine for Hypertension 14.2 Amlodipine for Chronic Stable Angina 14.3 Amlodipine for Vasospastic Angina 14.4 Amlodipine for Coronary Artery Disease 14.5 Amlodipine for Heart Failure 14.6 Atorvastatin for Prevention of Cardiovascular Disease 14.7 Atorvastatin for Primary Hyperlipidemia in Adults 14.8 Atorvastatin for Hypertriglyceridemia in Adults 14.9 Atorvastatin for Dysbetalipoproteinemia in Adults 14.10 Atorvastatin for Homozygous Familial Hypercholesterolemia in Adults and Pediatric Patients 14.11 Atorvastatin for Heterozygous Familial Hypercholesterolemia in Pediatric Patients 14.12 CADUET for Hypertension and Dyslipidemia 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5473667 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE CADUET (amlodipine and atorvastatin) is indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. Amlodipine Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Amlodipine may be used alone or in combination with other antihypertensive agents. Coronary Artery Disease (CAD) Chronic Stable Angina Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents. Vasospastic Angina (Prinzmetal’s or Variant Angina) Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy or in combination with other antianginal agents. Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction < 40%, amlodipine is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure. Atorvastatin Atorvastatin is indicated:  To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD  As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: 3 Reference ID: 5473667 o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).  As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH).  As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia o Hypertriglyceridemia 2 DOSAGE AND ADMINISTRATION CADUET Dosage of CADUET must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently. CADUET may be substituted for its individually titrated components. Patients may be given the equivalent dose of CADUET or a dose of CADUET with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect. CADUET may be used to provide additional therapy for patients already on one of its components. CADUET may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. Important Dosage Information Take CADUET orally once daily at any time of the day, with or without food. Amlodipine The usual initial antihypertensive oral dosage of amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily. Pediatric (age > 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy. Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently. Angina The recommended dosage of amlodipine for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect. Coronary Artery Disease The recommended dosage range of amlodipine for patients with CAD is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)]. Pediatrics The effective antihypertensive oral dose of amlodipine in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Atorvastatin Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin, and adjust the dosage if necessary. Recommended Dosage in Adult Patients The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended starting dosage of atorvastatin is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Dosage Modifications Due to Drug Interactions Concomitant use of atorvastatin with the following drugs requires dosage modification of atorvastatin [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. 4 Reference ID: 5473667 Anti-Viral Medications  In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg once daily.  In patients taking nelfinavir, do not exceed atorvastatin 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics  In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg once daily. For additional recommendations regarding concomitant use of atorvastatin with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS CADUET tablets are formulated for oral administration in the following strength combinations: Atorvastatin (mg) 10 20 40 80 Amlodipine (mg) 5 X X X X 10 X X X X Combinations of atorvastatin with 5 mg amlodipine are film-coated white tablets and combinations of atorvastatin with 10 mg amlodipine are film-coated blue tablets. 4 CONTRAINDICATIONS  Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].  Hypersensitivity to amlodipine, atorvastatin or any excipients in CADUET. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Myopathy and Rhabdomyolysis CADUET may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including CADUET. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher CADUET dosage [see Drug Interactions (7.3) and Use in Specific Populations (8.5, 8.6)]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis CADUET exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir or glecaprevir plus pibrentasvir with CADUET is not recommended. CADUET dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2)]. Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses ( > 1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir [see Adverse Reactions (6.1)]. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.3)]. Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking CADUET [see Drug Interactions (7.3)]. Discontinue CADUET if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if CADUET is discontinued. Temporarily discontinue CADUET in patients experiencing an acute 5 Reference ID: 5473667 or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the CADUET dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue CADUET if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of atorvastatin [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7)]. Consider liver enzyme testing before atorvastatin initiation and when clinically indicated thereafter. Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin. 5.4 Increased Angina and Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease. 5.5 Hypotension Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely. 5.6 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. 5.7 Increased Risk of Hemorrhagic Stroke in Patients on Atorvastatin 80 mg with Recent Hemorrhagic Stroke In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or Transient Ischemic Attack (TIA) within the preceding 6 months, were treated with atorvastatin 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)]. Consider the risk/benefit of use of atorvastatin 80 mg in patients with recent hemorrhagic stroke. 6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling:  Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]  Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]  Hepatic Dysfunction [see Warnings and Precautions (5.3)]  Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.6)] 6 Reference ID: 5473667 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions,the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. CADUET CADUET (amlodipine/atorvastatin) has been evaluated for safety in 1092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia. In general, treatment with CADUET was well tolerated. For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with CADUET, no adverse reactions peculiar to this combination have been observed. Adverse reactions are similar in terms of nature, severity, and frequency to those reported previously with amlodipine and atorvastatin. The following information is based on the clinical experience with amlodipine and atorvastatin. Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are dizziness and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows: Amlodipine 2.5 mg 5 mg 10 mg Placebo N=275 N=296 N=268 N=520 Edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitations 0.7 1.4 4.5 0.6 Other adverse reactions that were not clearly dose related but were reported at an incidence greater than 1.0% in placebo-controlled clinical trials include the following: Amlodipine (%) Placebo (%) (N=1730) (N=1250) Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal Pain 1.6 0.3 Somnolence 1.4 0.6 Edema, flushing, palpitations, and somnolence appear to be more common in women than in men. The following events occurred in < 1% but > 0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis. Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. General: allergic reaction, asthenia,2 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System: arthralgia, arthrosis, muscle cramps,2 myalgia. Psychiatric: sexual dysfunction (male2 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. 7 Reference ID: 5473667 Respiratory System: dyspnea,2 epistaxis. Skin and Appendages: angioedema, erythema multiforme, pruritus,2 rash,2 rash erythematous, rash maculopapular. Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus. Urinary System: micturition frequency, micturition disorder, nocturia. Autonomic Nervous System: dry mouth, sweating increased. Metabolic and Nutritional: hyperglycemia, thirst. Hemopoietic: leukopenia, purpura, thrombocytopenia. 2 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total TG, TC, HDL-C, uric acid, blood urea nitrogen, or creatinine. Atorvastatin In the atorvastatin placebo-controlled clinical trial database of 16066 patients (8755 atorvastatin vs. 7311 placebo; age range 10-93 years, 39% female, 91% White, 3% Black or African American, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). Table 2 summarizes adverse reactions, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials. Table 2. Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin-Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755 Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3 Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9 Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8 Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0 Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4.0 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 2.9 2.8 1.1 5.3 2.8 3.0 Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3 Other adverse reactions reported in placebo-controlled trials include: Body as a Whole: malaise, pyrexia Digestive System: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal System: musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and Nutritional System: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous System: nightmare 8 Reference ID: 5473667 Respiratory System: epistaxis Skin and Appendages: urticaria Special Senses: vision blurred, tinnitus Urogenital System: white blood cells urine positive. Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin. Treating to New Targets Study (TNT) In TNT, [see Clinical Studies (14.6)] 10,001 patients (age range 29–78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin 10 mg daily (n=5006) or atorvastatin 80 mg daily (n=4995). In the high-dose atorvastatin group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN twice within 4–10 days) occurred in 1.3% of individuals with atorvastatin 80 mg and in 0.2% of individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin group (0.3%) compared to the low-dose atorvastatin group (0.1%). Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4731 patients (age range 21–92 years, 40% female; 93% White, 3% Black or African American, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK ( > 10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group. In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin vs. 4% placebo). Adverse Reactions from Clinical Studies of Atorvastatin in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Black or African American, 1.6% Asian, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (8.4) and Clinical Studies (14.11)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of amlodipine and atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Amlodipine The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles. 9 Reference ID: 5473667 Atorvastatin Gastrointestinal Disorders: pancreatitis General Disorders: fatigue Hepatobiliary Disorders: fatal and non-fatal hepatic failure Immune System Disorders: anaphylaxis Injury: tendon rupture Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Nervous System Disorders: dizziness, peripheral neuropathy. There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric Disorders: depression Respiratory Disorders: interstitial lung disease Skin and Subcutaneous Tissue Disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis) 7 DRUG INTERACTIONS Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the Cmax: 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful. No drug interaction studies have been conducted with CADUET and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: Amlodipine 7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)]. CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)]. 7.2 Impact of Amlodipine on Other Drugs Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)]. Atorvastatin 7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 10 Reference ID: 5473667 Table 3. Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3)]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3)]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention:  Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended.  In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.  In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir do not exceed atorvastatin 20 mg.  In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration (2)].  Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin.  Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3)]. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [see Dosage and Administration (2)]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin ( > 1 gram/day niacin) with atorvastatin. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. 11 Reference ID: 5473667 Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin. 7.4 Drug Interactions that may Decrease Exposure to Atorvastatin Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them. Table 4. Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin and rifampin simultaneously. 7.5 Atorvastatin Effects on Other Drugs Table 5 presents atorvastatin’s effect on other drugs and instructions for preventing or managing them. Table 5. Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)]. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin. Digoxin Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients taking digoxin appropriately. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Atorvastatin Discontinue atorvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data). Amlodipine The limited available data based on postmarketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at 12 Reference ID: 5473667 doses approximately 10 and 20-times MRHD, respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Data Human Data Atorvastatin A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders– including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin Was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Amlodipine No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. 8.2 Lactation Risk Summary Atorvastatin 13 Reference ID: 5473667 There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including atorvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with CADUET [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)]. Data Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma). Amlodipine Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production. 8.4 Pediatric Use The safety and effectiveness of CADUET have not been established in pediatric populations. Amlodipine Amlodipine (2.5 to 5 mg daily) is effective in lowering blood pressure in patients 6 to 17 years [see Clinical Studies (14.1)]. The effect of amlodipine on blood pressure in patients less than 6 years of age is not known. Atorvastatin The safety and effectiveness of atorvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of atorvastatin for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females. The safety and effectiveness of atorvastatin as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established in pediatric patients 10 years of age and older with HoFH. Use of CADUET for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14)]. The safety and effectiveness of atorvastatin have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH). 8.5 Geriatric Use Safety and effectiveness of CADUET have not been established in geriatric populations. Amlodipine Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required [see Dosage and Administration (2)]. Atorvastatin Of the total number of atorvastatin-treated patients in clinical trials, 15813 (40%) were ≥ 65 years old and 2800 (7%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients. Advanced age (≥65 years) is a risk factor for atorvastatin -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving CADUET for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 14 Reference ID: 5473667 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of atorvastatin, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. CADUET is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. 10 OVERDOSAGE There is no information on overdosage with CADUET in humans. Amlodipine Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the MRHD on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension. If overdose should occur with amlodipine, initiate active cardiac and respiratory monitoring. Perform frequent blood pressure measurements. Should hypotension occur, provide cardiovascular support including elevation of the extremities and administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with specific attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Atorvastatin No specific antidotes for atorvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance. 11 DESCRIPTION CADUET (amlodipine and atorvastatin) tablets combine the calcium channel blocker amlodipine besylate with the HMG-CoA-reductase inhibitor atorvastatin calcium. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4 dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S. Atorvastatin calcium is chemically described as [R-(R, R)]-2-(4-fluorophenyl)-ß, -dihydroxy-5-(1-methylethyl)-3-phenyl 4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Its empirical formula is (C33H34FN2O5)2Ca•3H2O. 15 Reference ID: 5473667 • Ca~ • 3H,,O 2 The structural formulae for amlodipine besylate and atorvastatin calcium are shown below. H3C O H3C NH Cl O O CH3 O O C6H6O3 NH2 Amlodipine besylate Atorvastatin calcium CADUET contains amlodipine besylate, a white to off-white crystalline powder, and atorvastatin calcium, also a white to off-white crystalline powder. Amlodipine besylate has a molecular weight of 567.1 and atorvastatin calcium has a molecular weight of 1209.42. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Atorvastatin calcium is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol. CADUET is available as film-coated tablets containing:  5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 10 mg atorvastatin equivalent to 10.4 mg atorvastatin calcium.  5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 20 mg atorvastatin equivalent to 20.7 mg atorvastatin calcium.  5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 40 mg atorvastatin equivalent to 41.4 mg atorvastatin calcium.  5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 80 mg atorvastatin equivalent to 82.9 mg atorvastatin calcium.  10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 10 mg atorvastatin equivalent to 10.4 mg atorvastatin calcium.  10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 20 mg atorvastatin equivalent to 20.7 mg atorvastatin calcium.  10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 40 mg atorvastatin equivalent to 41.4 mg atorvastatin calcium.  10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 80 mg atorvastatin equivalent to 82.9 mg atorvastatin calcium. Each film-coated tablet also contains calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate, Opadry® II White 85F28751 (polyvinyl alcohol, titanium dioxide, PEG 3000, and talc) or Opadry® II Blue 85F10919 (polyvinyl alcohol, titanium dioxide, PEG 3000, talc, and FD&C blue #2). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action CADUET is a combination of two drugs, a dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of CADUET inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of CADUET is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Amlodipine Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion 16 Reference ID: 5473667 channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following: Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise. Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal’s or variant) angina. Atorvastatin Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles. 12.2 Pharmacodynamics Amlodipine Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina. With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg). In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria. As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks. Atorvastatin 17 Reference ID: 5473667 Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)]. Drug Interactions Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7.1)]. 12.3 Pharmacokinetics Absorption Amlodipine: After oral administration of therapeutic doses of amlodipine alone, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%. Atorvastatin: After oral administration alone, atorvastatin is rapidly absorbed; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC,LDL-C reduction is similar whether atorvastatin is given with or without food Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. CADUET: Following oral administration of CADUET, peak plasma concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and 1 to 2 hours post dosing, respectively. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from CADUET are not significantly different from the bioavailability of amlodipine and atorvastatin administered separately (see above). The bioavailability of amlodipine from CADUET was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from CADUET by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food. Distribution Amlodipine: Ex vivo studies have shown that approximately 93% of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Atorvastatin: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is  98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Elimination Metabolism Amlodipine: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Atorvastatin: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P4503A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Amlodipine: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Ten percent of the parent amlodipine compound and 60% of the metabolites of amlodipine are excreted in the urine. Atorvastatin: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours because of the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. 18 Reference ID: 5473667 Specific Populations Geriatric Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose of amlodipine may be required. Atorvastatin: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age  65 years) than in young adults. Pediatric Amlodipine: Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults. Atorvastatin: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population pharmacokinetics model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender Atorvastatin: Plasma concentrations of atorvastatin in females differ from those in males (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between males and females. Renal Impairment Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose. Atorvastatin: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin [see Use in Specific Populations (8.6)]. While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to clear atorvastatin or amlodipine since both drugs are extensively bound to plasma proteins. Hepatic Impairment Amlodipine: Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%. Atorvastatin: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations (8.7)]. Heart Failure Amlodipine: In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency. Effects of Other Drugs on CADUET Amlodipine: Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine. CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7.1)]. 19 Reference ID: 5473667 Atorvastatin: Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 6 shows effects of other drugs on the pharmacokinetics of atorvastatin. Table 6. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosage regimen Atorvastatin Dosage (mg) Ratio of AUC& & Ratio of Cmax #Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QDa for 28 days 8.69 10.66 #Tipranavir 500 mg BIDb/ritonavir 200 mg BIDb, 7 days 10 mg SDc 9.36 8.58 #Glecaprevir 400 mg QDa/pibrentasvir 120 mg QDa, 7 days 10 mg QDa for 7 days 8.28 22.00 #Telaprevir 750 mg q8hf, 10 days 20 mg SDc 7.88 10.60 #, ‡Saquinavir 400 mg BIDb/ritonavir 400 mg BIDb, 15 days 40 mg QDa for 4 days 3.93 4.31 #Elbasvir 50 mg QDa/grazoprevir 200 mg QDa, 13 days 10 mg SDc 1.94 4.34 #Simeprevir 150 mg QDa , 10 days 40 mg SDc 2.12 1.70 #Clarithromycin 500 mg BIDb, 9 days 80 mg QDa for 8 days 4.54 5.38 #Darunavir 300 mg BIDb/ritonavir 100 mg BIDb, 9 days 10 mg QDa for 4 days 3.45 2.25 #Itraconazole 200 mg QDa, 4 days 40 mg SDc 3.32 1.20 #Letermovir 480 mg QDa, 10 days 20 mg SDc 3.29 2.17 #Fosamprenavir 700 mg BIDb/ritonavir 100 mg BIDb, 14 days 10 mg QDa for 4 days 2.53 2.84 #Fosamprenavir 1400 mg BIDb, 14 days 10 mg QDa for 4 days 2.30 4.04 #Nelfinavir 1250 mg BIDb, 14 days 10 mg QDa for 28 days 1.74 2.22 #Grapefruit Juice, 240 mL QDa, 40 mg SDc 1.37 1.16 Diltiazem 240 mg QDa, 28 days 40 mg SDc 1.51 1.00 Erythromycin 500 mg QIDe, 7 days 10 mg SDc 1.33 1.38 Amlodipine 10 mg, single dose 80 mg SDc 1.18 0.91 Cimetidine 300 mg QIDe , 2 weeks 10 mg QDa for 2 weeks 1.00 0.89 Colestipol 10 g BIDb, 24 weeks 40 mg QDa for 8 weeks NA 0.74** 20 Reference ID: 5473667 Co-administered drug and Atorvastatin dosage regimen Dosage (mg) Ratio of AUC& & Ratio of Cmax Maalox TC® 30 mL QIDe, 17 days 10 mg QDa for 15 days 0.66 0.67 Efavirenz 600 mg QDa, 14 days 10 mg for 3 days 0.59 1.01 #Rifampin 600 mg QDa, 7 days (co-administered)† 40 mg SDc 1.12 2.90 #Rifampin 600 mg QDa, 5 days (doses separated)† 40 mg SDc 0.20 0.60 #Gemfibrozil 600 mg BIDb, 7 days 40 mg SDc 1.35 1.00 #Fenofibrate 160 mg QDa, 7 days 40 mg SDc 1.03 1.02 Boceprevir 800 mg TIDd, 7 days 40 mg SDc 2.32 2.66 & Represents ratio of treatments (co-administered drug plus atorvastatin vs atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL – 1.2 liters per day). ** Ratio based on a single sample taken 8-16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dosage d Three times daily e Four times daily f Every 8 hours Effects of CADUET on Other Drugs Amlodipine: Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates. In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin. Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time. Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7.2)]. Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N=6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2)]. 21 Reference ID: 5473667 Atorvastatin: Table 7 shows the effects of atorvastatin on the pharmacokinetics of other drugs. Table 7. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosage regimen Drug/Dosage (mg) Ratio of AUC Ratio of Cmax 80 mg QDa for 15 days Antipyrine, 600 mg SDc 1.03 0.89 80 mg QDa for 10 days # Digoxin 0.25 mg QDa, 20 days 1.15 1.20 40 mg QDa for 22 days Oral contraceptive QDa, 2 months – norethindrone 1 mg – ethinyl estradiol 35 g 1.28 1.19 1.23 1.30 10 mg SDc Tipranavir 500 mg BIDb/ritonavir 200 mg BIDb, 7 days 1.08 0.96 10 mg QDa for 4 days Fosamprenavir 1400 mg BIDb, 14 days 0.73 0.82 10 mg QDa for 4 days Fosamprenavir 700 mg BIDb/ritonavir 100 mg BIDb, 14 days 0.99 0.94 # See Section 7 for clinical significance. a b Once daily Twice daily c Single dosage Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Amlodipine Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the MRHD of 10 mg amlodipine/day.4 For the rat, the highest dose level was, on a mg/m2 basis, about twice the MRHD.4 Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome levels. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the MRHD4 of 10 mg/day on a mg/m2 basis). 4 Based on patient weight of 50 kg. Atorvastatin In a 2-year carcinogenicity study with atorvastatin calcium in rats at dose levels equivalent to 10, 30, and 100 mg atorvastatin/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0-24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given atorvastatin calcium at dose levels equivalent to 100, 200, or 400 mg atorvastatin/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0–24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There 22 Reference ID: 5473667 was aplasia and aspermia in the epididymis of 2 of 10 rats treated with atorvastatin calcium at a dose equivalent to 100 mg atorvastatin/kg/day for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg/day and epididymal weight was lower at 100 mg/kg/day. Male rats given the equivalent of 100 mg atorvastatin/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of atorvastatin calcium equivalent to 10, 40, or 120 mg atorvastatin/kg/day for 2 years. 14 CLINICAL STUDIES 14.1 Amlodipine for Hypertension Adult Patients The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients. Pediatric Patients Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults. 14.2 Amlodipine for Chronic Stable Angina The effectiveness of 5–10 mg/day of amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm). 14.3 Amlodipine for Vasospastic Angina In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p < 0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued from the study for lack of clinical improvement. 14.4 Amlodipine for Coronary Artery Disease In PREVENT, 825 patients with angiographically documented CAD were randomized to amlodipine (5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD. CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction < 40%. Patients (76% males, 89% Caucasian, 93% enrolled at U.S. sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p=0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 8). Effects in various subgroups are shown in Figure 2. 23 Reference ID: 5473667 In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound. Figure 1. Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine versus Placebo 1318 1250 1193 1157 1130 1098 1066 1039 594 # at risk Event Rate 0 6 12 18 24 0.0 0.05 0.10 0.15 0.20 0.25 Amlodipine Placebo P-value=0.003 Hazard Ratio=0.691 95% CI=(0.54, 0.88) Favors AmJodlpine Ji'avOO"s Placebo OvenD All Patients (N=J3JB} Age <65 (N=985) >=•• (N=•••l Gender Male (N=9B4) Female (N=334) Baseline Sitting SBP <= Mean• (N=600) > Mean• (N=6J B) Baseline Ves&el Di&ene ,m .. e (N=O) Multiple (N=J3Jo) B11Eline Ves11el& with Stmo&i11 At lel!!lsl one Vea111el with > 80% Sl.1!11.oBiB (N=ll50) No VeHel with> 60% Steno&i11 (N=465) PCI-t1lent strata No PCI (N =680) PCI Trthoul Stent Pl a 1?emerrt. (N=53} Stl!J'll Plai:!l!fflent (N=5115} 0.0 ---- ' ' --+--+ ' ' _____ , ---- ,A - _, o., 1.0 1., 1-laYord Ratio (95% Confldenee ln+enrol) • The mean sittinc baseline SBP is J ~ mmHg 2.0 Time (Months) Figure 2. Effects on Primary Endpoint of Amlodipine versus Placebo across Sub-Groups Table 8 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, 24 Reference ID: 5473667 hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine and placebo. Table 8. Incidence of Significant Clinical Outcomes for CAMELOT Clinical Outcomes N (%) Amlodipine (N=663) Placebo (N=655) Risk Reduction (p-value) Composite CV Endpoint 110 (16.6) 151 (23.1) 31% (0.003) Hospitalization for Angina* 51 (7.7) 84 (12.8) 42% (0.002) Coronary 78 103 27% Revascularization* (11.8) (15.7) (0.033) * Total patients with these events. 14.5 Amlodipine for Heart Failure Amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study. Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or amlodipine (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema. 14.6 Atorvastatin for Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% female; 95% White, 3% Black or African American, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤ 251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age > 55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL > 6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with antihypertensive therapy (goal BP < 140/90 mm Hg for patients without diabetes; < 130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of atorvastatin on lipid levels was similar to that seen in previous clinical trials. Atorvastatin significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin vs. 3.0% for placebo), p=0.0005 (see Figure 3)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin was seen regardless of baseline LDL levels. 25 Reference ID: 5473667 4.0 0.0 -··' - Alorvaslalln ,: - - - Placebo .•· ·'.,. ,. ~r , .. • ,#-# , _.,, ,. ,., ,✓ . .,, ... - .--' ,.- ••• ;· •' HR=0.64 (0.50--0.83) p=0.0005 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Figure 3. Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% White, 2% Black or African American, 2% South Asian, 1% other, 68% male), ages 40–75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL  160 mg/dL and triglycerides (TG)  600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the trial. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years; mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 4). An effect of atorvastatin was seen regardless of age, sex, or baseline lipid levels. Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the atorvastatin group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin group vs. 82 deaths in the placebo group (HR 0.73, p=0.059). 26 Reference ID: 5473667 0.2 ..., C Q) > w Cl C ·u C Q) ·~ a. 0.1 X w ~ ~ ~ Q) ii' ::; Cl) 0 0 ___ .,._., .. -· ,-- .-- ___ .. , , - _, -.. ,- ,, Atorvastatin 10 mg - - - - Atorvastatin 80 mg -- 2 .,.,- .,. , ,, ,., .... - , .. _,.,. , -- __ . .,.,. , - , .- HR 0.78 (0.69-0.89) P=0.0002 3 4 Time to First Major Cardiovascular Endpoint (Years) 5 15 15 15 10 10 10 5 0 Time to First Primary Endpoint Through Four (4) Years of Follow-up (Years) Cumulative Hazard (%) 1 2 3 4 5 Figure 4. Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS 15 10 5 0 Time to First Primary Endpoint Through Four (4) Years of Follow-up (Years) In the Treating to New Targets Study (TNT), the effect of atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% White, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level < 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin and followed for a median duration of 4.9 years. The primary endpoint was the time to first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin. Treatment with atorvastatin 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 5 and Table 9). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or sex. Figure 5. Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) Cumulative Hazard (%) Placebo Atorvastatin HR 0.63 (0.48-0.83) p=0.001 Placebo Atorvastatin Placebo Atorvastatin HR 0.63 (0.48-0.83) p=0.001 Placebo Atorvastatin 1 2 3 4 5 27 Reference ID: 5473667 Table 9. Overview of Efficacy Results in TNT Endpoint Atorvastatin 10 mg (N=5006) Atorvastatin 80 mg (N=4995) HRa (95% CI) PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89) Components of the Primary Endpoint CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03) Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93) Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67) Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96) SECONDARY ENDPOINTS* First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94) First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15) First CABG or other coronary revascularization procedureb 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpointb 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99) All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19) Components of All-Cause Mortality Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03) Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57) Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55) Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00) Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82) * Secondary endpoints not included in primary endpoint. HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons. a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 9). Of the predefined secondary endpoints, treatment with atorvastatin 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF. There was no significant difference between the treatment groups for all-cause mortality (Table 9). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group. 14.7 Atorvastatin for Primary Hyperlipidemia in Adults Atorvastatin reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. In two multicenter, placebo-controlled, dose-response trials in patients with hyperlipidemia, atorvastatin given as a single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 10.) 28 Reference ID: 5473667 Table 10. Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean % Change From Baseline)a Dose N TC LDL-C Apo B TG HDL-C Placebo 21 4 4 3 10 -3 10 22 -29 -39 -32 -19 6 20 20 -33 -43 -35 -26 9 40 21 -37 -50 -42 -29 6 80 23 -45 -60 -50 -37 5 a Results are pooled from 2 dose-response trials. In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin 10 mg per day or a fixed dose of the comparative agent (Table 11). Table 11. Mean Percentage Change from Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) Treatment (Daily Dosage) N Total-C LDL-C Apo B TG HDL-C Trial 1 Atorvastatin 10 mg 707 -27a -36a -28a -17a +7 Lovastatin 20 mg 191 -19 -27 -20 -6 +7 95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7, 2.0 Trial 2 Atorvastatin 10 mg 222 -25b -35b -27b -17b +6 Pravastatin 20 mg 77 -17 -23 -17 -9 +8 95% CI for Diff1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 Trial 3 Atorvastatin 10 mg 132 -29c -37c -34c -23c +7 Simvastatin 10 mg 45 -24 -30 -30 -15 +7 95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p  0.05 b Significantly different from pravastatin, ANCOVA, p  0.05 c Significantly different from simvastatin, ANCOVA, p  0.05 Table 11 does not contain data comparing the effects of atorvastatin 10 mg and higher dosage of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily exchangeable. 14.8 Atorvastatin for Hypertriglyceridemia in Adults The response to atorvastatin in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 12). For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267–1,502). Table 12. Combined Patients with Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo (N=12) Atorvastatin 10 mg (N=37) Atorvastatin 20 mg (N=13) Atorvastatin 80 mg (N=14) Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3) Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8) LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2) non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3) 29 Reference ID: 5473667 14.9 Atorvastatin for Dysbetalipoproteinemia in Adults The results of an open-label crossover trial of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 13). Table 13. Open-Label Crossover Trial of 16 Patients with Dysbetalipoproteinemia (Fredrickson Type III) Median % Change (min, max) Median (min, max) at Baseline (mg/dL) Atorvastatin10 mg Atorvastatin 80 mg Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30) Intermediate-densit y lipoprotein cholesterol (IDL-C) + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8) non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36) 14.10 Atorvastatin for Homozygous Familial Hypercholesterolemia in Adults and Pediatric Patients In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% < 18 years) with HoFH received maximum daily doses of 20 to 80 mg of atorvastatin. The mean LDL-C reduction in this trial was 18%. Twenty- five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%. 14.11 Atorvastatin for Heterozygous Familial Hypercholesterolemia in Pediatric Patients In a double-blind, placebo-controlled trial followed by an open-label phase, 187 males and post-menarchal females 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Black or African American, 1.6% Asian, 4.8% other) with HeFH or severe hypercholesterolemia, were randomized to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the trial required 1) a baseline LDL-C level  190 mg/dL or 2) a baseline LDL-C level  160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 219 mg/dL (range: 139-385 mg/dL) in the atorvastatin group compared to 230 mg/dL (range: 160-325 mg/dL) in the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%). Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 14). Table 14. Lipid-Altering Effects of Atorvastatin in Adolescent Males and Females with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change from Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apo B Placebo 47 -1.5 -0.4 -1.9 1.0 0.7 Atorvastatin 140 -31.4 -39.6 2.8 -12.0 -34.0 The mean achieved LDL-C value was 130.7 mg/dL (range: 70–242 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152–385 mg/dL) in the placebo group during the 26-week double-blind phase. Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 males and 81 females). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black, African American or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of <130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical trials in both adult and pediatric placebo-controlled trials. 30 Reference ID: 5473667 14.12 CADUET for Hypertension and Dyslipidemia In a double-blind, placebo-controlled study, a total of 1660 patients with co-morbid hypertension and dyslipidemia received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg), amlodipine alone (5 mg or 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg), or placebo. In addition to concomitant hypertension and dyslipidemia, 15% of the patients had diabetes mellitus, 22% were smokers, and 14% had a positive family history of cardiovascular disease. At eight weeks, all eight combination-treatment groups of amlodipine and atorvastatin demonstrated statistically significant dose-related reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP), and LDL-C compared to placebo, with no overall modification of effect of either component on SBP, DBP, and LDL-C (Table 15). Table 15. Effects of Amlodipine and Atorvastatin on Blood Pressure and LDL-C BP (mmHg) Atorvastatin Amlodipin e 0 mg 10 mg 20 mg 40 mg 80 mg 0 mg — -1.5/-0.8 -3.2/-0.6 -3.2/-1.8 -3.4/-0.8 5 mg -9.8/-4.3 -10.7/-4.9 -12.3/-6.1 -9.7/-4.0 -9.2/-5.1 10 mg -13.2/-7.1 -12.9/-5.8 -13.1/-7.3 -13.3/-6.5 -14.6/-7.8 LDL-C (% change) Atorvastatin Amlodipin e 0 mg 10 mg 20 mg 40 mg 80 mg 0 mg — -32.3 -38.4 -42.0 -46.1 5 mg 1.0 -37.6 -41.2 -43.8 -47.3 10 mg -1.4 -35.5 -37.5 -42.1 -48.0 16 HOW SUPPLIED/STORAGE AND HANDLING CADUET® tablets contain amlodipine besylate and atorvastatin calcium equivalent to amlodipine and atorvastatin in the dose strengths described below. CADUET tablets are differentiated by tablet color/size and are engraved with a unique number on one side. Combinations of atorvastatin with 5 mg amlodipine are oval and film-coated white tablets and combinations of atorvastatin with 10 mg amlodipine are oval and are film-coated blue tablets. CADUET tablets are supplied for oral administration in the following strengths and package configurations: Table 16. CADUET Packaging Configurations CADUET Package Configuration Tablet Strength mg (amlodipine / atorvastatin) NDC # Engraving Side 1 / Side 2 Tablet Color Tablet Shape Bottle of 30 5/10 0069-2150-30 or 0069-6180-30 CDT 051/Pfizer White Oval Bottle of 30 5/20 0069-2170-30 or 0069-6323-30 CDT 052/Pfizer White Oval Bottle of 30 5/40 0069-2190-30 or 0069-6565-30 CDT 054/Pfizer White Oval Bottle of 30 5/80 0069-2260-30 or 0069-6747-30 CDT 058/Pfizer White Oval Bottle of 30 10/10 0069-2160-30 or 0069-7810-30 CDT 101/Pfizer Blue Oval Bottle of 30 10/20 0069-2180-30 or 0069-7232-30 CDT 102/Pfizer Blue Oval Bottle of 30 10/40 0069-2250-30 or 0069-7654-30 CDT 104/Pfizer Blue Oval 31 Reference ID: 5473667 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 Bottle of 30 10/80 0069-2270-30 or 0069-7476-30 CDT 108/Pfizer Blue Oval Store at 25°C (77°F); excursions permitted to 15°C -30°C (59°F -86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that CADUET may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. Hepatic Dysfunction Inform patients that CADUET may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.3)]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with CADUET. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.6)]. Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if CADUET should be discontinued [see Use in Specific Populations (8.1)]. Lactation Advise patients that breastfeeding is not recommended during treatment with CADUET [see Use in Specific Populations (8.2)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0276-43.1 32 Reference ID: 5473667 PATIENT INFORMATION CADUET® (CAD-oo-et) (amlodipine and atorvastatin) Tablets Read the patient information that comes with CADUET before you start taking it, and each time you get a refill. There may be new information. This information does not replace talking with your healthcare provider about your condition or treatment. If you have any questions about CADUET, ask your healthcare provider or pharmacist. What is CADUET? CADUET is a prescription drug that combines Norvasc (amlodipine besylate) and Lipitor (atorvastatin calcium) in one pill. CADUET is used in adults who need both Norvasc and Lipitor. Norvasc is used to treat:  High blood pressure (hypertension) and  Chest pain (angina) and  Blocked arteries of the heart (coronary artery disease) Lipitor is used to lower the levels of “bad” cholesterol and triglycerides in your blood. It can also raise the levels of “good” cholesterol. Lipitor is also used to lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as: • age, smoking, high blood pressure, low levels of “good” cholesterol, heart disease in the family. Lipitor can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: • diabetic eye or kidney problems, smoking, or high blood pressure. CADUET has not been studied in children. Who should not use CADUET? Do not use CADUET if you:  Have liver problems (acute liver failure or decompensated cirrhosis).  Are allergic to anything in CADUET. The active ingredients are atorvastatin calcium and amlodipine besylate. Stop using CADUET and get medical help right away if you have symptoms of a serious allergic reaction including: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o fainting or feeling dizzy Reference ID: 5473667 o very rapid heartbeat o severe skin rash or itching o flu-like symptoms including fever, sore throat, cough, tiredness, and joint pain See the end of this leaflet for a complete list of ingredients. What should I tell my healthcare provider before taking CADUET? Tell your healthcare provider about all of your health conditions, including, if you:  have unexplained muscle aches or weakness  drink more than 2 glasses of alcohol daily  have heart disease  have diabetes  have thyroid problems  have kidney problems  had a stroke  are pregnant or plan to become pregnant. CADUET may harm your unborn baby. If you become pregnant, stop taking CADUET and call your healthcare provider right away.  are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take CADUET or breastfeed. You should not do both. Talk to your healthcare provider about the best way to feed your baby if you take CADUET. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. CADUET and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your healthcare provider if you take medicines for:  your immune system (cyclosporine)  cholesterol (gemfibrozil)  infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and  voriconazole)  birth control pills  heart failure (digoxin)  gout (colchicine)  niacin  fibrates  treating HIV, AIDS, or hepatitis C (anti-virals) o tipranavir plus ritonavir o glecaprevir plus pibrentasvir o ledipasvir plus sofosbuvir o simeprevir o saquinavir plus ritonavir o darunavir plus ritonavir o fosamprenavir o fosamprenavir plus ritonavir o elbasvir plus grazoprevir o letermovir o nelfinavir You can use nitroglycerin and CADUET together. If you take nitroglycerin for chest pain (angina), do not stop taking it while taking CADUET. Reference ID: 5473667 Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine. How should I take CADUET?  Take CADUET exactly as your healthcare provider tells you to take it.  Do not change your dose or stop CADUET without talking to your healthcare provider  Your healthcare provider may do blood tests to check your cholesterol levels during your treatment with CADUET. Your dose of CADUET may be changed based on these blood test results.  Take CADUET each day at any time of day. CADUET can be taken with or without food.  Do not break the tablets before taking them. Talk to your healthcare provider if you have a problem swallowing pills.  Your healthcare provider may start you on a cholesterol-lowering diet before giving you CADUET. Stay on this low-fat diet when you take CADUET.  If you miss a dose, take it as soon as you remember. Do not take CADUET if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of CADUET at the same time. If you take too much CADUET or overdose, call your healthcare provider or Poison Control Center at 1-800-222 1222 or go to the nearest emergency room right away. What should I avoid while taking CADUET?  Avoid drinking more than 1.2 liters of grapefruit juice each day. What are possible side effects of CADUET? CADUET can cause serious side effects including:  Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death. Tell your healthcare provider right away if you have: o unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take CADUET. o muscle problems that do not go away after your healthcare provider has told you to stop taking CADUET. Your healthcare provider may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: o are taking certain other medicines while you take CADUET o drink large amounts of grapefruit juice o are 65 years of age or older o have thyroid problems (hypothyroidism) that are not controlled o have kidney problems o are taking higher doses of CADUET Reference ID: 5473667  Liver problems. Your healthcare provider should do blood tests to check your liver before you start taking CADUET and if you have symptoms of liver problems while you take CADUET. Call your healthcare provider right away if you have the following symptoms of liver problems: o feel tired or weak o nausea or vomiting o loss of appetite o upper belly pain o dark amber colored urine o yellowing of your skin or the whites of your eyes  Low blood pressure or dizziness  Muscle rigidity, tremor and/or abnormal muscle movement  Increase in blood sugar level. Your blood sugar level may increase while you are taking CADUET. Exercise regularly and make healthy food choices to maintain healthy body weight. Call your healthcare provider right away if:  allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away  you have allergic skin reactions  Chest pain that does not go away or gets worse. Sometimes when you start CADUET or increase your dose, chest pain can get worse or a heart attack can happen. If this happens, call your healthcare provider or go to the emergency room right away. Common side effects of CADUET include:  nasal congestion, sore throat, runny nose  muscle and joint pain  diarrhea  pain in extremity  urinary tract infection  upset stomach  nausea  musculoskeletal pain  muscle spasms  trouble sleeping  throat pain  swelling of your legs or ankles Additional side effects have been reported: tiredness, tendon problems, memory loss, and confusion. Talk to your healthcare provider or pharmacist about side effects that bother you or do not go away. There are other side effects of CADUET. Ask your healthcare provider or pharmacist for a complete list. Reference ID: 5473667 How do I store CADUET?  Store CADUET at room temperature, 68°F to 77°F (20°C to 25°C).  Do not keep medicine that is out-of-date or that you no longer need.  Keep CADUET and all medicines out of the reach of children. General information about the safe and effective use of CADUET Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CADUET for a condition for which it was not prescribed. Do not give CADUET to other people, even if they have the same symptoms that you have. It may harm them. If you want more information about CADUET, talk with your healthcare provider . You can ask your pharmacist or healthcare provider for information about CADUET that is written for health professionals. What is high blood pressure (hypertension)? You have high blood pressure when the force of blood against the walls of your arteries stays high. This can damage your heart and other parts of your body. Drugs that lower blood pressure lower your risk of having a stroke or heart attack. What is angina (chest pain)? Angina is a pain that keeps coming back when part of your heart does not get enough blood. It feels like something is pressing or squeezing your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaw, or back. What is cholesterol? Cholesterol is a fat-like substance made in your body. It is also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol can clog your blood vessels. What is a heart attack? A heart attack occurs when heart muscle does not get enough blood. Symptoms include chest pain, trouble breathing, nausea, and weakness. Heart muscle cells may be damaged or die. The heart cannot pump well or may stop beating. What is a stroke? A stroke occurs when nerve cells in the brain do not get enough blood. The cells may be damaged or die. The damaged cells may cause weakness or problems speaking or thinking. WHAT ARE THE INGREDIENTS IN CADUET? Active ingredients: amlodipine besylate, atorvastatin calcium Reference ID: 5473667 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 Inactive ingredients: calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate Film coating: Opadry® II White 85F28751 (polyvinyl alcohol, titanium dioxide, PEG 3000, and talc) or Opadry® II Blue 85F10919 (polyvinyl alcohol, titanium dioxide, PEG 3000, talc, and FD&C blue #2) LAB-0347-14.1 Revised November 2024 Reference ID: 5473667	custom-source	2025-02-12T15:46:32.167671	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021540s050lbl.pdf', 'application_number': 21540, 'submission_type': 'SUPPL ', 'submission_number': 50}
80,149	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BRILINTA safely and effectively. See full prescribing information for BRILINTA. BRILINTA® (ticagrelor) tablets, for oral use Initial U.S. Approval: 2011 WARNING: BLEEDING RISK See full prescribing information for complete boxed warning. • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. (5.1, 6.1) • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage. (4.1, 4.2) • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery (CABG). (5.1, 6.1) • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events. (5.2) -------------------------- RECENT MAJOR CHANGES ------------------------- Dosage and Administration (2.2, 2.4) 03/2024 --------------------------- INDICATIONS AND USAGE ------------------------- BRILINTA is a P2Y12 platelet inhibitor indicated • to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS. (1.1) • to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of BRILINTA was established in a population with type 2 diabetes mellitus (T2DM). (1.2) • to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA). (1.3) ---------------------- DOSAGE AND ADMINISTRATION --------------------- • ACS or History of MI o Initiate treatment with 180 mg oral loading dose of BRILINTA. Then administer 90 mg twice daily during the first year. After one year, administer 60 mg twice daily. (2.2) • Patients with CAD and No Prior Stroke or MI o Administer 60 mg BRILINTA twice daily. (2.3) • Acute Ischemic Stroke o Initiate treatment with a 180 mg loading dose of BRILINTA then continue with 90 mg twice daily for up to 30 days. (2.4) Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. (2) However, in patients who have undergone PCI, consider single antiplatelet therapy with BRILINTA based on the evolving risk for thrombotic versus bleeding events. (2.2) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- • 60 mg and 90 mg tablets. (3) ---------------------------- CONTRAINDICATIONS ------------------------------ • History of intracranial hemorrhage. (4.1) • Active pathological bleeding. (4.2) • Hypersensitivity to ticagrelor or any component of the product. (4.3) -----------------------WARNINGS AND PRECAUTIONS ----------------------- • Dyspnea was reported more frequently with BRILINTA than with control agents in clinical trials. Dyspnea from BRILINTA is self-limiting. (5.3) • Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. (5.5) • Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). BRILINTA is not expected to impact PF4 antibody testing for HIT. (5.7) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (>5%) are bleeding and dyspnea. (5.1, 5.3, 6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- • Avoid use with strong CYP3A inhibitors or CYP3A inducers. (7.1, 7.2) • Opioids: Decreased exposure to ticagrelor. Consider use of parenteral anti- platelet agent. (7.3) • Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. (7.4) • Rosuvastatin plasma concentrations may increase. Monitor for statin-related adverse effects. (7.4) • Monitor digoxin levels with initiation of or any change in BRILINTA. (7.5) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Lactation: Breastfeeding not recommended. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: BLEEDING RISK 1 INDICATIONS AND USAGE 1.1 Acute Coronary Syndrome or a History of Myocardial Infarction 1.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction 1.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) 2 DOSAGE AND ADMINISTRATION 2.1 General Instructions 2.2 Acute Coronary Syndrome or a History of Myocardial Infarction 2.3 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction 2.4 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 History of Intracranial Hemorrhage 4.2 Active Bleeding 4.3 Hypersensitivity 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Bleeding 5.2 Discontinuation of BRILINTA in Patients Treated for Coronary Artery Disease 5.3 Dyspnea 5.4 Bradyarrhythmias 5.5 Severe Hepatic Impairment 5.6 Central Sleep Apnea 5.7 Laboratory Test Interferences 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Strong CYP3A Inhibitors 7.2 Strong CYP3A Inducers 7.3 Opioids 7.4 Simvastatin, Lovastatin, Rosuvastatin 7.5 Digoxin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Acute Coronary Syndromes and Secondary Prevention after Myocardial Infarction 14.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction 14.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) 16 HOW SUPPLIED/STORAGE AND HANDLING 1 Reference ID: 5473698 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: BLEEDING RISK • • • • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding (5.1, 6.1). Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage (4.1, 4.2). Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery (CABG) (5.1, 6.1). If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events (5.2). 1 INDICATIONS AND USAGE 1.1 Acute Coronary Syndrome or a History of Myocardial Infarction BRILINTA is indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies (14.1)]. 1.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction BRILINTA is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events [see Clinical Studies (14.2)]. While use is not limited to this setting, the efficacy of BRILINTA was established in a population with type 2 diabetes mellitus (T2DM). 1.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) BRILINTA is indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA) [see Clinical Studies (14.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Instructions Advise patients who miss a dose of BRILINTA to take their next dose at its scheduled time. For patients who are unable to swallow tablets whole, BRILINTA tablets can be crushed, mixed with water, and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater) [see Clinical Pharmacology (12.3)]. Do not administer BRILINTA with another oral P2Y12 platelet inhibitor. Avoid aspirin at doses higher than recommended [see Clinical Studies (14.1)]. 2 Reference ID: 5473698 2.2 Acute Coronary Syndrome or a History of Myocardial Infarction Initiate treatment with a 180 mg loading dose of BRILINTA. Administer the first 90 mg maintenance dose of BRILINTA, 6 to 12 hours after the loading dose. Administer 90 mg of BRILINTA twice daily during the first year after an ACS event. After one year, administer 60 mg of BRILINTA twice daily. Initiate BRILINTA with a daily maintenance dose of aspirin of 75 mg to 100 mg. However, in patients who have undergone percutaneous coronary intervention (PCI), consider single antiplatelet therapy with BRILINTA based on the evolving risk for thrombotic versus bleeding events [see Warnings and Precautions (5.1) and Clinical Studies (14)]. 2.3 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction Administer 60 mg of BRILINTA twice daily. Generally, use BRILINTA with a daily maintenance dose of aspirin of 75 mg to 100 mg [see Clinical Studies (14)]. 2.4 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) Initiate treatment with a 180 mg loading dose of BRILINTA and then continue with 90 mg twice daily for up to 30 days. Administer the first maintenance dose 6 to 12 hours after the loading dose. Use BRILINTA with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of aspirin of 75 mg to 100 mg [see Clinical Studies (14)]. 3 DOSAGE FORMS AND STRENGTHS BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side. BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet marked with “60” above “T” on one side. 4 CONTRAINDICATIONS 4.1 History of Intracranial Hemorrhage BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies (14.1, 14.2)]. 4.2 Active Bleeding BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 4.3 Hypersensitivity BRILINTA is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Bleeding Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 3 Reference ID: 5473698 Patients treated for acute ischemic stroke or TIA Patients at NIHSS >5 and patients receiving thrombolysis were excluded from THALES and use of BRILINTA in such patients is not recommended. 5.2 Discontinuation of BRILINTA in Patients Treated for Coronary Artery Disease Discontinuation of BRILINTA will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with BRILINTA for five days prior to surgery that has a major risk of bleeding. Resume BRILINTA as soon as hemostasis is achieved. 5.3 Dyspnea In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with BRILINTA developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients. In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment. If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent. 5.4 Bradyarrhythmias BRILINTA can cause ventricular pauses [see Adverse Reactions (6.1)]. Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2nd or 3rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may be at increased risk of developing bradyarrhythmias with ticagrelor. 5.5 Severe Hepatic Impairment Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of BRILINTA patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. 5.6 Central Sleep Apnea Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge. If central sleep apnea is suspected, consider further clinical assessment. 5.7 Laboratory Test Interferences False negative functional tests for Heparin Induced Thrombocytopenia (HIT) BRILINTA has been reported to cause false negative results in platelet functional tests (including the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with BRILINTA is required for interpretation of HIT functional 4 Reference ID: 5473698 5~------------------------------------~ ~ " ., > :;::, .. :i E :, u 4 3 2 N Patients with events KM % al 12 months - Ti90mg 9235 362 ( 3.9%) 4.5% - - Clopidogrel 9186 306 ( 33%) 3.8% o ..J-----..-------.------==;:::=====;:=====::;=====;:::::!.l 0 Nat risk Ti 90 mg 9235 Clopidogrel 9186 60 7563 7648 120 180 240 Days from First Study Drug Dose 7170 7302 6900 7065 5428 5540 300 4022 4103 360 3658 3727 tests. Based on the mechanism of BRILINTA interference, BRILINTA is not expected to impact PF4 antibody testing for HIT. 6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: • Bleeding [see Warnings and Precautions (5.1)] • Dyspnea [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. BRILINTA has been evaluated for safety in more than 58,000 patients. Bleeding in PLATO (Reduction in risk of thrombotic events in ACS) Figure 1 is a plot of time to the first non-CABG major bleeding event. Figure 1 - Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event (PLATO) Frequency of bleeding in PLATO is summarized in Tables 1 and 2. About half of the non-CABG major bleeding events were in the first 30 days. 5 Reference ID: 5473698 Table 1 – Non-CABG related bleeds (PLATO) BRILINTA N=9235 Clopidogrel N=9186 n (%) patients with event n (%) patients with event PLATO Major + Minor 713 (7.7) 567 (6.2) Major 362 (3.9) 306 (3.3) Fatal/Life-threatening 171 (1.9) 151 (1.6) Fatal 15 (0.2) 16 (0.2) Intracranial hemorrhage (Fatal/Life-threatening) 26 (0.3) 15 (0.2) PLATO Minor bleed: requires medical intervention to stop or treat bleeding. PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units. Fatal: A bleeding event that directly led to death within 7 days. * 90 mg BID No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel. In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Figure 2 and Table 2. 6 Reference ID: 5473698 T C % of patients who had an event following CABG 100 90 80 70 60 50 40 30 20 10 0 T C 55/84 52188 2 T C 5onos 42186 3 T C 561114 33n3 4 T C 39184 29169 5 T C 22ll9 27196 6 T C 29191 45/110 7 T C 25/74 40/107 >=8 T C 53/228 73/274 Days Figure 2 – ‘Major fatal/life-threatening’ CABG-related bleeding by days from last dose of study drug to CABG procedure (PLATO) X-axis is days from last dose of study drug prior to CABG. The PLATO protocol recommended a procedure for withholding study drug prior to CABG or other major surgery without unblinding. If surgery was elective or non-urgent, study drug was interrupted temporarily, as follows: If local practice was to allow antiplatelet effects to dissipate before surgery, capsules (blinded clopidogrel) were withheld 5 days before surgery and tablets (blinded ticagrelor) were withheld for a minimum of 24 hours and a maximum of 72 hours before surgery. If local practice was to perform surgery without waiting for dissipation of antiplatelet effects capsules and tablets were withheld 24 hours prior to surgery and use of aprotinin or other hemostatic agents was allowed. If local practice was to use IPA monitoring to determine when surgery could be performed both the capsules and tablets were withheld at the same time and the usual monitoring procedures followed. T Ticagrelor; C Clopidogrel. 7 Reference ID: 5473698 Table 2 – CABG-related bleeding (PLATO) BRILINTA* N=770 Clopidogrel N=814 n (%) patients with event n (%) patients with event PLATO Total Major 626 (81.3) 666 (81.8) Fatal/Life-threatening 337 (43.8) 350 (43.0) Fatal 6 (0.8) 7 (0.9) PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units. * 90 mg BID When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel. Other Adverse Reactions in PLATO Adverse reactions that occurred at a rate of 4% or more in PLATO are shown in Table 3. Table 3 – Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on BRILINTA (PLATO) BRILINTA* N=9235 Clopidogrel N=9186 Dyspnea 13.8 7.8 Dizziness 4.5 3.9 Nausea 4.3 3.8 * 90 mg BID Bleeding in PEGASUS (Secondary Prevention in Patients with a History of Myocardial Infarction) Overall outcome of bleeding events in the PEGASUS study are shown in Table 4. Table 4 – Bleeding events (PEGASUS) BRILINTA* N=6958 Placebo N=6996 Events / 1000 patient years Events / 1000 patient years TIMI Major 8 3 Fatal 1 1 Intracranial hemorrhage 2 1 TIMI Major or Minor 11 5 TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥5 g/dL, or a fall in hematocrit (Hct) of ≥15%. Fatal: A bleeding event that directly led to death within 7 days. TIMI Minor: Clinically apparent with 3-5 g/dL decrease in hemoglobin. * 60 mg BID 8 Reference ID: 5473698 7---r;:::=========;----------------------------, 6 0 events/N --- Ticagrelor 206/9562 - - - - - • Placebo 100/9531 __ .... --.. ---"" 3 6 9 12 15 -~ - 18 ----- -___ .. - .. - .. --- 21 24 27 30 ____ ,.r---------•-----' ..... --- 33 36 39 42 45 48 51 Months from randomization Nat risk 54 T 9562 8452 7928 7584 7309 70 18 6826 6572 6381 6183 5997 4806 4067 3187 2464 1680 1156 579 168 P 9531 90 15 8665 8391 8186 7947 7767 7527 7359 7137 6967 5697 4795 3843 2952 2020 1358 671 218 The bleeding profile of BRILINTA 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e.g., by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, stent, and medical history) for TIMI Major and TIMI Major or Minor bleeding events. Other Adverse Reactions in PEGASUS Adverse reactions that occurred in PEGASUS at rates of 3% or more are shown in Table 5. Table 5 – Non-hemorrhagic adverse reactions reported in >3.0% of patients in the ticagrelor 60 mg treatment group (PEGASUS) BRILINTA* N=6958 Placebo N=6996 Dyspnea 14.2% 5.5% Dizziness 4.5% 4.1% Diarrhea 3.3% 2.5% 60 mg BID Bleeding in THEMIS (Prevention of major CV events in patients with CAD and Type 2 Diabetes Mellitus) The Kaplan-Meier curve of time to first TIMI Major bleeding event is presented in Figure 3. Figure 3 - Time to first TIMI Major bleeding event (THEMIS) T = Ticagrelor; P = Placebo; N = Number of patients The bleeding events in THEMIS are shown below in Table 6. 9 Reference ID: 5473698 '#. Q) > ~ 3 E :::, 0 1.0 -r.============ev=e=n::::ts::;:/N:;====K==M==%:::;-------------------,.-----------i --- Ticagrelor 90 mg bd - - - - • Placebo 0.8 0.6 04 0.2 0 Nat risk T 5523 P 5493 5 5495 5486 28/5523 0.5% 7/5493 0.1% ~ - - - - - .----- --------------- I -- ------· - - 10 5471 5464 I 15 20 Days from randomization 5467 5459 5463 5454 25 5457 5451 30 5456 5450 34 1146 1216 Table 6 – Bleeding events (THEMIS) BRILINTA N=9562 Placebo N=9531 Events / 1000 patient years Events / 1000 patient years TIMI Major 9 4 TIMI Major or Minor 12 5 TIMI Major or Minor or Requiring medical attention 46 18 Fatal bleeding 1 0 Intracranial hemorrhage 3 2 Bleeding in THALES (Reduction in risk of stroke in patients with acute ischemic stroke or TIA) The Kaplan-Meier curve of time course of GUSTO severe bleeding events is presented in Figure 4. Figure 4 - Time course of GUSTO severe bleeding events KM%: Kaplan-Meier percentage evaluated at Day 30; T = Ticagrelor; P = placebo; N = Number of patients GUSTO Severe: Any one of the following: fatal bleeding, intracranial bleeding (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages < 10 mm evident only on gradient-echo magnetic resonance imaging), bleeding that caused hemodynamic compromise requiring intervention (e.g., systolic blood pressure <90 mmg Hg that required blood or fluid replacement, or vasopressor/inotropic support, or surgical intervention). Intracranial bleeding and fatal bleeding in THALES: In total, there were 21 intracranial hemorrhages (ICHs) for BRILINTA and 6 ICHs for placebo. Fatal bleedings, almost all ICH, occurred in 11 for BRILINTA and in 2 for placebo. 10 Reference ID: 5473698 Bradycardia In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6%, respectively, after 1 month. PLATO, PEGASUS, THEMIS and THALES excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). Lab abnormalities Serum Uric Acid: In PLATO, serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA 90 mg and approximately 0.2 mg/dL on clopidogrel. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). In PEGASUS, serum uric acid levels increased approximately 0.2 mg/dL from baseline on BRILINTA 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (1.5%, 1.1%). Mean serum uric acid concentrations decreased after treatment was stopped. Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA 90 mg compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria. In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving BRILINTA 60 mg, similar to aspirin alone. The frequency of renal related adverse events was similar for ticagrelor and aspirin alone regardless of age and baseline renal function. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. TTP is a serious condition which can occur after a brief exposure (<2 weeks) and requires prompt treatment. Immune system disorders: Hypersensitivity reactions including angioedema [see Contraindications (4.3)]. Respiratory Disorders: Central sleep apnea, Cheyne-Stokes respiration Skin and subcutaneous tissue disorders: Rash 7 DRUG INTERACTIONS 7.1 Strong CYP3A Inhibitors Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, 11 Reference ID: 5473698 clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see Clinical Pharmacology (12.3)]. 7.2 Strong CYP3A Inducers Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see Clinical Pharmacology (12.3)]. 7.3 Opioids As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying [see Clinical Pharmacology (12.3)]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists. 7.4 Simvastatin, Lovastatin, Rosuvastatin BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3)]. Brilinta increases serum concentration of rosuvastatin because rosuvastatin is a BCRP substrate [see Clinical Pharmacology (12.3)]. 7.5 Digoxin BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from case reports with BRILINTA use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. When ticagrelor was given to rats during late gestation and lactation, pup death and effects on pup growth were seen at approximately 10 times the MRHD (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of 12 Reference ID: 5473698 pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day (5.5 times the MRHD on a mg/m2 basis), delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred. In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis). 8.2 Lactation Risk Summary There are no data on the presence of ticagrelor or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ticagrelor and its metabolites were present in rat milk at higher concentrations than in maternal plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Breastfeeding is not recommended during treatment with BRILINTA. 8.4 Pediatric Use The safety and effectiveness of BRILINTA have not been established in pediatric patients. Effectiveness was not demonstrated in an adequate and well-controlled study conducted in 101 BRILINTA-treated pediatric patients, aged 2 to <18 for reducing the rate of vaso-occlusive crises in sickle cell disease. 8.5 Geriatric Use About half of the patients in PLATO, PEGASUS, THEMIS, and THALES were ≥65 years of age and at least 15% were ≥75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients. 8.6 Hepatic Impairment Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of BRILINTA in patients with severe hepatic impairment. There is limited experience with BRILINTA in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.3)]. Patients with End-Stage Renal Disease on dialysis Clinical efficacy and safety studies with BRILINTA did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, no clinically significant difference in concentrations of ticagrelor and its metabolite and platelet inhibition are expected compared to those observed in patients with normal renal function [see Clinical Pharmacology (12.3)]. It is not known whether these concentrations will lead to similar efficacy and safety in patients with ESRD on dialysis as were seen in PLATO, PEGASUS, THEMIS and THALES. 13 Reference ID: 5473698 10 OVERDOSAGE There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken. Platelet transfusion did not reverse the antiplatelet effect of BRILINTA in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG. 11 DESCRIPTION BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5 (propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is: Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature. BRILINTA 90 mg tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow. BRILINTA 60 mg tablets for oral administration contain 60 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black, and ferric oxide red. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent. 12.2 Pharmacodynamics The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist. 14 Reference ID: 5473698 100 a.. 90 0 licagrelor 180 mg <( ~ 80 ::) 0 70 C\J >, 60 .n "O 50 Q) u ::) 40 "O Clopidogrel 600 mg E 30 'cfi. 0: 20 10 0 0 2 3 4 5 6 7 8 lime (hour) The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 5, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP. As shown in Figure 6, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 6 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel. Figure 5 – Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel 15 Reference ID: 5473698 100 a.. 0 90 <( ~ 80 ::::i 0 70 C\J >, .0 "'O 50 Q) (.) ::::i 40 "'O C 30 ~ ~ 20 ct. 10 0 0 11. 0 100 ; 00 :, 0 "' ~ "O 1l 40 :, "O .E ~ 20 ~ 0 -~• -·• ················• ························· ~ ' 16 24 32 40 48 lime (hour) -- ■---· --- ■--------- 2 3 4 5 6 7 8 9 10 Time (day) Figure 6 – Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily ● Ticagrelor ▲Clopidogrel ■ Placebo Transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect [see Dosage and Administration (2)]. 12.3 Pharmacokinetics Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption BRILINTA can be taken with or without food. Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0). The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC. BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 –8.0) for AR-C124910XX. Distribution The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%). 16 Reference ID: 5473698 Intrinsic Factors Age: >65/18--45 years Gender: Female/Male Ethnicity: Japanese/Caucasian Renal Impainnent: Severe onnal End Stage Renal Disease on Hemodialys· ormal Hepatic Impairment: Mild omial • Single dose of BR.ILIN1}\ administered on a day wifhout dialysis. Mean effect and 90% CI Tic.agrelor l-a--1 ~ f-a-, 1--6-1 f---a-----1 f---¼---1 I ■ f---¼---l AR--C124910XX: ~ I-¼-! Recommendation No dose adjustment o dose adjustment No dose adjustment o dose adjustment No dose adjustment No dose adjustment O.S 1.0 1.5 2.0 2.5 0.5 LO 1.5 2.0 2.5 Change relative to reference I PK: ■ Cma" A AUC B.Rll..INT.4. bas not been studied in patients u,-i.tb moderate or s evere hepatic impain:oent Metabolism CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor. Ticagrelor is a BCRP inhibitor. Excretion The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite. Specific Populations The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 7. Effects are modest and do not require dose adjustment. Patients with End-Stage Renal Disease on Hemodialysis In patients with end stage renal disease on hemodialysis AUC and Cmax of BRILINTA 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when BRILINTA was administered immediately prior to dialysis showing that BRILINTA is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of BRILINTA was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function. Figure 7 – Impact of intrinsic factors on the pharmacokinetics of ticagrelor 17 Reference ID: 5473698 Mean effect and 90% Cl Interacting drug Ticagrelor AR-C124910XX Recommendation Strong CYP3A4 inhibitors: ■ ■ Avoid concomitant use Ketoconazole 200 mg, twice daily 14-; .... Moderate CYP3A4 inhibitors: ■ No dose adjustment Diltiazem 240 mg, once daily ~ Potent CYP3A4 inducers: ■ Avoid concomitant use Rifampin 600 mg, one daily .... Aspirin 300 mg, once daily Use <= 1 OOmg/day• Desmopressin 0.3 microgram/kg, 2 hour infusion No dose adjustment Heparin 100 IU kg, i.v. bolus No dose adjustment Enoxaparin 1 mg/kg sub-cutaneous No dose adjustment P-gP and CYP3A inhibitors: ■ No dose adjustment Cyclosporine 600 mg single oral dose .... Morphine 5 mg i.v. See Section 7.4 Fentanyl mean total dose 96 micrograms i,v. See Section 7.4 0 2 4 6 8 0 2 4 6 8 Change relative to reference PK: ■Cmax A AUC Effects of Other Drugs on BRILINTA CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 8 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., cyclosporine) increase ticagrelor exposure. Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine. Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition. Figure 8 – Effect of co-administered drugs on the pharmacokinetics of ticagrelor See Dosage and Administration (2) Effects of BRILINTA on Other Drugs In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. In vitro metabolism studies demonstrate that 18 Reference ID: 5473698 Interacting drug (Ticagrelor dose) Simvastatin 80 mg·: (Ticagrelor 180 mg, twice daily) Atorvastatin 80 mg•: (Ticagrelor 90 mg, twice daily) Levonorgestrel 0.15 mg, once daily: (Ticagrelor 90 mg, twice daily) Ethinyl Estradiol 0.03 mg, once daily: (Ticagrelor 90 mg, twice daily) Tolbutamide 500 mg: (Ticagrelor 180 mg, twice daily) Digoxin 0.25 mg, once daily: (Ticagrelor 400 mg, once daily) Cyclosporine 600 mg, single oral dose: (Ticagrelor 180 mg, single dose) 0 Mean Effect and 90% Cl ■ 0.5 1.0 ■ >----A-----< 1.5 2.0 2.5 Change relative to interacting drug alone •similar increases in AUC and Cmax were observed for all metabolites •·Monitor digoxin levels with initiation of or change in BRILINTA therapy Recommendation Maximum simvastatin dose: 40 mg No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment .. No dose adjustment I PK: ■ Cmax A AUG I ticagrelor is a BCRP inhibitor. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 9. Figure 9 – Impact of BRILINTA on the pharmacokinetics of co-administered drugs 12.5 Pharmacogenomics In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats. Mutagenesis Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay. 19 Reference ID: 5473698 Impairment of Fertility Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC). 14 CLINICAL STUDIES 14.1 Acute Coronary Syndromes and Secondary Prevention after Myocardial Infarction PLATO PLATO (NCT00391872) was a randomized double-blind study comparing BRILINTA (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months. PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Median exposure to study drug was 276 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO. Table 7 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality. 20 Reference ID: 5473698 13 12 ---- 11 -_.., .... 10 9 ~ 8 ., ~ 7 "' "5 6 E :, 0 5 4 ' 3 -- Ti 90mg Clopidogrel N 9333 9291 2 Patients with events 864 ( 9.3%) 1014 (10.9%) KM % at 12 months 9.8% 11.7% HR (95% Cl) 0.84 (0.77, 0.92) p-value 0.0003 0 0 60 120 180 240 300 360 Days from Randomization Nat risk Ti 90 mg 9333 8628 8460 8219 6743 5161 4147 Clopidogrel 9291 8521 8362 8124 6650 5096 4074 Table 7 – Patients with outcome events (PLATO) BRILINTA N=9333 Clopidogrel N=9291 Hazard Ratio (95% CI) p-value Events / 1000 patient years Events / 1000 patient years Composite of CV death, MI, or stroke 111 131 0.84 (0.77, 0.92) 0.0003 CV death 32 43 0.74 Non-fatal MI 64 76 0.84 Non-fatal stroke 15 12 1.24 Secondary endpoints† CV death 45 57 0.79 (0.69, 0.91) 0.0013 MI‡ 65 76 0.84 (0.75, 0.95) 0.0045 Stroke‡ 16 14 1.17 (0.91, 1.52) 0.22 All-cause mortality 51 65 0.78 (0.69, 0.89) 0.0003 Dosed at 90 mg bid. †Note: rates of first events for the components CV Death, MI and Stroke are the actual rates for first events for each component and do not add up to the overall rate of events in the composite endpoint. ‡Including patients who could have had other non-fatal events or died. The Kaplan-Meier curve (Figure 10) shows time to first occurrence of the primary composite endpoint of CV death, non fatal MI or non-fatal stroke in the overall study. Figure 10 – Time to first occurrence of CV death, MI, or stroke (PLATO) The curves separate by 30 days [relative risk reduction (RRR) 12%] and continue to diverge throughout the 12-month treatment period (RRR 16%). Among 11,289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.009). The results were similar for drug-eluting and bare metal stents. 21 Reference ID: 5473698 Characteristics HR (95% Cl) Ticagrelor Clopidogrel HR (95% Cl) n/N (%/yr) n/N (%/yr) Overall Treatment Effect • Primary Endpoint (100%) 864/9333 (11.07) 1014/9291 (13.06) 0.84 (0.77, 0.92) Geographic region us (8%) I 84/707 (13.89) 67/706 (11 .05) 1.27 (0.92, 1.75) Outside US (92%) - 780/8626 (10.83) 947/8585 (13.23) 0.81 (0.74, 0.90) ASA by median dose I I >=300 (5%) 68/464 (17.77) 50/492 (12.31) 1.45 (1 .01 , 2.09) >100 - <300 (6%) 64/525 (15.14) 65/527 (15.26) 0.99 (0.70, 1 .40) <=100 (83%) .. 565/7733 (8.59) 723/7706 (11 .06) 0.77 (0.69, 0.86) Planned Treatment Approach Invasive treatment (72%) -.- 569/6732 (10.09) 668/6676 (11 .93) 0.84 (0.75, 0.94) Medical treatment (28%) 295/2601 (13.63) 346/2615 (16.00) 0.85 (0.73, 1.00) Early PCI (<24 hours after randomization) No (50%) -.- 515/4704 (13.27) 607/4666 (15.88) 0.84 (0.74, 0.94) Yes (50%) --- 349/4629 (8.89) 407/4625 (10.33) 0.85 (0.74, 0.98) Patients undergoing CABG after randomization No (90%) • 724/8402 (10.31) 852/8323 (12.23) 0.84 (0.76, 0.93) Yes (10%) 140/931 (17.89) 162/968 (20.29) 0.89(0.71 , 1.12) Diabetes History No (75%) • 555/7007 (9.41) 664/6955 (11 .35) 0.83 (0.74, 0.92) Yes (25%) 309/2326 (16.21) 350/2336 (18.31) 0.88 (0.76, 1.03) Prior TINStroke No (94%) • 764/8762 (10.41) 899/8700 (12.32) 0.84 (0.76, 0.93) Yes (6%) 100/564 (21.62) 115/588 (25.01) 0.87 (0.66, 1.13) Glycoprotein lib/Illa Inhibitor I I No (73%) --- 625/6811 (11.00) 746/6751 (13.30) 0.82 (0.74, 0.92) Yes (27%) 239/2522 (11.26) 268/2540 (12.44) 0.90 (0.76, 1.07) Age Group I I <65 years (57%) --- 360/5310 (7.98) 427/5333 (9.36) 0.85 (0.74, 0.97) >=65 years (43%) --- 503/4022 (15.26) 587/3957 (18.34) 0.83 (0.74, 0.94) <75 years (85%) • 641 /7936 (9.59) 763/7808 (11 .58) 0.82 (0.74, 0.91) >=75 years (15%) 222/1396 (19.84) 251 /1482 (21 .39) 0.94(0.78, 1.12) Sex _._ Male (72%) 586/6678 (10.48) 686/6658 (12.27) 0.85 (0.76, 0.95) Female (28%) ------ 278/2655 (12.56) 328/2633 (15.10) 0.83 (0.71 , 0.97) I Race I Caucasian (92%) - 769/8566 (10.71) 893/8511 (12.51) 0.85 (0.77, 0.94) Black (1 %) 14/115 (15.11) 21 /114 (24.00) 0.63 (0.32, 1.23) Asian (6%) 66/542 (14.68) 77/554 (16.94) 0.87 (0.62, 1.21) Other (1%) 15/109 (17.68) 23/112 (28.37) 0.63 (0.33, 1.21) 0.25 0.5 1.0 2.0 4.0 Ticagrelor Better I Clopidogrel Better A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Some of these are shown in Figure 11. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below. Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., aspirin maintenance dose, use of PCI). Figure 11 – Subgroup analyses of (PLATO) Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 22 Reference ID: 5473698 ASA Dose licagrelor Oopidogrel Region (mg) N E N E HR (95% Cl) us > = 300 324 40 352 27 1.62 (0.99, 2.64 ) > 100 - < 300 22 2 16 2 < = 100 284 19 263 24 0.73 (0.40, 1.33) Non-US > = 300 140 28 140 23 1.23 ( 0.71, 2.14) > 100 - < 300 503 62 511 63 1.()() ( 0.71, 1.42 ) <= 100 7449 546 7443 699 0.78 (0.69, 0.87 ) • I I I I 0.125 0.50 1 2 4 8 "r-icag,elor Better I Clopidogrel ee:er Regional Differences Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable. A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome. Aspirin Dose The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses (≤100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 10 shows overall results by median aspirin dose. Figure 12 shows results by region and dose. Figure 12 – CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO) Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI. Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of BRILINTA. 23 Reference ID: 5473698 11 ···- Ti 90 mg - Ti60mg - - Placebo - 10 N 7050 7045 7067 _, ,,- Patients with events 493 ( 7.0%) 487 ( 6.9%) 578 ( 8.2%) J r 9 KM % at 36 months 7.8% 7.8% 9.0% --- HR (95% Cl) 0.85 (0.75, 0.96) 0.84 (0.74, 0.95) , r 8 p-value 0.0080 0.0043 ,. - r -- ,. ,. 'ift. 7 - ,. Cl> ,. - > 6 - ; ,. - .. - :i 5 ,., E ,.- ::, .,. ,. 0 , - 4 .,. 3 2 0 0 120 240 360 480 600 720 840 960 1080 1200 1320 Days from Randomization Nat risk Ti 90 mg 7050 6951 6851 6769 6703 6345 5921 4951 3651 2038 692 Ti 60 mg 7045 6948 6857 6784 6711 6357 5904 4926 3698 2055 710 Placebo 7067 6950 6842 6761 6658 6315 5876 4899 3646 2028 714 PEGASUS The PEGASUS TIMI-54 study (NCT01225562) was a 21,162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75 150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints. Patients were eligible to participate if they were ≥50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled. Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months. Patients were predominantly male (76%) Caucasian (87%) with a mean age of 65 years, and 99.8% of patients received prior aspirin therapy. The Kaplan-Meier curve (Figure 13) shows time to first occurrence of the primary composite endpoint of CV death, non fatal MI or non-fatal stroke. Figure 13 – Time to First Occurrence of CV death, MI or Stroke (PEGASUS) Ti = Ticagrelor BID, CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier; N = Number of patients. 24 Reference ID: 5473698 Both the 60 mg and 90 mg regimens of BRILINTA in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea. Table 8 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone. Table 8 – Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS) BRILINTA N=7045 Placebo N=7067 HR (95% CI) p-value Events / 1000 patient years Events / 1000 patient years Time to first CV death, MI, or stroke† 26 31 0.84 (0.74, 0.95) 0.0043 ,§ CV Death‡ 9 11 0.83 (0.68, 1.01) Myocardial infarction§ 15 18 0.84 (0.72, 0.98) Stroke§ 5 7 0.75 (0.57, 0.98) All-cause mortality‡ 16 18 0.89 (0.76, 1.04) CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction; N = Number of patients. 60 mg BID † Primary composite endpoint ‡ Secondary endpoints § The event rate for the components CV death, MI and stroke are calculated from the actual number of first events for each component. In PEGASUS, the relative risk reduction (RRR) for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar. The treatment effect of BRILINTA 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 14. 25 Reference ID: 5473698 Characteristics HR(95% Cl) Overall Treatment Effect Primary endpofnt (100%) Age group <65 years (46%) 65-75 years (42%) >75 years (12%) Se)( Male (76%) Female (24%) Race Ca~sian (8tl%) Non-Caucasian (14%) Weighl. group <70 kg (23%) 70-90 kg (50%) >90 kg (27%) BMI <30 kg/m"2 (67%) >~3o kglm~2 (32%) Geographic regioo US (12%) Outside us (88%} Hlstory or >1 Ml (>~1 year prior Yes (Ho/o) No (83%) 10 randomization) 11me rrom qualifying Ml to rando mizabOn <2 years (61 % ) >~2 years (38%) Type of qualifying Ml STE.Ml(54%) NSTEMI (40%) C>Jabetes Mellrtus Yes (32%) No (68%) Mullivessel Coronary Artery Dis ease Yes(60%) No (40%) Creatinr~ Clearance (Coci<ron. <60 mUmin (19%) >~60mUmin (79%) History or PC I Yes (83%) No(17%) Type or stenl Any OES (39%) SM$ only(36%) Current smOller Yes (17%) No(83%) Time since prev. ADP receptor <30 days (34%) 30 days lo 12 months (32%) >12 mooths (23%) Gault) at e(lro1men! blocker treatmenl I I • ■ I I - I - I • • I I •• I I - -- - I ■ I I ' L " ■ I ' - I •• I _ ,- l --- I ■, -- I -- I ■ I ~ - ' I • I - I I I I 0,5 0.75 1.0 Tlcagrelor Better I - I 1.5 Placebo Better Ticagrelor n/N (%/yr) 487 17045 (2.62) 3283 (2.24) 12913 (2.71 ) 31849 (3.81 ) 195/ 209 8 3511 5364 (2.47) 1661 (3.09) 1361 411 /6077 (2.55) 61968 (3.09) 7 1121 1636 (2.63) 3457 (2.53) 1941 (2.74) 232/ 1421 2901 4692 (2.35) 12335 (3.13) 194 6 51863 (2.93) /6182 (2.58) 422 1431 1168 (4.66) 5876 (2.21) 3441 2931 4331 (2.60) 9412704 (2.65) 1 2181 3757 (2.19) 12842 (3.09) 231 20 512308 (3.38 l 4736 (2.25) 282/ 290/ 4190 (2.64) 2852 (2.57) 1961 1281 1320 (3.75) 5610 (2.36) 352/ 362/ 5874 (2.34) 1170 (4.03) 1251 1 aa/2769 (2.63) 2598 (2.00) 1401 941 1206 (2.99) 5838 (2.54) 3931 1 14 6512391 (2.70) 312231 (2.41 ) 1,s51 (2.39) 10aJ I 2.0 Placebo n/N (%/yr) 57817067 (3.10) 2.4313154 (2,93) 22513074 (2,76) 110/839 (5.01 ) 43515350 (3.09) 14311717 (3.14) 60916124 (3.13) 69/943 (2 .90) 14511575 (3.54) 27713658 (2,86) 15511822 (3.23) 39114827 (3.07} 186/2223 (3.18) 821872(3,67) 49616190 (3.03} 168/1188 (5.43) 410/5879 (2.64) 37514333 (3.34) 20212724 (2,74 ) 26813809 (2.68) 26212643 (3.47) 23912257 (4.03) 33914810 (2,67) 355/4213 (3.23) 22312854 (2 .92) 18411382 (5.09) 38315565 (2.60) 430/5835 (2,79) 14811231 (4.61) 222/2784 (3.08) 15612532 (2 .29) 108J1143 (3.64) 46915919 (3.00) 216/2403 (3.52) 17512230 (2.98) 10011645 (2.21) HR(95% Cl) 0,84 ( 0.74, 0.95) 0,76 { 0,63, 0.91) 0,98 { 0.81, 1.18) 0.76 ( 0.57, 1.01 ) 0,79 ( 0.69, 0.91 } 0.98 ( 0.78, 1.24) 0,81 ( 0.71, 0.92) 1.07 ( 0.77. 1.48) 0.74 ( 0.58, 0.95) 0,88 ( 0.74, 1.05) 0.85 ( 0.67. 1.06) 0.76 ( 0.65. 0.88) 0,99(0.81 , 1.21) 0,78 ( 0,56. 1.08) 0.85 ( 0, 74, 0.96) 0.85 ( 0.68. 1.06) 0.63 ( 0.72, 0.96) 0,77 ( 0.66, 0.90) 0.96 ( 0.79, 1.17) 0.81 ( 0.68, 0.97) 0.89 ( 0.74, 1.06) 0.83 ( 0.69. 1.00} 0,84 { 0, 72, 0.98) 0,81 ( 0, 70, 0.95) 0.88 ( 0.72. 1.06) 0.72(0,58. 0.91 ) 0,90 ( 0,78, 1.05) 0,63 ( 0, 72, 0.96) 0.87 ( 0.68. 1.10) 0.85 ( 0.70, 1.03) 0.67 ( 0.69. 1.09) 0.82 ( 0.62, 1.08) 0.84 (0,74, 0.96) 0, 76 { 0.62, 0.93) 0.81 ( 0.65. 1.01) 1.08 ( 0.82, 1.42} Figure 14 – Subgroup analyses of ticagrelor 60 mg (PEGASUS) Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 14.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction THEMIS The THEMIS study (NCT01991795) was a double-blind, parallel group, study in which 19,220 patients with CAD and Type 2 Diabetes Mellitus (T2DM) but no history of MI or stroke were randomized to twice daily BRILINTA or placebo, on a background of 75-150 mg of aspirin. The primary endpoint was the composite of first occurrence of CV death, MI, and stroke. CV death, MI, ischemic stroke, and all-cause death were assessed as secondary endpoints. Patients were eligible to participate if they were ≥ 50 years old with CAD, defined as a history of PCI or CABG, or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery and T2DM treated for at least 6 months with 26 Reference ID: 5473698 glucose-lowering medication. Patients with previous intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, known bleeding diathesis, and coagulation disorder were excluded. Patients taking anticoagulants or ADP receptor antagonists were excluded from participating, and patients who developed an indication for those medications during the trial were discontinued from study drug. Patients were treated for a median of 33 months and up to 58 months. Patients were predominantly male (69%) with a mean age of 66 years. At baseline, 80% had a history of coronary artery revascularization; 58% had undergone PCI, 29% had undergone a CABG and 7% had undergone both. The proportion of patients studied in the US was 12%. Patients in THEMIS had established CAD and other risk factors that put them at higher cardiovascular risk. BRILINTA was superior to placebo in reducing the incidence of CV death, MI, or stroke. The effect on the composite endpoint was driven by the individual components MI and stroke; see Table 9. Table 9 – Primary composite endpoint, primary endpoint components, and secondary endpoints (THEMIS) BRILINTA N=9619 Placebo N=9601 HR (95% CI) p-value Events / 1000 patient years Events / 1000 patient years Time to first CV death, MI, or stroke 24 27 0.90 (0.81, 0.99) 0.04 CV death† 12 11 1.02 (0.88, 1.18) Myocardial infarction† 9 11 0.84 (0.71, 0.98) Stroke† 6 7 0.82 (0.67, 0.99) Secondary endpoints CV death 12 11 1.02 (0.88, 1.18) Myocardial infarction 9 11 0.84 (0.71, 0.98) Ischemic stroke 5 6 0.80 (0.64, 0.99) All-cause death 18 19 0.98 (0.87, 1.10) CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction. * Primary endpoint † The event rate for the components CV death, MI and stroke are calculated from the actual number of first events for each component. 27 Reference ID: 5473698 <!) oJ) cd i= <!) Q ... <!) 0.. <!) .2:: "o:! '3 s ;::l C.) 14--r;::=========:::=;---------------------------, events/N --- Ticagrelor 736/9619 ----- · Placebo 818/9601 8 6 4 0 3 6 9 12 15 18 21 24 27 30 33 Months from randomization Nat risk 36 39 42 45 48 51 54 T 9619 9504 9416 9332 9237 9150 9074 8987 8909 8816 8692 6994 5974 4794 3664 2528 1684 816 170 P 9601 9499 9414 9337 9246 9161 9076 8984 8909 8807 8692 7000 5934 4815 3682 2529 1685 799 174 The Kaplan-Meier curve (Figure 15) shows time to first occurrence of the primary composite endpoint of CV death, MI, or stroke. Figure 15 - Time to First Occurrence of CV death, MI or Stroke (THEMIS) T = Ticagrelor; P = Placebo; N = Number of patients. The treatment effect of BRILINTA appeared similar across patient subgroups, see Figure 16. 28 Reference ID: 5473698 Characteristic HR (95%CI) Ticagrelor Placebo HR (95% CI) n/N (%/yr) n/N (%/yr) All patients in full analy sis set (100%) 736/9619 (2.41) 818/9601 (2.68) 0.90 (0.81, 0.99) Age (years) < 65 (41 %) 243/3975 (I .90) 290/3959 (2.29) 0.83 (0.70, 0.98) 65- 75 (46%) 330/4443 (2.34) 372/4447 (2.62) 0.89 (0 77, 1.03) > 75 (12%) 163/1201 ( 4.46) 156/1195 (4.19) 1.07 (0.86, 1.33) Sex Male (69%) 505/6576 (240) 579/6613 (2.74) 0.88 (0.78, 0.99) Female (31 %) 231/3043 (2.42) 239/2988 (2.53) 0.96 (0.80, 115) Race White (71%) 536/6838 (2.44) 620/6858 (2.82) 0.87 (0.77, 0.97) Black or African American (2%) 22/205 (3.62) 22/198 (3.66) 0.99 (0.55, 1.79) Asian (23%) 149/2211 (2.16) 151/2195 (2.19) 0.98 (0.78, 1.23) Other (4%) 29/365 (2.59) 25/350 (231) 112 (0.66, 1.92) Body mass index (kgim2) S 30 (57%) 404/5534 (230) 448/5462 (2.59) 0.89 (0.78, 1.02) > 30 (43%) · 1 331/4076 (2.55) 369/4130 (2.79) 0.91 (0.79, 1.06) Geographic region US(l 2%) ~ 100/1126 (2.89) 120/1140 (341) 0.85 (0.65, 1.11) Non-US (88%) 636/8493 (2.35) 698/8461 (2.58) 0.91 (0.82, 1 01) Aspirin dose at baseline (mg) S 100 (95%) - 699/9120 (2.41) 770/9111 (2.65) 0.91 (0.82, 1.01) > 100 (4%) ◄ ■ . 1 26/346 (2.38) 37/343 (3.39) 0.70 (0.42, 1.16) HbAlc at baseline(%) S 7 (47%) 295/4564 (2.00) 317/4544 (2.15) 0.93 (0.79, 1 09) > 7 (50%) 420/4819 (2.78) 479/4823 (3.17) 0.88 (0.77, 1 00) eGFR (M DRD) at baseline (mL/min/1.73 m2) S 60 (24%) 266/2293 (3.77) 274/2256 (3.91) 0.96 (0.81, 1.14) > 60 (75%) 461/7164 (2.00) 525/717 4 (2.28) 0.88 (0.78, 1 00) Insulin use at baseline Yes (29%) 286/2798 (3.27) 323/2710 (3.83) 0.85 (0.73, 1 00) No (71%) History of angina 450/6821 (2.06) 495/6891 (2.24) 0.92 (0.81, 1 05) Yes (56%) 420/5444 (2.42) 484/5357 (2.85) 0.85 (0.75, 0.97) No (44%) 316/4175 (2.39) 334/4244 (2.46) 0.97 (0.83, 1.13) M ultivessel coronary artery disease (> 1 vessel) Yes (62%) 523/5951 (2.78) 559/5984 (2.94) 0.95 (0.84, 1.07) No (38%) History of PC! 211/3637 (1.81) 258/3595 (2.25) 0.81 (0.67, 0.97) Yes (58%) 404/5558 (2 28) 480/5596 (270) 0.85 (0 74, 0.97) No (42%) 332/4061 (2.59) 338/4005 (2.65) 0.98 (0.84, 1.14) PC! with stent Yes (54%) -■- 367/5101 (2.25) 457/5194 (2.77) 0.81 (0.71, 0.93) No (4%) 37/457 (2.55) 23/402 (1.74) 1.47 (0.87, 2.48) Time since most recent PC! (years) < 1 (6%) .. 34/586 (1.86) 58/559 (344) 0.54 (0.36, 0.83) I - 3 (21 %) 135/2005 (2.13) 164/2043 (2.54) 0.84 (0.67, 1.05) > 3 (31%) 235/2966 (2.46) 258/2993 (2.67) 0.92 (0.77, 1.10) History of CABG Yes (29%) 236/2796 (2.64) 262/2741 (2.98) 0.89 (0.74, 1 06) No (71%) 500/6823 (231) 556/6860 (2.56) 0.91 (0.80, 1.02) Time since most recent CABG (years) S 5 (16%) 102/1498 (2.11) 112/1511 (231) 0.91 (0.70, 1.20) > 5 (13%) 134/1298 (3.25) 150/1228 (3.80) 0.85 (0.68, 1.08) Current smoker Yes(!!%) 3 90/1056 (2. 71) 88/1038 (2.67) LOI (0.76, 1.36) No (89%) 646/8562 (2.37) 730/8563 (2.68) 0.89 (0.80, 0.98) Duration of diabetes (years) S 10 (50%) 303/4815 (1.96) 351/4887 (2.24) 0.88 (0.75, 1 02) > 10 (49%) 433/4798 (2.87) 466/4710 (3.14) 0.91 (0.80, 1 04) 0.5 2 Ticagrelor Better Placebo Better Figure 16 –Subgroup analyses of ticagrelor (THEMIS) Note: The figure above presents effects in various subgroups all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 29 Reference ID: 5473698 14.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) THALES The THALES study (NCT03354429) was a 11,016-patient, randomized, double-blind, parallel-group study of BRILINTA 90 mg twice daily versus placebo in patients with acute ischemic stroke or transient ischemic attack (TIA). The primary endpoint was the first occurrence of the composite of stroke and death up to 30 days. Ischemic stroke was assessed as one of the secondary endpoints. Patients were eligible to participate if they were ≥40 years old, with non-cardioembolic acute ischemic stroke (NIHSS score ≤5) or high-risk TIA (defined as ABCD2 score ≥6 or ipsilateral atherosclerotic stenosis ≥50% in the internal carotid or an intracranial artery). Patients who received thrombolysis or thrombectomy within 24 hours prior to randomization were not eligible. Patients were randomized within 24 hours of onset of an acute ischemic stroke or TIA to receive 30 days of either BRILINTA (90 mg twice daily, with an initial loading dose of 180 mg) or placebo, on a background of aspirin initially 300-325 mg then 75-100 mg daily. The median treatment duration was 31 days. BRILINTA was superior to placebo in reducing the rate of the primary endpoint (composite of stroke and death), corresponding to a relative risk reduction (RRR) of 17% and an absolute risk reduction (ARR) of 1.1% (Table 10). The effect was driven primarily by a significant reduction in the stroke component of the primary endpoint (19% RRR, 1.1% ARR). Table 10 - Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoint (THALES) BRILINTA Placebo N=5523 N=5493 HR (95% CI) p-value n (patients with event) KM% n (patients with event) KM% Time to first Stroke or Death 303 5.4% 362 6.5% 0.83 (0.71, 0.96) 0.015 Time to first Stroke* 284 5.1% 347 6.3% 0.81 (0.69, 0.95) Time to Death* 36 0.6% 27 0.5% 1.33 (0.81, 2.19) Secondary Endpoint Time to first Ischemic Stroke 276 5.0% 345 6.2% 0.79 (0.68, 0.93) 0.004 CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier percentage calculated at 30 days; N = Number of patients *The number of patients with the event of interest. In the time to first stroke, patients who died are censored at the time of death. The Kaplan-Meier curve (Figure 17) shows the time to first occurrence of the primary composite endpoint of stroke and death. 30 Reference ID: 5473698 3 ---r;=============e=v=e=n=ts=/N==K=M=,=1/o:;----------------------,-----~ '#- (1) > 6 iii 4 :j E ::, 0 2 --- Ticagrelor 90 mg bd - - - - • Placebo 1-- - -1 I I 1-- 1 .. -.1-- 303/5523 54% 362/5493 6.5% - -r - .. r - .. -- __ ,---- - ___ ,. ___ ,1 __ .. _,_ .. - __ .. _,. ___ ,_ .. -- 0c.;,='---------~------~-----~------~------~------1--------,--, 0 Nat risk T 5523 P 5493 5 5314 5253 10 5257 5181 15 20 Days from randomization 5241 5159 5227 5146 25 5215 5138 30 5209 5126 34 1091 1135 Figure 17 – Time to First Occurrence of Stroke or Death (THALES) KM%: Kaplan-Meier percentage evaluated at Day 30; T=Ticagrelor; P=placebo; N=Number of patients BRILINTA’s treatment effect on stroke and on death accrued over the first 10 days and was sustained at 30 days. Although not studied, this suggests that shorter treatment could result in similar benefit and reduced bleeding risk. The treatment effect of BRILINTA was generally consistent across pre-defined subgroups (Figure 18). 31 Reference ID: 5473698 Characteristic All patients in full analysis set (1 00%) Age (years) <65 (48%) 65-75 (32%) >75 (20%) Sex Male (61%) Female (39%) Race White (54%) Black or African American ( < 1 o/c o) Asian (43%) Other (3%) Weight (kg) <70 (43%) 270 (57%) BM! (kglm2) <30 (81 %) 230 (19%) Geographic region Asia and Australia ( 43%) Europe (51%) North America ( < 1 % ) Central and South America ( 6% Diagnosis of index event Stroke NIHSS score :S3 (6 1 %) Stroke NIHSS score 4 or 5 (30o/c o) TIA (9%) - -- Time from index event to randonn ·sation (h) <12 (33%) 212 (67%) Time from index event to loading <12 (30%) 212 (69%) Diabetes mellitus Yes (29%) No (71%) Hypertension Yes (77%) No (23%) Prior ischaemic stroke or TIA Yes (20%) No (80%) Prior ischaemic heart disease Yes (10%) No (90%) Prior ASA Yes (13%) No (87%) Prior statin treatment Yes (16%) No (84%) Smoking status Current (2 7%) Former (17%) Never (56%) dose (h) 0.5 HR(95%CI) -I I- - - ,_ ,- ------ ~ - -- ----- - -- -- -- -- -- -- -----· - 1 -- - ·- ,----- ------ - 0.8 Ticagrelor Better Ticagrelor Placebo HR(95% Cl) n/N ( % ) n/N (%) 303/5523 (5.5%) 362/5493 (6.6%) 0.83 (0.71, 0.96) 132/2676 (4.9%) 164/2632 (6.2%) 0.79 (0.63, 0.99) 101/1749 (5.8%) 122/1809 (6.7%) 0.85 (0.65, 1.11) 70/1098 ( 6.4%) 76/1052 (7.2%) 0.88 (0.64, 1.22) 198/3415 (5.8%) 235/3322 (7.1 %) 0.82 (0.68, 0.99) 105/2108 (5.0%) 127/2171 (5.8%) 0.85 (0.65, 1.10) 108/2973 (3.6%) 137/2948 (4.6%) 0.78 (0.60, 1.00) 2/21 (9.5%) 2/32 (6.3%) 186/2353 (7.9%) 213/2339 (9.1 %) 0.86 (0.71, 1.05) 7/176 (4.0%) 10/174 (5.7%) 0.69 (0.26, 1.82) 127/2324 (5.5%) 162/2388 (6.8%) 0.80 (0.63, I.OJ) 172/3174 (5.4%) 195/3073 (6.3%) 0.85 (0.69, 1.04) 258/4446 (5.8%) 301/4429 (6.8%) 0.85 (0.72, 1.00) 41/1047 (3.9%) 56/1026 (5.5%) 0.71 (0.48, 1.06) 184/2373 (7.8%) 213/2356 (9.0%) 0.85 (0.70, 1.04) 105/2814 (3.7%) 131/2803 (4.7%) 0.79 (0.61, 1.03) 1/12 (8.3%) 0/11 (<1%) 13/324 ( 4.0%) 18/323 (5.6%) 0.71 (0.35, 1.46) 158/3359 ( 4.7%) 190/3312 (5.7%) 0.82 (0.66, I.OJ) 129/1673 (7.7%) 150/1641 (9.1 %) 0.84 (0.66, 1.06) 16/491 (3.3%) 22/540 ( 4.1 %) 0.80 (0.42, 1.52) 98/1812 (5.4%) 114/1776 (6.4%) 0.84 (0.64, 1.10) 205/3711 (5.5%) 248/3717 (6.7%) 0.82 (0.69, 0.99) 89/1655 (5.4%) 106/1659 (6.4%) 0.84 (0.63, 1.11) 211/3823 (5.5%) 254/3787 (6.7%) 0.82 (0.68, 0.98) 115/1589 (7.2%) 121/1557 (7.8%) 0.93 (0.72, 1.20) 188/3934 (4.8%) 241/3936 (6.1 %) 0.78 (0.64, 0.94) 228/4298 (5.3%) 286/4222 (6.8%) 0.78 (0.65, 0.93) 75/1225 (6.1%) 76/1271 (6.0%) 102 (0.74, 1.41) 59/1122 (5.3%) 88/1101 (8.0%) 0.65 (0.46, 0.90) 244/4401 (5.5%) 274/4392 (6.2%) 0.89 (0.75, 1.05) 31/532 (5.8%) 30/533 (5.6%) 104 (0.63, 1.71) 272/4991 (5.4%) 332/4960 (6.7%) 0.81 (0.69, 0.95) 41/754 (5.4%) 36/679 (5.3%) 102 (0.65, 1.60) 262/4769 (5.5%) 326/4814 (6.8%) 0.81 (0.69, 0.95) 41/865 (4.7%) 46/879 (5.2%) 0.90 (0.59, 1.37) 262/4658 (5.6%) 316/4614 (6.8%) 0.82 (0.69, 0.96) 83/1504 (5.5%) 102/1428 (7.1 %) 0.77 (0.57, 1.03) 52/980 (5.3%) 53/925 (5.7%) 0.93 (0.63, 1.36) 168/3038 (5.5%) 207/3140 (6.6%) 0.83 (0.68, 1.02) 1.25 2 Placebo Better Figure 18 – Subgroup analyses of ticagrelor 90 mg (THALES) Note: The figure above presents effects in various subgroups all of which are baseline characteristics and were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. At Day 30, there was an absolute reduction of 1.2% (95% CI: -2.1%, -0.3%) in the incidence of non-hemorrhagic stroke and death (excluding fatal bleed) favoring ticagrelor (294 events: 5.3%) over placebo (359 events: 6.5%) in the intention 32 Reference ID: 5473698 to-treat population. In the same population, there was an absolute increase of 0.4% (95% CI: 0.2%, 0.6%) in the incidence of GUSTO severe bleeding unfavorable to ticagrelor arm (28 events: 0.5%) compared to the placebo arm (7 events: 0.1%). 16 HOW SUPPLIED/STORAGE AND HANDLING BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet with a “90” above “T” on one side: Bottles of 60 – NDC 0186-0777-60 100 count Hospital Unit Dose – NDC 0186-0777-39 BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet with a “60” above “T” on one side: Bottles of 60 – NDC 0186-0776-60 Storage and Handling Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP controlled room temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Advise patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin. Advise patients that they: • Will bleed and bruise more easily • Will take longer than usual to stop bleeding • Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine. Advise patients to contact their doctor if they experience unexpected shortness of breath, especially if severe. Advise patients to inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure. Advise women that breastfeeding is not recommended during treatment with BRILINTA [see Use in Specific Populations (8.2)]. BRILINTA® is a trademark of the AstraZeneca group of companies. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 © AstraZeneca 2024 33 Reference ID: 5473698 MEDICATION GUIDE BRILINTA® (brih-LIN-tah) (ticagrelor) tablets What is the most important information I should know about BRILINTA? BRILINTA is used to lower your chance of having, or dying from, a heart attack or stroke. BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. In cases of serious bleeding, such as internal bleeding, the bleeding may result in the need for blood transfusions or surgery. While you take BRILINTA: • you may bruise and bleed more easily • you are more likely to have nose bleeds • it will take longer than usual for any bleeding to stop Call your healthcare provider right away, if you have any of these signs or symptoms of bleeding while taking BRILINTA: • bleeding that is severe or that you cannot control • pink, red or brown urine • vomiting blood or your vomit looks like “coffee grounds” • red or black stools (looks like tar) • coughing up blood or blood clots Do not stop taking BRILINTA without talking to the healthcare provider who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Your healthcare provider may instruct you to stop taking BRILINTA 5 days before surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your healthcare provider should tell you when to start taking BRILINTA again, as soon as possible after surgery. Taking BRILINTA with aspirin BRILINTA is taken with aspirin, unless your healthcare provider specifically tells you otherwise. Talk to your healthcare provider about the dose of aspirin that you should take with BRILINTA. In most cases, you should not take a dose of aspirin higher than 100 mg daily. Do not take doses of aspirin higher than what your healthcare provider tells you to take. Tell your healthcare provider if you take other medicines that contain aspirin, and do not take new over-the-counter medicines with aspirin in them. What is BRILINTA? BRILINTA is a prescription medicine used to: • decrease your risk of death, heart attack, and stroke in people with a blockage of blood flow to the heart (acute coronary syndrome or ACS) or a history of a heart attack. BRILINTA can also decrease your risk of blood clots in your stent in people who have received stents for the treatment of ACS. • decrease your risk of a first heart attack or stroke in people who have a condition where the blood flow to the heart is decreased (coronary artery disease or CAD) who are at high risk for having a heart attack or stroke. • decrease your risk of stroke in people who are having a stroke (acute ischemic stroke) or mini-stroke (transient ischemic attack or TIA). It is not known if BRILINTA is safe and effective in children. Do not take BRILINTA if you: • have a history of bleeding in the brain • are bleeding now • are allergic to ticagrelor or any of the ingredients in BRILINTA. See the end of this Medication Guide for a complete list of ingredients in BRILINTA. Before taking BRILINTA, tell your healthcare provider about all of your medical conditions, if you: • have had bleeding problems in the past • have had any recent serious injury or surgery • plan to have surgery or a dental procedure. See “What is the most important information I should know about BRILINTA?” • have a history of stomach ulcers or colon polyps • have lung or breathing problems, such as COPD or asthma • have liver problems Reference ID: 5473698 • have a history of stroke • are pregnant or plan to become pregnant. It is not known if BRILINTA will harm your unborn baby. You and your healthcare provider should decide if you will take BRILINTA. • are breastfeeding or plan to breastfeed. It is not known if BRILINTA passes into your breast milk. You should not breastfeed during treatment with BRILINTA. Talk to your healthcare provider about the best way to feed your baby during treatment with BRILINTA. Tell all of your healthcare providers and dentists that you are taking BRILINTA. They should talk to the healthcare provider who prescribed BRILINTA for you before you have any surgery or procedure. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works. Certain medicines may increase your risk of bleeding. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take BRILINTA? • Take BRILINTA exactly as prescribed by your healthcare provider. • Your healthcare provider will tell you how many BRILINTA tablets to take and when to take them. • Take BRILINTA with aspirin, unless your healthcare provider specifically tells you otherwise. See “What is the most important information I should know about BRILINTA?” • You may take BRILINTA with or without food. • Take BRILINTA two times each day, around the same times each day. • If you miss your scheduled dose of BRILINTA, take your next dose at its scheduled time. Do not take 2 doses at the same time unless your healthcare provider tells you to. • If you take too much BRILINTA, call your healthcare provider or local poison control center or go to the nearest emergency room right away. If you are unable to swallow the tablet(s) whole, you may crush the BRILINTA tablet(s) and mix it with water. Drink all the water right away. Refill the glass with water, stir, and drink all the water. BRILINTA may also be given through certain nasogastric (NG) tubes. Ask your healthcare provider for instructions on how to take BRILINTA through a NG tube. What are the possible side effects of BRILINTA? BRILINTA can cause serious side effects, including: • See “What is the most important information I should know about BRILINTA?” Shortness of breath. Tell your healthcare provider if you have new, worsening or unexpected shortness of breath when you are at rest, at night, or when you are doing any activity. Slow or irregular heartbeat. Irregular breathing. Tell your healthcare provider if you develop irregular breathing patterns when asleep or awake such as speeding up, slowing down or short pauses in breathing. Your healthcare provider will decide if you need further evaluation. These are not all of the possible side effects of BRILINTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store BRILINTA? • Store BRILINTA at room temperature between 68°F to 77°F (20°C to 25°C). Keep BRILINTA and all medicines out of the reach of children. General information about the safe and effective use of BRILINTA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRILINTA for a condition for which it was not prescribed. Do not give BRILINTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BRILINTA that is written for health professionals. Reference ID: 5473698 What are the ingredients in BRILINTA? Active ingredient: ticagrelor 90 mg tablets: Inactive ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow. 60 mg tablets: Inactive ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black and ferric oxide red. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 For more information call 1-800-236-9933 or go to www.Brilinta.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2024 Reference ID: 5473698	custom-source	2025-02-12T15:46:32.991626	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022433s037lbl.pdf', 'application_number': 22433, 'submission_type': 'SUPPL ', 'submission_number': 37}
80,176	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NOREPINEPHRINE BITARTRATE IN DEXTROSE injection safely and effectively. See full prescribing information for NOREPINEPHRINE BITARTRATE IN DEXTROSE injection. NOREPINEPHRINE BITARTRATE IN DEXTROSE injection, for intravenous use Initial U.S. Approval: 1950 -----------------------------INDICATIONS AND USAGE--------------------------- Norepinephrine Bitartrate in Dextrose Injection is a catecholamine indicated for restoration of blood pressure in adult patients with acute hypotensive states. (1) ------------------------DOSAGE AND ADMINISTRATION-----------------------  No further dilution prior to infusion is required. (2.1)  Initiate at 8 to 12 mcg/min, and adjust the rate to maintain blood pressure sufficient to maintain the circulation of vital organs. (2.2)  The average maintenance dose ranges from 2 to 4 mcg/min. (2.2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Injection: 250-mL single dose-containers with  4 mg equivalent of norepinephrine (16 mcg/mL) in 5% dextrose.  8 mg equivalent of norepinephrine (32 mcg/mL) in 5% dextrose.  16 mg equivalent of norepinephrine (64 mcg/mL) in 5% dextrose. -------------------------------CONTRAINDICATIONS-------------------------------  None. (4) ------------------------WARNINGS AND PRECAUTIONS-----------------------  Tissue Ischemia: Infuse Norepinephrine Bitartrate in Dextrose Injection into a large vein. To prevent sloughing and necrosis in areas in with extravasation, infiltrate the area with an adrenergic blocking agent in saline. (5.1)  Hypotension After Abrupt Discontinuation: Gradually taper a norepinephrine infusion to prevent hypotension. (5.2)  Cardiac Arrhythmias: Norepinephrine Bitartrate in Dextrose Injection may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. (5.3) -------------------------------ADVERSE REACTIONS------------------------------ Serious adverse reactions are described in greater detail in other sections [see Warnings and Precautions (5.1, 5.2, & 5.3)]. Most common adverse reactions are hypertension, bradycardia, ischemic injury, anxiety, headache, respiratory difficulty, pulmonary edema, and extravasation necrosis at injection site. (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS--------------------------------  Monoamine oxidase inhibitors (MAOI) or tricyclic antidepressants of the triptyline or imipramine types may result in hypertension. (7.1, 7.2)  Antidiabetics: Norepinephrine can decrease insulin sensitivity and raise blood glucose (7.3)  Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. (7.4) --------------------------USE IN SPECIFIC POPULATIONS---------------------  Elderly patients may be at greater risk of developing adverse reactions (8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2023 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Dosage 2.3 Drug Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tissue Ischemia 5.2 Hypotension after Abrupt Discontinuation 5.3 Cardiac Arrhythmias 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 MAO-Inhibiting Drugs 7.2 Tricyclic Antidepressants 7.3 Antidiabetics 7.4 Halogenated Anesthetics 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5281159 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Norepinephrine Bitartrate in Dextrose Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions Correct Hypovolemia Address hypovolemia before initiation of Norepinephrine Bitartrate in Dextrose Injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions (5.1)]. Administration Norepinephrine Bitartrate in Dextrose Injection is a ready to administer product that requires no further dilution prior to infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Infuse Norepinephrine Bitartrate in Dextrose Injection into a large vein. Avoid infusions into the veins of the leg in the elderly or in patients with occlusive vascular disease of the legs [see Warnings and Precautions (5.1)]. Avoid using a catheter-tie-in technique. The choice of appropriate concentration of Norepinephrine Bitartrate in Dextrose Injection depends on clinical fluid volume requirements. Use higher concentration solutions in patients requiring fluid restriction. Discontinuation When discontinuing the infusion, reduce the flow rate gradually. Avoid abrupt withdrawal. 2.2 Dosage After an initial dosage of 8 to 12 mcg per minute via intravenous infusion, assess patient response and adjust dosage to maintain desired hemodynamic effect. Monitor blood pressure every two minutes until the desired hemodynamic effect is achieved, and then monitor blood pressure every five minutes for the duration of the infusion. Typical maintenance intravenous dosage is 2 to 4 mcg per minute. Reference ID: 5281159 2.3 Drug Incompatibilities Avoid contact with iron salts, alkalis, or oxidizing agents. Whole blood or plasma, if indicated to increase blood volume, should be administered separately. 3 DOSAGE FORMS AND STRENGTHS Injection: Norepinephrine bitartrate in 5% dextrose is a colorless to slightly yellow solution for intravenous infusion, supplied in 250-mL single dose containers as:  4 mg equivalent of norepinephrine (16 mcg/mL).  8 mg equivalent of norepinephrine (32 mcg/mL).  16 mg equivalent of norepinephrine (64 mcg/mL). 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Tissue Ischemia Administration of Norepinephrine Bitartrate in Dextrose Injection to patients who are hypotensive from hypovolemia can result in severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite “normal” blood pressure. Address hypovolemia prior to initiating Norepinephrine Bitartrate in Dextrose Injection [see Dosage and Administration (2.1)]. Avoid Norepinephrine Bitartrate in Dextrose Injection in patients with mesenteric or peripheral vascular thrombosis, as this may increase ischemia and extend the area of infarction. Gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions. Monitor for changes to the skin of the extremities in susceptible patients. Extravasation of Norepinephrine Bitartrate in Dextrose Injection may cause necrosis and sloughing of surrounding tissue. To reduce the risk of extravasation, infuse into a large vein, check the infusion site frequently for free flow, and monitor for signs of extravasation [see Dosage and Administration (2.1)]. Emergency Treatment of Extravasation To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with 5 to 10 mg of phentolamine mesylate in 10 to 15 mL of 0.9% Sodium Chloride Injection in adults. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. Reference ID: 5281159 5.2 Hypotension after Abrupt Discontinuation Sudden cessation of the infusion rate may result in marked hypotension. When discontinuing the infusion, gradually reduce the Norepinephrine Bitartrate in Dextrose Injection infusion rate while expanding blood volume with intravenous fluids. 5.3 Cardiac Arrhythmias Norepinephrine Bitartrate in Dextrose Injection elevates intracellular calcium concentrations and may cause arrhythmias, particularly in the setting of hypoxia or hypercarbia. Perform continuous cardiac monitoring of patients with arrhythmias. 6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in other sections: • Tissue Ischemia [see Warnings and Precautions (5.1)] • Hypotension [see Warnings and Precautions (5.2)] • Cardiac Arrhythmias [see Warnings and Precautions (5.3)] The most common adverse reactions are hypertension and bradycardia. The following adverse reactions can occur: Nervous system disorders: Anxiety, headache Respiratory disorders: Respiratory difficulty, pulmonary edema General disorders and administration site conditions: Extravasation, injection site necrosis [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS 7.1 MAO-Inhibiting Drugs Co-administration of Norepinephrine Bitartrate in Dextrose Injection with monoamine oxidase (MAO) inhibitors or other drugs with MAO-inhibiting properties (e.g., linezolid) can cause severe, prolonged hypertension. If administration of Norepinephrine Bitartrate in Dextrose Injection cannot be avoided in patients who recently have received any of these drugs and in whom, after discontinuation, MAO activity has not yet sufficiently recovered, monitor for hypertension. 7.2 Tricyclic Antidepressants Co-administration of Norepinephrine Bitartrate in Dextrose Injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of Norepinephrine Bitartrate in Dextrose Injection cannot be avoided in these patients, monitor for hypertension. Reference ID: 5281159 7.3 Antidiabetics Norepinephrine Bitartrate in Dextrose Injection can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs. 7.4 Halogenated Anesthetics Concomitant use of Norepinephrine Bitartrate in Dextrose Injection with halogenated anesthetics (e.g., cyclopropane, desflurane, enflurane, isoflurane, and sevoflurane) may lead to ventricular tachycardia or ventricular fibrillation. Monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data consisting of a small number of case reports and multiple small trials involving the use of norepinephrine in pregnant women at the time of delivery have not identified an increased risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus from hypotension associated with septic shock, myocardial infarction and stroke which are medical emergencies in pregnancy and can be fatal if left untreated. (see Clinical Considerations). In animal reproduction studies, using high doses of intravenous norepinephrine resulted in lowered maternal placental blood flow. Clinical relevance to changes in the human fetus is unknown since the average maintenance dose is ten times lower (see Data). Increased fetal reabsorptions were observed in pregnant hamsters after receiving daily injections at approximately 2 times the maximum recommended dose on a mg/m3 basis for four days during organogenesis (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypotension associated with septic shock, myocardial infarction, and stroke are medical emergencies in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock, myocardial infarction and stroke may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of norepinephrine on the fetus. Reference ID: 5281159 Data Animal Data A study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2-4 mcg/min in human, on a mg/kg basis) exhibited a significant decrease in maternal placental blood flow. Decreases in fetal oxygenation, urine and lung liquid flow were also observed. Norepinephrine administration to pregnant rats on Gestation Day 16 or 17 resulted in cataract production in rat fetuses. In hamsters, an increased number of resorptions (29.1% in study group vs. 3.4% in control group), fetal microscopic liver abnormalities and delayed skeletal ossification were observed at approximately 2 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day from Gestation Day 7-10). 8.2 Lactation Risk Summary There are no data on the presence of norepinephrine in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Clinically relevant exposure to the infant is not expected based on the short half-life and poor oral bioavailability of norepinephrine. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of norepinephrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Avoid administration of Norepinephrine Bitartrate in Dextrose Injection into the veins in the leg in elderly patients [see Warnings and Precautions (5.1)]. 10 OVERDOSAGE Overdosage with Norepinephrine Bitartrate in Dextrose Injection may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output. In case of overdosage, discontinue Norepinephrine Bitartrate in Dextrose Injection until the condition Reference ID: 5281159 of the patient stabilizes. 11 DESCRIPTION Norepinephrine Bitartrate in Dextrose Injection contains norepinephrine, a sympathomimetic amine. Norepinephrine is sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine which differs from epinephrine by the absence of a methyl group on the nitrogen atom. Chemically, norepinephrine bitartrate monohydrate is (-)--(aminomethyl) -3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula: Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Norepinephrine Bitartrate in Dextrose Injection is supplied as a sterile aqueous solution administered by intravenous infusion. Each mL contains the equivalent of 16, 32, or 64 micrograms of norepinephrine base supplied as 31.90, 63.80, and 127.60 micrograms per mL of norepinephrine bitartrate monohydrate. It contains dextrose monohydrate (50 mg/mL) and may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. It has a target pH of 3.7. The air in the containers has been displaced by nitrogen gas. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Norepinephrine is a peripheral vasoconstrictor (alpha-adrenergic action) and an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action). 12.2 Pharmacodynamics The primary pharmacodynamic effects of norepinephrine are cardiac stimulation and vasoconstriction. Cardiac output is generally unaffected, although it can be decreased, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. Coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. After intravenous administration, a pressor response occurs rapidly and reaches steady state within 5 minutes. The pharmacologic actions of norepinephrine are terminated primarily by uptake and Reference ID: 5281159 metabolism in sympathetic nerve endings. The pressor action stops within 1-2 minutes after the infusion is discontinued. 12.3 Pharmacokinetics Absorption Following initiation of intravenous infusion, the steady state plasma concentration is achieved in 5 min. Distribution Plasma protein binding of norepinephrine is approximately 25%. It is mainly bound to plasma albumin and to a smaller extent to prealbumin and alpha 1-acid glycoprotein. The volume of distribution is 8.8 L. Norepinephrine localizes mainly in sympathetic nervous tissue. It crosses the placenta but not the blood-brain barrier. Elimination The mean half-life of norepinephrine is approximately 2.4 min. The average metabolic clearance is 3.1 L/min. Metabolism Norepinephrine is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4- hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglycol. Excretion Norepinephrine metabolites are excreted in urine primarily as the sulfate conjugates and, to a lesser extent, as the glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and fertility studies have not been performed. 16 HOW SUPPLIED/STORAGE AND HANDLING Norepinephrine Bitartrate in Dextrose Injection for intravenous infusion is a colorless to slightly yellow solution available in single-dose, ready-to-use containers in an amber/foil overwrap. Each 250 mL of Norepinephrine Bitartrate in Dextrose Injection , 4 mg/250 mL, 8 mg/250 mL, and 16 mg/250 mL contains the equivalent of 4 mg, 8 mg, and 16 mg of norepinephrine, respectively (provided as Reference ID: 5281159 norepinephrine bitartrate monohydrate). Norepinephrine Bitartrate in Dextrose Injection is available in the following: Product Description NDC Number Twenty containers of 4 mg/250 mL NDC 0338-0112-20 Twenty containers of 8 mg/250 mL NDC 0338-0108-20 Twenty containers of 16 mg/250 mL NDC 0338-0116-20 Store at room temperature [20°C to 25°C (68°F to 77°F)], excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Once the overwrap is removed, the bag can be stored at room temperature for up to 30 days. 17 PATIENT COUNSELING INFORMATION Risk of Tissue Damage Advise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions (5.1)]. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Ireland Baxter and Viaflo are trademarks of Baxter International Inc. or its subsidiaries. CB-30-02-860 Reference ID: 5281159 Each 100 mL of sterile, nonpyrogenic solution contains: Norepinephrine Bitartrate Monohydrate USP equivalent to 1.6 mg norepinephrine and 5 g Dextrose Monohydrate in Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. Single Dose Only – Discard unused portion. For Intravenous Use. Recommended dosage: See prescribing information. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep in overwrap until ready to use. Once removed from overwrap, bag can be stored at room temperature and should be used within 30 days. Viaflo container is not made with natural rubber latex, DEHP, or PVC. Rx Only Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Ireland CB-35-05-133 NDC 0338-0112-20 EZPE7748 For Intravenous Infusion Only LOT EXP Do not use this port Viaflo container 4 mg / 250 mL (16 mcg / mL) Norepinephrine Bitartrate in 5% Dextrose Injection ( 0 1 ) 0 0 3 0 3 3 8 0 1 1 2 2 0 3 250 mL NDC 0338-0108-20 EZPE7788 For Intravenous Infusion Only LOT EXP Do not use this port Each 100 mL of sterile, nonpyrogenic solution contains: Norepinephrine Bitartrate Monohydrate USP equivalent to 3.2 mg norepinephrine and 5 g Dextrose Monohydrate in Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. Single Dose Only - Discard unused portion. For Intravenous Use. Recommended dosage: See prescribing information. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep in overwrap until ready to use. Once removed from overwrap, bag can be stored at room temperature and should be used within 30 days. Viaflo container is not made with natural rubber latex, DEHP, or PVC. Rx Only Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Ireland CB-35-05-134 Viaflo container Norepinephrine Bitartrate in 5% Dextrose Injection 8 mg / 250 mL (32 mcg / mL) ( 0 1 ) 0 0 3 0 3 3 8 0 1 0 8 2 0 6 250 mL Each 100 mL of sterile, nonpyrogenic solution contains: Norepinephrine Bitartrate Monohydrate USP equivalent to 6.4 mg norepinephrine and 5 g Dextrose Monohydrate in Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. Single Dose Only - Discard unused portion. For Intravenous Use. Recommended dosage: See prescribing information. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep in overwrap until ready to use. Once removed from overwrap, bag can be stored at room temperature and should be used within 30 days. Viaflo container is not made with natural rubber latex, DEHP, or PVC. Rx Only Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Ireland NDC 0338-0116-20 EZPE7758 Viaflo container For Intravenous Infusion Only LOT EXP Do not use this port CB-35-05-144 Norepinephrine Bitartrate in 5% Dextrose Injection 16 mg / 250 mL (64 mcg / mL) 250 mL -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ NORMAN L STOCKBRIDGE 11/21/2023 04:14:17 PM Signature Page 1 of 1 Reference ID: 5281159 (	custom-source	2025-02-12T15:46:33.109410	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214313Orig1s003lbl.pdf', 'application_number': 214313, 'submission_type': 'SUPPL ', 'submission_number': 3}
80,151	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SPRAVATO safely and effectively. See full prescribing information for SPRAVATO. SPRAVATO® (esketamine) nasal spray, CIII Initial U.S. Approval: 1970 (ketamine) WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. ● Risk for sedation, dissociation, and respiratory depression after administration. Monitor patients for at least two hours after administration. (5.1, 5.2, 5.3) ● Potential for abuse and misuse. Consider the risks and benefits of prescribing SPRAVATO prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse. (5.4) ● SPRAVATO is only available through a restricted program called the SPRAVATO REMS. (5.5) ● Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients. (5.6) ----------------------------RECENT MAJOR CHANGES------------------------- Warnings and Precautions (5.8) 11/2024 -----------------------------INDICATIONS AND USAGE-------------------------- SPRAVATO is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of: • Treatment-resistant depression (TRD) in adults. (1) • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. (1) Limitations of Use: • The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO. (1) • SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established. (1) ------------------------DOSAGE AND ADMINISTRATION---------------------- • Administer SPRAVATO intranasally under the supervision of a healthcare provider. (2.1) • Assess blood pressure prior to and after administration. (2.1) • TRD: Evidence of therapeutic benefit should be evaluated at the end of the 4-week induction phase to determine need for continued treatment. (2.2) • Depressive symptoms in MDD with acute suicidal ideation or behavior: Evidence of therapeutic benefit should be evaluated after 4 weeks to determine need for continued treatment. Treatment beyond 4 weeks has not been systematically evaluated. (2.3) • See Full Prescribing Information for recommended dosage. (2.2, 2.3) • See Full Prescribing Information for important administration instructions. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Nasal Spray: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine. (3) -----------------------------CONTRAINDICATIONS------------------------------- • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation. (4) • Intracerebral hemorrhage. (4) • Hypersensitivity to esketamine, ketamine, or any of the excipients. (4) -------------------------WARNINGS AND PRECAUTIONS--------------------- • Increases in Blood Pressure: Patients with cardiovascular and cerebrovascular conditions and risk factors may be at an increased risk of associated adverse effects. (5.7) • Cognitive Impairment: SPRAVATO may impair attention, judgment, thinking, reaction speed and motor skills. (5.8) • Impaired Ability to Drive and Operate Machinery: Do not drive or operate machinery until the next day after a restful sleep. (5.9) • Embryo-fetal Toxicity: May cause fetal harm. Consider pregnancy planning and prevention in females of reproductive potential. (5.11, 8.1, 8.3) ------------------------------ADVERSE REACTIONS------------------------------ The most commonly observed adverse reactions (incidence 5% and at least twice that of placebo plus oral antidepressant): • TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk. (6) • Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. (6) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS----------------------- • Lactation: Breastfeeding not recommended. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5473909 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 17 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Important Considerations Prior to Initiating and During Therapy 2.2 Treatment-Resistant Depression 2.3 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior 2.4 Administration Instructions 2.5 Post-Administration Observation 2.6 Missed Treatment Session(s) DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Sedation 5.2 Dissociation 5.3 Respiratory Depression 5.4 Abuse and Misuse 5.5 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) 5.6 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 5.7 Increase in Blood Pressure 5.8 Cognitive Impairment 5.9 Impaired Ability to Drive and Operate Machinery 5.10 Ulcerative or Interstitial Cystitis 5.11 Embryo-fetal Toxicity ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience DRUG INTERACTIONS 7.1 Central Nervous System Depressants 7.2 Psychostimulants 7.3 Monoamine Oxidase Inhibitors (MAOIs) USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology CLINICAL STUDIES 14.1 Treatment-Resistant Depression 14.2 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior 14.3 Special Safety Studies HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5473909 2 FULL PRESCRIBING INFORMATION WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS Sedation ● Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1)]. Dissociation ● Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2)]. Respiratory Depression ● Respiratory depression has been observed in postmarketing experience [see Warnings and Precautions (5.3)]. Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Warnings and Precautions (5.1, 5.2, 5.3)]. Abuse and Misuse ● SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.4)]. Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.5)]. Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.6)]. Reference ID: 5473909 3 1 2 INDICATIONS AND USAGE SPRAVATO is indicated, in conjunction with an oral antidepressant, for the treatment of: • Treatment-resistant depression (TRD) in adults • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior Limitations of Use: • The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see Clinical Studies (14.2)]. Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO. • SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established. DOSAGE AND ADMINISTRATION 2.1 Important Considerations Prior to Initiating and During Therapy SPRAVATO must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision. Respiratory Status Assessment During Treatment • Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session [see Warnings and Precautions (5.3)]. Blood Pressure Assessment Before and After Treatment • Assess blood pressure prior to dosing with SPRAVATO [see Warnings and Precautions (5.7)]. • If baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of SPRAVATO treatment [see Warnings and Precautions (5.7)]. Do not administer SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk [see Contraindications (4)]. • After dosing with SPRAVATO, reassess blood pressure at approximately 40 minutes (which corresponds with the Cmax) and subsequently as clinically warranted. • If blood pressure is decreasing and the patient appears clinically stable for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor [see Warnings and Precautions (5.7)]. Reference ID: 5473909 4 Food and Liquid Intake Recommendations Prior to Administration Because some patients may experience nausea and vomiting after administration of SPRAVATO [see Adverse Reactions (6.1)], advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration. Nasal Corticosteroid or Nasal Decongestant Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO [see Clinical Pharmacology (12.3)]. 2.2 Treatment-Resistant Depression Administer SPRAVATO in conjunction with an oral antidepressant (AD). The recommended dosage of SPRAVATO for the treatment of TRD in adults is shown in Table 1. Dosage adjustments should be made based on efficacy and tolerability. Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine need for continued treatment. Table 1: Recommended Dosage for SPRAVATO for TRD Adults Induction Phase Maintenance Phase Weeks 1 to 4: Administer twice per week Weeks 5 to 8: Administer once weekly Week 9 and after: Administer every 2 weeks or once weekly Day 1 starting dose: 56 mg Subsequent doses: 56 mg or 84 mg 56 mg or 84 mg 56 mg or 84 mg * Dosing frequency should be individualized to the least frequent dosing to maintain remission/response. 2.3 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior Administer SPRAVATO in conjunction with an oral antidepressant (AD). The recommended dosage of SPRAVATO for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks. Dosage may be reduced to 56 mg twice per week based on tolerability. After 4 weeks of treatment with SPRAVATO, evidence of therapeutic benefit should be evaluated to determine need for continued treatment. The use of SPRAVATO, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior. Reference ID: 5473909 5 Nasal Spray Device ----Tip ~=--- Nose rest ' ~ icator 1-----1 - ---' ~ -"----- ~---°' Finger rest ---- Plunger Each device delivers two sprays containing a total of 28 mg of esketamine. Indicator One device contains 2 sprays. (1 spray for each nostril) 2 green dots (0 mg delivered) l green dot • No green dots Device full One spray delivered Two sprays (28 mg) delivered Device empty 2.4 Administration Instructions SPRAVATO is for nasal use only. The nasal spray device delivers a total of 28 mg of esketamine. To prevent loss of medication, do not prime the device before use. Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device. Follow these administration instructions and read the Instructions for Use before administration: Reference ID: 5473909 6 J1jij,f .t Get ready Before first device only: Instruct patient to blow nose before first device only. Confirm required number of devices. 56 mg= 2 devices 84 mg = 3 devices Eii§•fi Prepare device Healthcare professional: • Check expiralion date ('EXP'). If expired. get a nev: device. • Peel blister and remove device. Healthcare professional: Do not prime device. This will result in a loss of medication. Check that indicator shows 2 green dots. It not. dispose oi device ,:md get " new one. Hand device to patient. Reference ID: 5473909 7 Prepare patient Instruct the patient to: • Hold device as shown with the thumb gently supporting the plunger. • Do not press the plunger. Instruct the patient to: • Recline head at about 45 degrees during administration to keep medication inside the nose. Reference ID: 5473909 8 - Patient sprays once into each nostril Instruct the patient to: • Insert tip straight into the first nostril. • Nose rest should touch the skin between the nostrils. Instruct the patient to: • Sniff gently after spraying to keep medication inside nose. Instruct the patient to: • Close opposite nostril. • Breathe in through nose while pushing plunger all the way up until it stops. Instruct the patient to: • Switch hands to insert tip into the second nostril. • Repeat Step 4 to deliver second spray. a b c d Reference ID: 5473909 9 3 , J·j{ij,;) Confirm delivery and rest Healthcare professional: • Take device from patient. • Check that indicator shows no green dots. If you see a green dot, have patient spray again into the second nostril. • Check indicator again to confirm device is empty. Disposal Dispose of used device( s) per facility procedure for a Schedule Ill drug product and per applicable federal, state, and local regulations. Instruct the patient to: • Rest in a comfortable position (preferably, semi-reclined) for 5 minutes after each device. • If liquid drips out, dab nose with a tissue. & Do not blow nose. Next device 56mg½0 ¼ 0 Healthcare professional: • Repeat Steps 2-5 for the next device. IMPORTANT: Ensure that patient waits 5 minutes after each device to allow medication to absorb. 2.5 Post-Administration Observation During and after SPRAVATO administration at each treatment session, observe the patient for at least 2 hours until the patient is safe to leave [see Warnings and Precautions (5.1, 5.2, 5.3, 5.7)]. Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery, until the next day after a restful sleep [see Warnings and Precautions (5.9)]. 2.6 Missed Treatment Session(s) If a patient misses treatment session(s), provided there is no worsening of their depressive symptoms, the patient should continue the current dosing schedule. For patients who miss treatment session(s) during maintenance treatment and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule (e.g., if doses missed during weekly dosing, revert to twice weekly dosing). DOSAGE FORMS AND STRENGTHS Nasal Spray: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg esketamine. Reference ID: 5473909 10 4 5 CONTRAINDICATIONS SPRAVATO is contraindicated in patients with: • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation [see Warnings and Precautions (5.7)] • History of intracerebral hemorrhage [see Warnings and Precautions (5.7)] • Hypersensitivity to esketamine, ketamine, or any of the excipients. WARNINGS AND PRECAUTIONS 5.1 Sedation SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing. In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified Observer’s Assessment of Alertness/Sedation scale (MOAA/S) [see Adverse Reactions (6.1)], and 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0). Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting[see Dosage and Administration (2.5)]. Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants [see Drug Interactions (7.1)]. SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5)]. 5.2 Dissociation The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO-treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale) [see Adverse Reactions (6.1)]. Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated only if the benefit outweighs the risk. Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5)]. SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5)]. Reference ID: 5473909 11 5.3 Respiratory Depression In post marketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest [see Adverse Reactions (6.2)]. Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5)]. SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5)]. 5.4 Abuse and Misuse SPRAVATO contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient’s risk for abuse or misuse prior to prescribing SPRAVATO and monitor all patients receiving SPRAVATO for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of SPRAVATO. Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and monitor for signs of abuse or dependence [see Drug Abuse and Dependence (9)]. SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5)]. 5.5 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) SPRAVATO is available only through a restricted program under a REMS called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, respiratory depression, abuse and misuse [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.3, 5.4)]. Important requirements of the SPRAVATO REMS include the following: • Healthcare settings must be certified in the program and ensure that SPRAVATO is: − Only dispensed and administered in healthcare settings. − Patients treated in outpatient settings (e.g. medical offices and clinics) must be enrolled in the program. − Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO [see Dosage and Administration (2.5)]. • Pharmacies must be certified in the REMS and must only dispense SPRAVATO to healthcare settings that are certified in the program. Reference ID: 5473909 12 Further information, including a list of certified pharmacies is available at www.SPRAVATOrems.com or 1-855-382-6022. 5.6 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients (SPRAVATO is not approved in pediatric patients), the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients Age Range (Years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ≥65 6 fewer patients * SPRAVATO is not approved in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. Reference ID: 5473909 13 5.7 Increase in Blood Pressure SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO administration and last approximately 4 hours [see Adverse Reactions (6.1)]. Approximately 8% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage) [see Contraindications (4)]. Before prescribing SPRAVATO, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO outweigh its risks. Assess BP prior to administration of SPRAVATO. In patients whose BP is elevated prior to SPRAVATO administration (as a general guide: >140/90 mmHg) a decision to delay SPRAVATO therapy should take into account the balance of benefit and risk in individual patients. BP should be monitored for at least 2 hours after SPRAVATO administration [see Dosage and Administration (2.1, 2.5)]. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness or focal neurological deficits) immediately for emergency care. Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants or monoamine oxidase inhibitors (MAOIs) [see Drug Interactions (7.2, 7.3)]. In patients with history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure. 5.8 Cognitive Impairment Short-Term Cognitive Impairment In a study in healthy volunteers, a single dose of SPRAVATO caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose. Reference ID: 5473909 14 6 Long-Term Cognitive Impairment Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. In 1-year and 3-year, long-term, open-label clinical trials in adults, the effect of SPRAVATO on cognitive functioning remained stable over time as evaluated by the Cogstate computerized battery and Hopkins Verbal Learning Test-Revised. 5.9 Impaired Ability to Drive and Operate Machinery Two placebo-controlled studies were conducted to assess the effects of SPRAVATO on the ability to drive [see Clinical Studies (14.3)]. The effects of SPRAVATO 84 mg were comparable to placebo at 6 hours and 18 hours post-dose. However, two SPRAVATO-treated subjects in one of the studies discontinued the driving test at 8 hours post-dose because of SPRAVATO-related adverse reactions. Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO. 5.10 Ulcerative or Interstitial Cystitis Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO-treated patients than in placebo-treated patients [see Adverse Reactions (6)]. No cases of esketamine-related interstitial cystitis were observed in any of the studies, which included treatment for up to a year. Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO, and refer to an appropriate healthcare provider as clinically warranted. 5.11 Embryo-fetal Toxicity Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero. Advise women of reproductive potential to consider pregnancy planning and prevention [see Use in Specific Populations (8.1, 8.3)]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Sedation [see Warnings and Precautions (5.1)] • Dissociation [see Warnings and Precautions (5.2)] • Respiratory Depression [see Warnings and Precautions (5.3)] Reference ID: 5473909 15 • Increase in Blood Pressure [see Warnings and Precautions (5.7)] • Cognitive Impairment [see Warnings and Precautions (5.8)] • Impaired Ability to Drive and Operate Machinery [see Warnings and Precautions (5.9)] • Ulcerative or Interstitial Cystitis [see Warnings and Precautions (5.10)] • Embryo-fetal Toxicity [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment-Resistant Depression SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14.1)] from five Phase 3 studies (3 short-term and 2 long-term studies) and one Phase 2 dose-ranging study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 479 (30%) received at least 6 months of treatment, and 178 (11%) received at least 12 months of treatment. Adverse Reactions Leading to Discontinuation of Treatment In short-term studies in adults <65 years old (Study 1 pooled with another 4-week study), the proportion of patients who discontinued treatment because of an adverse reaction was 4.6% in patients who received SPRAVATO plus oral AD compared to 1.4% for patients who received placebo nasal spray plus oral AD. For adults ≥65 years old, the proportions were 5.6% and 3.1%, respectively. In Study 2, a long-term maintenance study, the discontinuation rates because of an adverse reaction were similar for patients receiving SPRAVATO plus oral AD and placebo nasal spray plus oral AD in the maintenance phase, at 2.6% and 2.1%, respectively. Across all Phase 3 studies, adverse reactions leading to SPRAVATO discontinuation in more than 2 patients were (in order of frequency): anxiety (1.2%), depression (0.9%), blood pressure increased (0.6%), dizziness (0.6%), suicidal ideation (0.5%), dissociation (0.4%), nausea (0.4%), vomiting (0.4%), headache (0.3%), muscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack (0.2%) and sedation (0.2%). Most Common Adverse Reactions The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence 5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk. Table 3 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD at any dose and greater than patients treated with placebo nasal spray plus oral AD. Reference ID: 5473909 16 Table 3: Adverse Reactions Occurring in ≥2% of Adult TRD Patients Treated with SPRAVATO + Oral AD at Any Dose and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD SPRAVATO + Oral AD (N=346) Placebo + Oral AD (N=222) Cardiac disorders Tachycardia* 6 (2%) 1 (0.5%) Ear and labyrinth disorders Vertigo* 78 (23%) 6 (3%) Gastrointestinal disorders Nausea 98 (28%) 19 (9%) Vomiting 32 (9%) 4 (2%) Diarrhea 23 (7%) 13 (6%) Dry mouth 19 (5%) 7 (3%) Constipation 11 (3%) 3 (1%) General disorders and administration site conditions Feeling drunk 19 (5%) 1 (0.5%) Feeling abnormal 12 (3%) 0 (0%) Investigations Blood pressure increased* 36 (10%) 6 (3%) Nervous system disorders Dizziness* 101 (29%) 17 (8%) Sedation* 79 (23%) 21 (9%) Headache* 70 (20%) 38 (17%) Dysgeusia* 66 (19%) 30 (14%) Hypoesthesia* 63 (18%) 5 (2%) Lethargy* 37 (11%) 12 (5%) Dysarthria* 15 (4%) 0 (0%) Tremor 12 (3%) 2 (1%) Mental impairment 11 (3%) 2 (1%) Psychiatric disorders Dissociation* 142 (41%) 21 (9%) Anxiety* 45 (13%) 14 (6%) Insomnia 29 (8%) 16 (7%) Euphoric mood 15 (4%) 2 (1%) Renal and urinary disorders Pollakiuria 11 (3%) 1 (0.5%) Respiratory, thoracic and mediastinal disorders Nasal discomfort* 23 (7%) 11 (5%) Reference ID: 5473909 17 Throat irritation 23 (7%) 9 (4%) Oropharyngeal pain 9 (3%) 5 (2%) Skin and subcutaneous tissue disorders Hyperhidrosis 14 (4%) 5 (2%) * The following terms were combined: Anxiety includes: agitation; anticipatory anxiety; anxiety; fear; feeling jittery; irritability; nervousness; panic attack; tension Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dissociation includes: delusional perception; depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; feeling of body temperature change; hallucination; hallucination, auditory; hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred; visual impairment Dizziness includes: dizziness; dizziness exertional; dizziness postural; procedural dizziness Dysarthria includes: dysarthria; slow speech; speech disorder Dysgeusia includes: dysgeusia; hypogeusia Headache includes: headache; sinus headache Hypoesthesia includes: hypoesthesia; hypoesthesia oral, hypoesthesia teeth, pharyngeal hypoesthesia Lethargy includes: fatigue; lethargy Nasal discomfort includes: nasal crusting; nasal discomfort; nasal dryness; nasal pruritus Sedation includes: altered state of consciousness; hypersomnia; sedation; somnolence Tachycardia includes: extrasystoles; heart rate increased; tachycardia Vertigo includes: vertigo; vertigo positional Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior SPRAVATO was evaluated for safety in 262 adults for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior [see Clinical Studies (14.2)] from two Phase 3 studies (Study 3 and Study 4) and one Phase 2 study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 184 (81%) received all eight doses over a 4-week treatment period. Adverse Reactions Leading to Discontinuation of Treatment In short-term studies in adults (pooled Study 3 and Study 4), the proportion of patients who discontinued treatment because of an adverse reaction was 6.2% for patients who received SPRAVATO plus oral AD compared to 3.6% for patients who received placebo nasal spray plus oral AD. Adverse reactions leading to SPRAVATO discontinuation in more than 1 patient were (in order of frequency): dissociation-related events (2.6%), blood pressure increased (0.9%), dizziness-related events (0.9%), nausea (0.9%), and sedation-related events (0.9%). Most Common Adverse Reactions The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence 5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. Table 4 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD and greater than patients treated with placebo nasal spray plus oral AD. Reference ID: 5473909 18 Table 4: Adverse Reactions Occurring in ≥2% of Adult Patients with MDD and Acute Suicidal Ideation or Behavior Treated with SPRAVATO + Oral AD and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD SPRAVATO + Oral AD (N=227) Placebo + Oral AD (N=225) Cardiac disorders Tachycardia* 8 (4%) 2 (1%) Ear and labyrinth disorders Vertigo 14 (6%) 1 (0.4%) Gastrointestinal disorders Nausea 61 (27%) 31 (14%) Vomiting 26 (11%) 12 (5%) Constipation 22 (10%) 14 (6%) Dry mouth 8 (4%) 6 (3%) Toothache 5 (2%) 2 (1%) General disorders and administration site conditions Feeling drunk 8 (4%) 1 (0.4%) Feeling of relaxation 5 (2%) 3 (1%) Investigations Blood pressure increased* 34 (15%) 14 (6%) Musculoskeletal and connective tissue disorders Myalgia 5 (2%) 1 (0.4%) Nervous system disorders Dizziness* 103 (45%) 34 (15%) Sedation* 66 (29%) 27 (12%) Dysgeusia* 46 (20%) 29 (13%) Hypoesthesia* 30 (13%) 4 (2%) Lethargy* 10 (4%) 4 (2%) Confusional state 5 (2%) 0 (0%) Psychiatric disorders Dissociation* 108 (48%) 30 (13%) Anxiety* 34 (15%) 20 (9%) Euphoric mood 17 (7%) 1 (0.4%) Intentional self-injury 7 (3%) 3 (1%) Dysphoria 5 (2%) 0 (0%) Renal and urinary disorders Pollakiuria* 5 (2%) 2 (1%) Reference ID: 5473909 19 I I Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 10 (4%) 3 (1%) Throat irritation 9 (4%) 5 (2%) Skin and subcutaneous tissue disorders Hyperhidrosis* 11 (5%) 5 (2%) * The following terms were combined: Anxiety includes: agitation; anxiety; anxiety disorder; fear; irritability; nervousness; panic attack; psychomotor hyperactivity; tension Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dissociation includes: depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; hallucination; hallucination, auditory; hallucination, visual; hallucinations, mixed; hyperacusis; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred Dizziness includes: dizziness; dizziness exertional; dizziness postural Dysgeusia includes: dysgeusia; hypogeusia Hyperhidrosis includes: cold sweat; hyperhidrosis Hypoesthesia includes: hypoesthesia; hypoesthesia oral; intranasal hypoesthesia; pharyngeal hypoesthesia Lethargy includes: fatigue; lethargy; psychomotor retardation Pollakiuria includes: micturition urgency; pollakiuria Sedation includes: sedation; somnolence; stupor Tachycardia includes: heart rate increased; sinus tachycardia; tachycardia Sedation Sedation was evaluated by adverse event reports and the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S). In the MOAA/S, 5 means “responds readily to name spoken in normal tone” and 0 means “no response after painful trapezius squeeze.” Any decrease in MOAA/S from pre-dose is considered to indicate the presence of sedation, and such a decrease occurred in a higher number of patients on SPRAVATO than placebo during the short-term TRD studies. Dose-related increases in the incidence of sedation (MOAA/S score <5) were observed in a fixed-dose TRD study [see Warnings and Precautions (5.1)]. Table 5 presents the incidence of sedation (MOAA/S score <5) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD. Table 5: Incidence of Sedation (MOAA/S Score <5) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study with Adult Patients <65 Years of Age with TRD and Flexible-Dose Study with Patients ≥65 Years of Age with TRD) Patients <65 years Patients ≥65 years Placebo + Oral AD SPRAVATO + Oral AD 56 mg 84 mg Placebo + Oral AD SPRAVATO + Oral AD 28 to 84 mg Number of patients* N=112 N=114 N=114 N=63 N=72 Sedation (MOAA/S score <5) 11% 50% 61% 19% 49% * Patients who were evaluated with MOAA/S In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, there was a higher incidence of sedation (MOAA/S score <5) in patients treated with SPRAVATO plus oral AD compared to patients treated with placebo plus oral AD, similar to the TRD study results in Table 5. Reference ID: 5473909 20 Dissociation/Perceptual Changes SPRAVATO can cause dissociative symptoms (including derealization and depersonalization) and perceptual changes (including distortion of time and space, and illusions). In clinical trials, dissociation was transient and occurred on the day of dosing. Dissociation was evaluated by adverse event reports and the Clinician-Administered Dissociative States Scale (CADSS). A CADSS total score of more than 4 indicates the presence of dissociative symptoms, and such an increase to a score of 4 or more occurred in a higher number of patients on SPRAVATO compared to placebo during the short-term TRD studies. Dose-related increases in the incidence of dissociative symptoms (CADSS total score >4 and change >0) were observed in a fixed-dose TRD study [see Warnings and Precautions (5.2)]. Table 6 presents the incidence of dissociation (CADSS total score >4 and change >0) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD. Table 6: Incidence of Dissociation (CADSS Total Score >4 and Change >0) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study with Adult Patients <65 Years of Age with TRD and Flexible-Dose Study with Patients ≥65 Years of Age with TRD) Patients <65 years Patients ≥65 years Placebo + Oral AD SPRAVATO + Oral AD Placebo + Oral AD SPRAVATO + Oral AD 28 to 84 mg 56 mg 84 mg Number of patients* N=113 N=113 N=116 N=65 N=72 CADSS total score >4 and change >0 5% 61% 69% 12% 75% * Number of patients who were evaluated with CADSS In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral AD also demonstrated a higher number (84%) with dissociation (CADSS total score >4 and change >0) compared to patients treated with placebo plus oral AD (16%). Increase in Blood Pressure The mean placebo-adjusted increases in systolic and diastolic blood pressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients with TRD receiving SPRAVATO plus oral antidepressants [see Warnings and Precautions (5.7)]. Table 7 presents increases in blood pressure in short-term trials with patients <65 years of age and ≥65 years of age with TRD. Table 7: Increases in Blood Pressure in Double-blind, Randomized, Placebo-Controlled, Short-Term Trials of SPRAVATO + Oral AD Compared to Placebo Nasal Spray + Oral AD in the Treatment of TRD in Adult Patients Patients <65 years Patients ≥65 years SPRAVATO Placebo + SPRAVATO Placebo + Oral + Oral AD Oral AD + Oral AD AD N=346 N=222 N=72 N=65 Systolic blood pressure ≥180 mmHg 9 (3%) -- 2 (3%) 1 (2%) Reference ID: 5473909 21 ≥40 mmHg increase 29 (8%) 1 (0.5%) 12 (17%) 1 (2%) Diastolic blood pressure ≥110 mmHg 13 (4%) 1 (0.5%) -- -- ≥25 mmHg increase 46 (13%) 6 (3%) 10 (14%) 2 (3%) In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral antidepressants demonstrated similar mean placebo-adjusted increases in SBP and DBP compared to patient with TRD, as well as similar rates of increases to SBP ≥180 mmHg or ≥40 mmHg increases in SBP, and similar rates of increases to DBP ≥110 mmHg or ≥25 mmHg increases in DBP, compared to the TRD study results in Table 7. Nausea and Vomiting SPRAVATO can cause nausea and vomiting. Most of these events occurred on the day of dosing and resolved the same day, with the median duration not exceeding 1 hour in most subjects across dosing sessions. Rates of reported nausea and vomiting decreased over time across dosing sessions from the first week of treatment in the short-term studies, as well as over time with long-term treatment. Table 8 presents the incidence and severity of nausea and vomiting in a short-term study with patients with TRD. Table 8: Incidence and Severity of Nausea and Vomiting in a Double-blind, Randomized, Placebo- Controlled, Fixed-Dose Study in Adult Patients with TRD Treatment (+ Oral AD) Nausea Vomiting N All Severe All Severe SPRAVATO 56 mg 115 31 (27%) 0 7 (6%) 0 SPRAVATO 84 mg 116 37 (32%) 4 (3%) 14 (12%) 3 (3%) Placebo Nasal Spray 113 12 (11%) 0 2 (2%) 0 In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients demonstrated similar incidence and severity of reported nausea and vomiting compared to the TRD study results described above. Sense of Smell Sense of smell was assessed over time; no difference was observed between patients treated with SPRAVATO plus oral AD and those treated with placebo nasal spray plus oral AD during the double-blind maintenance phase of Study 2 [see Clinical Studies (14.1)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SPRAVATO. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, thoracic and mediastinal disorders: respiratory depression (including respiratory arrest) Reference ID: 5473909 22 7 8 Vascular disorders: hypotension DRUG INTERACTIONS 7.1 Central Nervous System Depressants Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation [see Warnings and Precautions (5.1)]. Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants. 7.2 Psychostimulants Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure [see Warnings and Precautions (5.7)]. Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants. 7.3 Monoamine Oxidase Inhibitors (MAOIs) Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure [see Warnings and Precautions (5.7)]. Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research programs/pregnancyregistry/antidepressants/. Risk Summary SPRAVATO is not recommended during pregnancy. There are insufficient data on SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women (see Data). Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero. There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations). If a woman becomes pregnant while being treated with SPRAVATO, treatment with esketamine should be discontinued and the patient should be counseled about the potential risk to the fetus. Published studies in pregnant primates demonstrate that the administration of drugs that block N-methyl-D-aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring. There are no data on pregnancy Reference ID: 5473909 23 exposures in primates corresponding to periods prior to the third trimester in humans [see Use in Specific Populations (8.2)]. In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the post-weaning period. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Data Animal Data Based on published data, when female monkeys were treated intravenously with racemic ketamine at anesthetic dose levels in the third trimester of pregnancy, neuronal cell death was observed in the brains of their fetuses. This period of brain development translates into the third trimester of human pregnancy. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits. Racemic ketamine was administered intranasally to pregnant rats during the period of organogenesis at doses of 15, 50, and 150 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for embryo-fetal toxicity in rats was the highest dose of 150 mg/kg/day. Estimating 50% of the exposure to be from esketamine, the NOAEL associated with esketamine plasma exposure (AUC) is 12-times the AUC exposure at the MRHD of 84 mg/day. In pregnant rabbits, racemic ketamine was administered intranasally from gestational day 6 to 18 at doses of 10, 30, and 100 mg/kg/day. The high dose was lowered from 100 to 50 mg/kg after 5 days of dosing due to excessive mortality in the pregnant rabbits. Skeletal malformations were observed at doses ≥ 30 mg/kg/day, which were maternally toxic. The NOAEL for skeletal malformations was associated with a plasma esketamine exposure (AUC) that was 0.3 times the AUC exposure at MRHD of 84 mg/day. Reference ID: 5473909 24 Administration of esketamine to pregnant rats during pregnancy and lactation at intranasal doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat) produced AUC exposures 0.07, 0.5, and 0.7 times the MRHD of 84 mg/day, respectively. Maternal toxicity was observed at doses ≥ 15 mg/kg/day. In addition, a dose-dependent delay in the age of attainment of Preyer response reflex was observed in pups at all doses during the preweaning period. This sensory/motor developmental measure was tested starting on postnatal day (PND) 9, and the effect normalized by PND 19 in treatment groups as compared with PND 14 for the majority of the control animals. There is no NOAEL for this delay in sensory/motor response observed in pups during the preweaning period. During the postweaning period, a decrease in motor activity was observed at doses ≥ 15 mg/kg which is 0.5-times the human exposure at the MRHD of 84 mg/day. The NOAEL for maternal toxicity and decreased motor activity during the postweaning period was 4.5 mg/kg/day which was associated with a plasma exposure (AUC) that was 0.07-times the AUC exposure at MRHD of 84 mg/day. 8.2 Lactation Risk Summary Esketamine is present in human milk. There are no data on the effects of SPRAVATO on the breastfed infant or on milk production. Published studies in juvenile animals report neurotoxicity (see Data). Because of the potential for neurotoxicity, advise patients that breast-feeding is not recommended during treatment with SPRAVATO. Data Published juvenile animal studies demonstrate that the administration of drugs that block NMDA receptors, such as ketamine, during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but this window may extend out to approximately 3 years of age in humans. 8.3 Females and Males of Reproductive Potential Contraception Based on published animal reproduction studies, SPRAVATO may cause embryo-fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. However, it is not clear how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential during treatment with SPRAVATO. 8.4 Pediatric Use The safety and effectiveness of SPRAVATO in pediatric patients have not been established. Reference ID: 5473909 25 9 8.5 Geriatric Use Of the total number of patients in Phase 3 clinical studies exposed to SPRAVATO, (N=1601), 194 (12%) were 65 years of age and older, and 25 (2%) were 75 years of age and older. No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age. The mean esketamine Cmax and AUC values were higher in elderly patients compared with younger adult patients [see Clinical Pharmacology (12.3)]. The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO plus a newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oral antidepressant in patients ≥ 65 years of age. SPRAVATO was initiated at 28 mg twice weekly and could be titrated to 56 mg or 84 mg administered twice-weekly. At the end of four weeks, there was no statistically significant difference between groups on the primary efficacy endpoint of change from baseline to Week 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS). 8.6 Hepatic Impairment The mean esketamine AUC and t1/2 values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function [see Clinical Pharmacology (12.3)]. SPRAVATO-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time. SPRAVATO has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended [see Clinical Pharmacology (12.3)]. DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance SPRAVATO contains esketamine hydrochloride, the (S)-enantiomer of ketamine and a Schedule III controlled substance under the Controlled Substances Act. 9.2 Abuse Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Abuse is the intentional, non-therapeutic use of a drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Careful consideration is advised prior to use of individuals with a history of substance use disorder, including alcohol. SPRAVATO may produce a variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and to be “spaced out”. Monitoring for signs of abuse and misuse is recommended. Reference ID: 5473909 26 10 11 Abuse Potential Study A cross-over, double-blind abuse potential study of SPRAVATO and ketamine was conducted in recreational polydrug users (n=34) who had experience with perception-altering drugs, including ketamine. Ketamine, the racemic mixture of arketamine and esketamine, is a Schedule III controlled substance and has known abuse potential. In this study, the mean “Drug Liking at the Moment” and “Take Drug Again” scores for single doses of intranasal SPRAVATO (84 mg and 112 mg – the maximum recommended dose and 1.3 times the maximum recommended dose, respectively) were similar to these scores in the intravenous ketamine (0.5 mg/kg infused over 40 minutes) control group. However, these scores were greater in the SPRAVATO and ketamine groups compared to the placebo group. The 112 mg dose of intranasal SPRAVATO was associated with significantly higher scores for “Hallucinating,” “Floating,” “Detached,” and “Spaced Out” than the 84 mg dose of intranasal SPRAVATO and the intravenous ketamine dose. 9.3 Dependence Physical dependence has been reported with prolonged use of ketamine. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug. There were no withdrawal symptoms captured up to 4 weeks after cessation of esketamine treatment. Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly) large doses of ketamine for long periods of time. Such withdrawal symptoms are likely to occur if esketamine were similarly abused. Reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety. Therefore, monitor SPRAVATO-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug. Tolerance has been reported with prolonged use of ketamine. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Similar tolerance would be expected with prolonged use of esketamine. OVERDOSAGE Management of Overdosage There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug involvement should be considered. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org). DESCRIPTION SPRAVATO® contains esketamine hydrochloride, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine. The chemical Reference ID: 5473909 27 e .HCI 12 name is (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. Its molecular formula is C13H16ClNO.HCl and its molecular weight is 274.2. The structural formula is: Esketamine hydrochloride is a white or almost white crystalline powder that is freely soluble in water and in methanol, and soluble in ethanol. SPRAVATO nasal spray is intended for nasal administration. Esketamine hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each device delivers two sprays with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5. The inactive ingredients are citric acid monohydrate, edetate disodium, sodium hydroxide, and water for injection. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of SPRAVATO (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. A large increase in heart rate (i.e., >10 bpm) was observed in both intranasal and intravenous esketamine treatment groups. The totality of evidence from the nonclinical and clinical data indicates a lack of clinically relevant QTc prolongation at the therapeutic dose of esketamine. 12.3 Pharmacokinetics Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in Cmax and AUC values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly dose proportional between 56 mg and 84 mg. No accumulation of esketamine in plasma was observed following twice a week administration. Reference ID: 5473909 28 Absorption The mean absolute bioavailability is approximately 48% following nasal spray administration. The time to reach maximum esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of a treatment session. The inter-subject variability of esketamine ranges from 27% to 66% for Cmax and 18% to 45% for AUC∞. The intra-subject variability of esketamine is approximately 15% for Cmax and 10% for AUC∞. Distribution The mean steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. Protein binding of esketamine was approximately 43% to 45%. The brain-to-plasma ratio of noresketamine is 4- to 6-times lower than that of esketamine. Elimination After Cmax was reached following intranasal administration, the decline in plasma esketamine concentrations was biphasic, with rapid decline for the initial 2 to 4 hours and a mean terminal half-life (t1/2) that ranged from 7 to 12 hours. The mean clearance of esketamine is approximately 89 L/hour following intravenous administration. The elimination of the major metabolite, noresketamine, from plasma is slower than esketamine. The decline of noresketamine plasma concentrations is biphasic, with rapid decline for the initial 4 hours and a mean terminal t1/2 of approximately 8 hours. Metabolism Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19. Noresketamine is metabolized via CYP-dependent pathways and certain subsequent metabolites undergo glucuronidation. Excretion Less than 1% of a dose of nasal esketamine is excreted as unchanged drug in urine. Following intravenous or oral administration, esketamine-derived metabolites were primarily recovered in urine (≥ 78% of a radiolabeled dose) and to a lesser extent in feces (≤ 2% of a radiolabeled dose). Specific Populations Exposures of esketamine in specific populations are summarized in Figure 1. No significant differences in the pharmacokinetics of SPRAVATO nasal spray were observed for sex and total body weight (>39 to 170 kg) based on population PK analysis. There is no clinical experience with SPRAVATO nasal spray in patients on renal dialysis or with severe (Child-Pugh class C) hepatic impairment. Reference ID: 5473909 29 Po1mlation Dcscri11tion Age: 65-81 years/22-50 years 75-85 /2-1-5-1 years Race: Japanese/White Chinese/White Korean/White Hepatic lm1rnirmcnt: Moderate/Normal Mild/Normal Renal lm11airment: Severe (not on dialysis)/Normal Moderate/Nonna! Mild/Normal Allergic Rhinitis: Allergic Rhinitis/Normal PK Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Fohl Change and 90%CI 1-----+----l ■ ■ ■ 1------a-1 ■ 0.5 1.0 1.5 2.0 2.5 <---Change Relative to Reference---> Figure 1: Effect of Specific Populations on the Pharmacokinetics of Esketamine Drug Interaction Studies The effect of other drugs on the exposures of intranasally administered esketamine are summarized in Figure 2. The effect of SPRAVATO on the exposures of other drugs are summarized in Figure 3. Based on these results, none of the drug-drug interactions are clinically significant. Reference ID: 5473909 30 Interacting Drug Cyt,ochrome P450 Inducer Rifampin Cytochrome NSO 2B6 Inhibitor Ticlopidin ytochr,ome 450 3 Inhibitor Clarithrom ·cin .- ·al ortioosteroid: Momctasone fur-oate a. al Decongestant: rmetazoline HCI PK max AOC max AU Cmax AUC max AU Cmax AUC Fold Ch11nge and 90 1/o I ■ i-a-; • 0.5 JO <- ~ han<>e Relati e lo Reference--> Int ractin~ Drug PK Fold han~c and 901/o I ub trat of hcpati YP286: C3upr pi n * ub trate of hcpati YPJ * 'max A idaz lam 'max A 0. 1.0 I S honge Rel 1i,·c to Rcfcrcn ) s * The potential for cytochrome P450 induction by esketamine was assessed. Intranasal esketamine (84 mg) was administered twice weekly for 2 weeks. Bupropion or midazolam was administered at baseline and 24 hours after the last dose of esketamine. Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Esketamine * * Administered 1 hour before intranasal esketamine Figure 3: Effect of Esketamine on the Pharmacokinetics of Co-Administered Drugs In Vitro Studies Enzyme Systems: Esketamine has modest induction effects on CYP2B6 and CYP3A4 in human hepatocytes. Esketamine and its major metabolites do not induce CYP1A2. Esketamine and its Reference ID: 5473909 31 13 major circulating metabolites did not show inhibition potential against CYPs and UGTs, except for a weak reversible inhibition of noresketamine on CYP3A4. Transporter Systems: Esketamine is not a substrate of transporters P-glycoprotein (P-gp; multidrug resistance protein 1), breast cancer resistance protein (BCRP), or organic anion transporter (OATP) 1B1, or OATP1B3. Esketamine and its major circulating metabolites do not inhibit these transporters or multi-drug and toxin extrusion 1 (MATE1) and MATE2-K, or organic cation transporter 2 (OCT2), OAT1, or OAT3. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Once-daily intranasal administration of esketamine at doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat) did not increase the incidence of tumors in a 2-year rat carcinogenicity study. At the highest dose, the AUC exposure to esketamine was lower than the human exposure (AUC) at the maximum recommended human dose (MRHD) of 84 mg. Once-daily subcutaneous administration of esketamine up to 75 mg/kg/day (reduced to 40 mg/kg/day during week 17) did not increase the incidence of tumors in a 6-month study in transgenic (Tg.rasH2) mice. Mutagenesis Esketamine was not mutagenic with or without metabolic activation in the Ames test. Genotoxic effects with esketamine were seen in a screening in vitro micronucleus test in the presence of metabolic activation. However, intravenously-administered esketamine was devoid of genotoxic properties in an in vivo bone marrow micronucleus test in rats and an in vivo Comet assay in rat liver cells. Impairment of Fertility Esketamine was administered intranasally to both male and female rats before mating, throughout the mating period, and up to day 7 of gestation at doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat), which are approximately 0.05, 0.3, and 0.6-times the maximum recommended human dose (MRHD) of 84 mg/day based on mean AUC exposures, respectively. Estrous cycle irregularities were observed at the high dose of 45 mg/kg/day and increased time to mate was observed at doses ≥ 15 mg/kg/day without an overall effect on mating or fertility indices. The No Observed Adverse Effect Level (NOAEL) for mating and fertility is 45 mg/kg/day which is 0.6 times the esketamine exposures at MRHD of 84 mg/day. 13.2 Animal Toxicology and/or Pharmacology Neurotoxicity In a single-dose neuronal toxicity study where esketamine was administered intranasally to adult female rats, there were no findings of neuronal vacuolation in the brain up to an estimated dose equivalent of 45 mg/kg for a 200-gram rat with a safety margin of 1.8 and 4.5 times the clinical exposures for AUC and Cmax, respectively, to the MRHD of 84 mg/day. In a second single-dose Reference ID: 5473909 32 14 neurotoxicity study conducted with intranasally administered esketamine to adult female rats, there were no findings of neuronal necrosis up to a dose equivalent of 270 mg/kg for a 200-gram rat which has a safety margin of 18-fold and 23-fold, respectively, to AUC and Cmax exposures at the MRHD of 84 mg/day. Neuronal vacuolation was not examined in this study. In a single-dose neuronal toxicity study in adult rats, subcutaneously administered racemic ketamine caused neuronal vacuolation in layer I of the retrosplenial cortex of the brain without neuronal necrosis at a dose of 60 mg/kg. The NOAEL for vacuolation in this study was 15 mg/kg. Estimating 50% of the exposure to be from esketamine, the NOAEL for neuronal vacuolation is 1.6-times and 4.5-times and the NOAEL for neuronal necrosis is 10-times and 16-times exposures, respectively, for AUC and Cmax to the clinical exposure at the MRHD of 84 mg/day. The relevance of these findings to humans is unknown. CLINICAL STUDIES 14.1 Treatment-Resistant Depression Short-Term Study SPRAVATO was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short- term (4-week), Phase 3 study (Study 1; NCT02418585) in adult patients 18 to <65 years old with treatment-resistant depression (TRD). Patients in Study 1 met DSM-5 criteria for major depressive disorder (MDD) and in the current depressive episode, had not responded adequately to at least two different antidepressants of adequate dose and duration. After discontinuing prior antidepressant treatments, patients in Study 1 were randomized to receive twice weekly doses of intranasal SPRAVATO (flexible dose; 56 mg or 84 mg) or intranasal placebo. All patients also received open-label concomitant treatment with a newly initiated daily oral antidepressant (AD) (duloxetine, escitalopram, sertraline, or extended-release venlafaxine as determined by the investigator based on patient’s prior treatment history). SPRAVATO could be titrated up to 84 mg starting with the second dose based on investigator discretion. The demographic and baseline disease characteristics of patients in Study 1 were similar for the SPRAVATO and placebo nasal spray groups. Patients had a median age of 47 years (range 19 to 64 years) and were 62% female, 93% Caucasian, and 5% Black. The newly initiated oral AD was an SSRI in 32% of patients and an SNRI in 68% of patients. In Study 1, the primary efficacy measure was change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at the end of the 4-week double-blind induction phase. The MADRS is a ten-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression. SPRAVATO plus a newly initiated oral AD demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus a newly initiated oral AD (see Table 9). Reference ID: 5473909 33 0 Q) -5 C Q) (/) co cc -10 E _g ~-15 C co .c. (.) -20 ~ ' 'o-----o ......................... ------........ .....().. ~ SPRAVATO + Oral AD -0- Placebo Nasal Spray+ Oral AD ----- ~ ..... ..... ........... ..... "'O -25 ~------,...----------------.-----------------.-- Dax_o 24 Hrs. (8 ) Days Day15 Day22 Day28 Table 9: Primary Efficacy Results for Change from Baseline in MADRS Total Score at Week 4 in Patients with TRD in Study 1 Treatment Group Number of Patients Mean Baseline Score (SD) LS Mean (SE) Change from Baseline to end of Week 4 LS Mean Difference (95% CI) SPRAVATO (56 mg or 84 mg) + Oral AD† 114 37.0 (5.7) -19.8 (1.3) -4.0 (-7.3; -0.6) Placebo nasal spray + Oral AD 109 37.3 (5.7) -15.8 (1.3) - SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval; AD=antidepressant * Difference (SPRAVATO + Oral AD minus Placebo nasal spray + Oral AD) in least-squares mean change from baseline † SPRAVATO + Oral AD was statistically significantly superior to placebo nasal spray + oral AD Time Course of Treatment Response Figure 4 shows the time course of response for the primary efficacy measure (MADRS) in Study 1. Most of SPRAVATO’s treatment difference compared to placebo was observed at 24 hours. Between 24 hours and Day 28, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 28. At Day 28, 67% of the patients randomized to SPRAVATO were receiving 84 mg twice weekly. Figure 4: Least Squares Mean Change from Baseline in MADRS Total Score Over Time in Patients with TRD in Study 1* (Full Analysis Set) * Note: In this flexible-dose study, dosing was individualized based on efficacy and tolerability. Few subjects (<10%) had reduction in 34 Reference ID: 5473909 SPRAVATO dosage from 84 mg to 56 mg twice weekly. Treatment-Resistant Depression – Long-term Study Study 2 (NCT02493868) was a long-term randomized, double-blind, parallel-group, multicenter maintenance-of-effect study in adults 18 to <65 years of age who were known remitters and responders to SPRAVATO. Patients in this study were responders in one of two short-term controlled trials (Study 1 and another 4-week study) or in an open-label direct-enrollment study in which they received flexibly-dosed SPRAVATO (56 mg or 84 mg twice weekly) plus daily oral AD in an initial 4-week phase. Stable remission was defined as a MADRS total score ≤ 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction ≥ 50% for the last 2 weeks of optimization and not in remission. After at least 16 initial weeks of treatment with SPRAVATO and an oral AD, stable remitters and stable responders were randomized separately to continue intranasal treatment with SPRAVATO or switch to placebo nasal spray, in both cases with continuation of their oral AD. The primary study endpoint was time to relapse in the stable remitter group. Relapse was defined as a MADRS total score ≥22 for 2 consecutive weeks or hospitalization for worsening depression or any other clinically relevant event indicative of relapse. The demographic and baseline disease characteristics of the two groups were similar. Patients had a median age of 48 years (range 19 to 64 years) and were 66% female, 90% Caucasian, and 4% Black. Patients in stable remission who continued treatment with SPRAVATO plus oral AD experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on placebo nasal spray plus an oral AD (see Figure 5). Reference ID: 5473909 35 100 80 Q) 1/) C. Placebo Nasal Spray + Oral AD "' a; 60 er "' r - • .c ~ .l!l 40 C: Q) SPRAVATO + Oral AD ~ Q. - 0 c 20 Q) e Q) Q. 0 Number of Subjects at Risk Placebo Nasal Spray + Oral AD 86 52 34 22 12 7 3 3 3 2 0 SPRAVATO + Oral AD 90 74 53 31 20 10 7 6 2 0 8 16 24 32 40 48 56 64 72 80 Weeks since Entering Maintenance Phase Figure 5: Time to Relapse in Patients with TRD in Stable Remission in Study 2* (Full Analysis Set) * Note: The estimated hazard ratio (95% CI) of SPRAVATO + Oral AD relative to Placebo nasal spray + Oral AD based on weighted estimates was 0.49 (95% CI: 0.29, 0.84). However, the hazard ratio did not appear constant throughout the trial. Time to relapse was also significantly delayed in the stable responder population. These patients experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus oral AD (see Figure 6). Reference ID: 5473909 36 100 80 <1) (/) Q_ "' oi 60 0:: "' £ ~ .l!l 40 C <1) ~ 0.. 0 c 20 <1) ~ <1) 0.. 0 Placebo Nasal Spray + Oral AD 59 SPRAVATO + Oral AD 62 0 r , // 35 49 8 •' • - - - - I 19 35 16 - ' 13 26 24 Placebo Nasal Spray + Oral AD 1 ,------- ---------------- SPRAVATO + Oral AD Number of Subjects at Risk 4 15 32 2 11 40 2 7 48 6 5 56 64 Weeks since Entering Maintenance Phase 0 2 72 0 2 80 0 88 Figure 6: Time to Relapse in Patients in Stable Response in Patients with TRD in Study 2* (Full Analysis Set) * Note: The estimated hazard ratio (95% CI) of SPRAVATO + Oral AD relative to Placebo nasal spray + Oral AD based on Cox proportional hazards model was 0.30 (95% CI: 0.16, 0.55). In Study 2, based on depressive symptomatology, the majority of stable remitters (69%) received every-other-week dosing for the majority of time during the maintenance phase; 23% of stable remitters received weekly dosing. Among stable responders, 34% received every-other-week dosing and 55% received weekly dosing the majority of time during the maintenance phase. Of the patients randomized to SPRAVATO, 39% received the 56 mg dose and 61% received the 84 mg dose. 14.2 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior SPRAVATO was evaluated in two identical Phase 3 short-term (4-week) randomized, double-blind, multicenter, placebo-controlled studies, Study 3 (NCT03039192) and Study 4 (NCT03097133), in adults with moderate-to-severe MDD (MADRS total score >28) who had active suicidal ideation and intent. In these studies, patients received treatment with SPRAVATO 84 mg or placebo nasal spray twice-weekly for 4 weeks. After the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (AD) (AD monotherapy or AD plus augmentation therapy) as determined by the investigator. After completion of the 4-week treatment period with SPRAVATO/placebo, study follow-up continued through Day 90. Reference ID: 5473909 37 The baseline demographic and disease characteristics of patients in Study 3 and Study 4 were similar between the SPRAVATO plus standard of care or placebo nasal spray plus standard of care treatment groups. The median patient age was 40 years (range 18 to 64 years), 61% were female; 73% Caucasian and 6% Black; and 63% of patients had at least one prior suicide attempt. Prior to entering the study, 92% of the patients were receiving antidepressant therapy. During the study, as part of standard of care treatment, 40% of patients received AD monotherapy, 54% of patients received AD plus augmentation therapy, and 6% received both AD monotherapy/AD plus augmentation therapy. The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after first dose (Day 2). In Study 3 and Study 4, SPRAVATO plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care (see Table 10). Table 10: Primary Efficacy Results for Change from Baseline in MADRS Total Score at 24 Hours After First Dose (Studies 3 and 4) Study No. Treatment Group§ Number of Patients Mean Baseline Score (SD) LS Mean Change from Baseline to 24 hr Post First Dose (SE) LS Mean Difference (95% CI)† Study 3 SPRAVATO 84 mg + SOC‡ 111 41.3 (5.87) -15.9 (1.04) -3.8 (-6.56; -1.09) Placebo nasal spray + SOC 112 41.0 (6.29) -12.0 (1.02) - Study 4 SPRAVATO 84 mg + SOC‡ 113 39.4 (5.21) -16.0 (1.02) -3.9 (-6.60; -1.11) Placebo nasal spray + SOC 113 39.9 (5.76) -12.2 (1.05) - SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval; SOC=standard of care. § SOC treatment included an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (antidepressant monotherapy or antidepressant monotherapy plus augmentation therapy). † Difference (SPRAVATO + SOC minus placebo nasal spray + SOC) in least-squares mean change from baseline. ‡ SPRAVATO + SOC were statistically significantly superior to placebo nasal spray + SOC. The secondary efficacy measure was the change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) score at 24 hours after first dose (Day 2). The CGI-SS-r is a one- item, clinician-rated assessment used to rate the current severity of a patient’s suicidal ideation and behavior. Scores on the CGI-SS-r range from 0 to 6, with higher scores indicating more severe suicidal ideation and behavior. In Study 3 and Study 4, SPRAVATO plus standard of care did not demonstrate superiority compared to placebo nasal spray plus standard of care in improving CGI- SS-r. Time Course of Treatment Response In both Study 3 and Study 4, SPRAVATO’s treatment difference compared to placebo was observed starting at 4 hours. Between 4 hours and Day 25, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 25. Figure 7 depicts time course of the primary efficacy measure of change in MADRS total score from Study 3. Reference ID: 5473909 38 0 I I -5 I I I Q) I C = -10 Q) (/) ro en E 2 -15 - b... 'o. ' ..... ..... Q) "0- 0) C ----o.... ro ..c -20 0 -- 'O---o----0..- -----.- -o -25 --- SPRAVATO + SOC -0- Placebo + SOC -30 Figure 7: Least Squares Mean Change from Baseline in MADRS Total Score Over Time in Study 3 (Full Analysis Set) * Note: In Study 3, after the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. Approximately 19% of patients had reduction in SPRAVATO dosage from 84 mg to 56 mg twice weekly. 14.3 Special Safety Studies Effects on Driving Two studies were conducted to assess the effects of SPRAVATO on driving skills; one study in adult patients with major depressive disorder (Study 5) and one study in healthy subjects (Study 6). On-road driving performance was assessed by the mean standard deviation of the lateral position (SDLP), a measure of driving impairment. A single-blind, placebo-controlled study in 25 adult patients with major depressive disorder evaluated the effects of a single 84 mg dose of intranasal SPRAVATO on next day driving and the effect of repeated administration of 84 mg of intranasal SPRAVATO on same-day driving performance (Study 5). For the single dose treatment phase, an ethanol-containing beverage was used as a positive control. The SDLP after administration of single 84 mg dose of SPRAVATO nasal spray was similar to placebo 18 hours post-dose. For the multiple dose treatment phase, the SDLP after repeated administration of 84 mg intranasal SPRAVATO was similar to placebo 6 hours post-dose on Day 11, Day 18, and Day 25. Reference ID: 5473909 39 16 17 A randomized, double-blind, cross-over, placebo-controlled study in 23 healthy subjects evaluated the effects of a single 84-mg dose of esketamine nasal spray on driving (Study 6). Mirtazapine (30 mg) was used as a positive control. Driving performance was assessed at 8 hours after SPRAVATO or mirtazapine administration. The SDLP 8 hours after SPRAVATO nasal spray administration was similar to placebo. Two subjects discontinued the driving test after receiving SPRAVATO because of a perceived inability to drive after experiencing post-dose adverse reactions; one subject reported pressure behind the eyes and paresthesia of the hands and feet, the other reported headache with light sensitivity and anxiety. HOW SUPPLIED/STORAGE AND HANDLING SPRAVATO® nasal spray is available as an aqueous solution of esketamine hydrochloride in a stoppered glass vial within a nasal spray device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine (supplied as 32.3 mg of esketamine hydrochloride). SPRAVATO is available in the following presentations: • 56 mg Dose Kit: Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose) (NDC 50458-028-02). • 84 mg Dose Kit: Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose) (NDC 50458-028-03). Within each kit, each 28 mg device is individually packaged in a sealed blister (NDC 50458-028-00). Storage Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Disposal SPRAVATO nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Sedation, Dissociation, and Respiratory Depression Inform patients that SPRAVATO has potential to cause sedation, dissociative symptoms (including perception disturbances), dizziness, vertigo, anxiety, and respiratory depression. Advise patients that they will need to be observed by a healthcare provider until these effects resolve [see Boxed Warning, Warnings and Precautions (5.1, 5.2, 5.3)]. Reference ID: 5473909 40 Potential for Abuse, Misuse, and Dependence Advise patients that SPRAVATO is a federally controlled substance because it can be abused or lead to dependence [see Warnings and Precautions (5.4), Drug Abuse and Dependence (9)]. SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) SPRAVATO is available only through a restricted program called the SPRAVATO REMS [see Warnings and Precautions (5.5)]. Inform the patient of the following notable requirements: • Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the SPRAVATO REMS Program prior to administration. • SPRAVATO must be administered under the direct observation of a healthcare provider. • Patients must be monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO. Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted [see Boxed Warning and Warnings and Precautions (5.6)]. Increases in Blood Pressure Advise patients that SPRAVATO can cause increases in blood pressure. Inform patients that after treatment sessions they should be advised that they may need to be observed by a healthcare provider until these effects resolve [see Warnings and Precautions (5.7)]. Impaired Ability to Drive and Operate Machinery Caution patients that SPRAVATO may impair their ability to drive or operate machinery. Instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination such as driving a motor vehicle or operating machinery until the next day after a restful sleep. Advise patients that they will need someone to drive them home after each treatment session [see Warnings and Precautions (5.9)]. Pregnancy Advise pregnant women and women of reproductive potential of the potential risk to a fetus. Advise patients to notify their healthcare provider if they are pregnant or intend to become pregnant during treatment with SPRAVATO. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SPRAVATO during pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise women not to breastfeed during treatment with SPRAVATO [see Use in Specific Populations (8.2)]. Reference ID: 5473909 41 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2019 Janssen Pharmaceutical Companies Reference ID: 5473909 42 MEDICATION GUIDE SPRAVATO® (sprah vah’ toe) CIII (esketamine) nasal spray What is the most important information I should know about SPRAVATO? SPRAVATO can cause serious side effects, including: • Sedation, dissociation, and respiratory depression. SPRAVATO may cause sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation), and breathing problems (respiratory depression and respiratory arrest). o Tell your healthcare provider right away if you feel like you cannot stay awake or if you feel like you are going to pass out. o Your healthcare provider must monitor you for serious side effects for at least 2 hours after taking SPRAVATO. Your healthcare provider will decide when you are ready to leave the healthcare setting. • Abuse and misuse. There is a risk for abuse and physical and psychological dependence with SPRAVATO treatment. Your healthcare provider should check you for signs of abuse and dependence before and during treatment with SPRAVATO. o Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs. o Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. • SPRAVATO Risk Evaluation and Mitigation Strategy (REMS). Because of the risks for sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program called the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) Program. SPRAVATO can only be administered at healthcare settings certified in the SPRAVATO REMS Program. Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the program. Reference ID: 5473909 1 • Increased risk of suicidal thoughts and actions. Antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. SPRAVATO is not for use in children. o Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a higher risk of having suicidal thoughts and actions. These include people who have (or have a family history of) depression or a history of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o Pay close attention to any changes, especially sudden changes, in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. o Tell your healthcare provider right away if you have any new or sudden changes in mood, behavior, thoughts, or feelings. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Tell your healthcare provider right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you: o suicide attempts o worsening depression o thoughts about suicide or dying o other unusual changes in behavior or mood What is SPRAVATO? SPRAVATO is a prescription medicine used along with an antidepressant taken by mouth to treat: • adults with treatment-resistant depression (TRD) • depressive symptoms in adults with major depressive disorder (MDD) with suicidal thoughts or actions SPRAVATO is not for use as a medicine to prevent or relieve pain (anesthetic). It is not known if SPRAVATO is safe and effective as an anesthetic medicine. It is not known if SPRAVATO is safe and effective for use in preventing suicide or in reducing suicidal thoughts or actions. SPRAVATO is not for use in place of hospitalization if your healthcare provider determines that hospitalization is needed, even if improvement is experienced after the first dose of SPRAVATO. It is not known if SPRAVATO is safe and effective in children. Do not take SPRAVATO if you: • have blood vessel (aneurysmal vascular) disease (including in the brain, chest, abdominal aorta, arms and legs) • have an abnormal connection between your veins and arteries (arteriovenous malformation) • have a history of bleeding in the brain • are allergic to esketamine, ketamine, or any of the other ingredients in SPRAVATO. See the end of this Medication Guide for a complete list of ingredients in SPRAVATO. If you are not sure if you have any of the above conditions, talk to your healthcare provider before taking SPRAVATO. Reference ID: 5473909 2 Before you take SPRAVATO, tell your healthcare provider about all of your medical conditions, including if you: • have heart or brain problems, including: o high blood pressure (hypertension) o slow or fast heartbeats that cause shortness of breath, chest pain, lightheadedness, or fainting o history of heart attack o history of stroke o heart valve disease or heart failure o history of brain injury or any condition where there is increased pressure in the brain • have liver problems • have ever had a condition called “psychosis” (see, feel, or hear things that are not there, or believe in things that are not true). • are pregnant or plan to become pregnant. SPRAVATO may harm your baby. You should not take SPRAVATO if you are pregnant. o Tell your healthcare provider right away if you become pregnant during treatment with SPRAVATO. o If you are able to become pregnant, talk to your healthcare provider about methods to prevent pregnancy during treatment with SPRAVATO. o There is a pregnancy registry for women who are exposed to SPRAVATO during pregnancy. The purpose of the registry is to collect information about the health of women exposed to SPRAVATO and their baby. If you become pregnant during treatment with SPRAVATO, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research programs/pregnancyregistry/antidepressants/. • are breastfeeding or plan to breastfeed. You should not breastfeed during treatment with SPRAVATO. Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Taking SPRAVATO with certain medicines may cause side effects. Especially tell your healthcare provider if you take central nervous system (CNS) depressants, psychostimulants, or monoamine oxidase inhibitors (MAOIs) medicines. Ask your healthcare provider if you are not sure if you take these medicines. Your healthcare provider can tell you if it is safe to take SPRAVATO with your other medicines. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How will I take SPRAVATO? • You will take SPRAVATO nasal spray yourself, under the supervision of a healthcare provider in a healthcare setting. Your healthcare provider will show you how to use the SPRAVATO nasal spray device. • Your healthcare provider will tell you how much SPRAVATO you will take and when you will take it. • Follow your SPRAVATO treatment schedule exactly as your healthcare provider tells you to. • During and after each use of the SPRAVATO nasal spray device, you will be checked by a healthcare provider who will decide when you are ready to leave the healthcare setting. • You will need to plan for a caregiver or family member to drive you home after taking SPRAVATO. Reference ID: 5473909 3 • If you miss a SPRAVATO treatment, your healthcare provider may change your dose and treatment schedule. • Some people taking SPRAVATO get nausea and vomiting. You should not eat for at least 2 hours before taking SPRAVATO and not drink liquids at least 30 minutes before taking SPRAVATO. • If you take a nasal corticosteroid or nasal decongestant medicine, take these medicines at least 1 hour before taking SPRAVATO. What should I avoid while taking SPRAVATO? • Do not drive, operate machinery, or do anything where you need to be completely alert after taking SPRAVATO. Do not take part in these activities until the next day following a restful sleep. See “What is the most important information I should know about SPRAVATO?” What are the possible side effects of SPRAVATO? SPRAVATO may cause serious side effects, including: • See “What is the most important information I should know about SPRAVATO?” • Increased blood pressure. SPRAVATO can cause a temporary increase in your blood pressure that may last for about 4 hours after taking a dose. Your healthcare provider will check your blood pressure before taking SPRAVATO and for at least 2 hours after you take SPRAVATO. Tell your healthcare provider right away if you get chest pain, shortness of breath, sudden severe headache, change in vision, or seizures after taking SPRAVATO. • Problems with thinking clearly. Tell your healthcare provider if you have problems thinking or remembering. • Bladder problems. Tell your healthcare provider if you develop trouble urinating, such as a frequent or urgent need to urinate, pain when urinating, or urinating frequently at night. The most common side effects of SPRAVATO when used along with an antidepressant taken by mouth include: • feeling disconnected from • decreased feeling of sensitivity (numbness) yourself, your thoughts, • feeling anxious feelings and things around you • lack of energy • dizziness • increased blood pressure • nausea • vomiting • feeling sleepy • feeling drunk • spinning sensation • feeling very happy or excited If these common side effects occur, they usually happen right after taking SPRAVATO and go away the same day. These are not all the possible side effects of SPRAVATO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about SPRAVATO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about SPRAVATO that is written for healthcare providers. What are the ingredients in SPRAVATO? Active ingredient: esketamine hydrochloride Inactive ingredients: citric acid monohydrate, edetate disodium, sodium hydroxide, and water for injection Reference ID: 5473909 4 Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2019 Janssen Pharmaceutical Companies For more information, go to www.SPRAVATO.com or call 1-800-526-7736. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2023 Reference ID: 5473909 5	custom-source	2025-02-12T15:46:33.425957	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/211243s015lbl.pdf', 'application_number': 211243, 'submission_type': 'SUPPL ', 'submission_number': 15}
80,177	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INFUVITE ADULT safely and effectively. See full prescribing information for INFUVITE ADULT INFUVITE ADULT (multiple vitamins injection), for intravenous use Initial U.S. Approval: 2003 --------------------------- INDICATIONS AND USAGE -------------------------- INFUVITE ADULT is a combination of vitamins indicated for prevention of vitamin deficiency in adults and children aged 11 and older receiving parenteral nutrition (1) ---------------------- DOSAGE AND ADMINISTRATION ---------------------- • INFUVITE ADULT is a combination product that contains the following vitamins: ascorbic acid, vitamin A, vitamin D, thiamine, riboflavin, pyridoxine, niacinamide, dexpanthenol, vitamin E, vitamin K1, folic acid, biotin, and vitamin B12 (2.1) • INFUVITE ADULT is for administration by intravenous infusion after dilution (2.1) • Recommended daily dosage is 10 mL (2.1) • INFUVITE ADULT is supplied as a single dose and as a pharmacy bulk package. o Single Dose: Add one daily dose of 10 mL (5 mL from Vial 1 and 5 mL from Vial 2) to not less than 500 mL, and preferably 1000 mL, of intravenous dextrose, saline or similar infusion solutions. (2.2) o Pharmacy Bulk Package: Add the contents of Vial 1 to the contents of Vial 2. This provides ten 10 mL daily doses. Take 10 mL from Vial 2 and add to not less than 500 mL, and preferably 1000 mL, of intravenous dextrose, saline or similar infusion solutions. (2.2) • After dilution in an intravenous infusion, refrigerate resulting solution unless used immediately. Use solution within 24 hours after dilution (2.2) • Monitor blood vitamin concentrations (2.3) • See Full Prescribing Information for drug incompatibilities (2.4) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- • INFUVITE ADULT supplied as single dose is an injection consisting of two vials labeled Vial 1 (5 mL) and Vial 2 (5 mL) (3) • INFUVITE ADULT supplied as a pharmacy bulk package is an injection consisting of two vials labeled Vial 1 (50 mL) and Vial 2 (50 mL fill in 100 mL Vial) (3) ------------------------------ CONTRAINDICATIONS ----------------------------- • Hypersensitivity to any of the vitamins or excipients (4) • Existing hypervitaminosis (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Risk of Aluminum Toxicity: For at risk patients (renal failure or those with prolonged therapy), consider periodic monitoring of aluminum levels (5.1) • Allergic Reactions: To thiamine may occur (5.2) • Hypervitaminosis A: Patients with renal failure or liver disease may be at higher risk (5.3) • Decreased Anticoagulant Effect of Warfarin: Monitor INR (5.4, 7.1) • Interferes with Megaloblastic Anemia Diagnosis: Avoid during testing for this disorder (5.5) • Risk of Vitamin Deficiencies or Excesses: Monitor blood vitamin concentrations (5.6) • False Negative Urine Glucose Tests: Due to vitamin C (5.7) ------------------------------ ADVERSE REACTIONS ----------------------------- Adverse reactions have included anaphylaxis and anaphylactoid reactions including shortness of breath, wheezing and angioedema, rash, erythema, pruritis, headache, dizziness, agitation, anxiety, diplopia (6) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- Effect of INFUVITE ADULT on other drugs: • Antibiotics: Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin (7.1) • Bleomycin: Ascorbic acid and riboflavin may reduce the activity of bleomycin (7.1) • Levodopa: Pyridoxine may decrease blood levels of levodopa and levodopa efficacy may decrease (7.1) • Phenytoin: Folic acid may decrease phenytoin blood levels and increase risk of seizure activity (7.1) • Methotrexate: Folic acid may decrease response to methotrexate (7.1) Effects of other drugs on INFUVITE ADULT: • Hydralazine, Isoniazid: Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements (7.2). • Phenytoin: May decrease folic acid concentrations (7.2) • Chloramphenicol: In patients with pernicious anemia, the hematologic response to vitamin B12 therapy may be inhibited (7.2) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Pregnancy and Lactation: Pregnant and lactating patients should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant and nonlactating patients (8.1, 8.2) • Renal Impairment: Monitor renal function, calcium, phosphorus and vitamin A levels in patients with renal impairment (8.6) • Hepatic Impairment: Monitor vitamin A level in patients with liver disease, high alcohol consumption (8.7) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 Reference ID: 5474648 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage Instructions 2.2 Preparation and Administration Instructions 2.3 Monitoring Vitamin Blood Levels 2.4 Drug Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity 5.2 Allergic Reactions to Thiamine 5.3. Hypervitaminosis A 5.4 Decreased Anticoagulant Effect of Warfarin 5.5 Interference with Diagnosis of Megaloblastic Anemia 5.6 Potential to Develop Vitamin Deficiencies or Excesses 5.7 Interference with Urine Glucose Testing 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Drug Interactions Affecting Co-Administered Drugs 7.2 Drug Interactions Affecting Vitamin Levels 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE INFUVITE ADULT is a combination of vitamins indicated for the prevention of vitamin deficiency in adults and children aged 11 and older receiving parenteral nutrition. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage Instructions INFUVITE ADULT is a combination product that contains the following vitamins: ascorbic acid, vitamin A, vitamin D, thiamine, riboflavin, pyridoxine, niacinamide, dexpanthenol, vitamin E, vitamin K1, folic acid, biotin, and vitamin B12. INFUVITE ADULT is supplied as a single dose or as a pharmacy bulk package for intravenous use intended for administration by intravenous infusion after dilution. INFUVITE ADULT Single Dose: • Provides one daily dose of 10 mL (5 mL of Vial 1 plus 5 mL of Vial 2) which must be diluted prior to intravenous administration [see Dosage and Administration (2.2)]. INFUVITE ADULT Pharmacy Bulk Package: • Provides ten 10 mL daily doses when the content of vial 1 is transferred into the content of vial 2. One 10 mL dose is then added directly to intravenous fluid. Pharmacy bulk package of INFUVITE ADULT is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion [see Dosage and Administration (2.2)]. Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins. 2.2 Preparation and Administration Instructions Do not administer INFUVITE ADULT as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and possible tissue irritation. Reference ID: 5474648 INFUVITE ADULT Single Dose: • Use only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Add 5 mL of Vial 1 and 5 mL of Vial 2 to at least 500 mL to 1000 mL, of intravenous dextrose or saline solutions. • Discard unused portion. • Visually inspect for particulate matter and discoloration prior to administration. • After INFUVITE ADULT is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in INFUVITE ADULT, particularly A, D and riboflavin, are light sensitive. INFUVITE ADULT Pharmacy Bulk Package: • Use only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Transfer the contents of Vial 1 into the contents of Vial 2 to provide ten 10 mL single doses. • Each bulk vial closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. • Once the closure system has been penetrated, complete dispensing from the pharmacy bulk vial should be completed within 4 hours. The mixed solution may be refrigerated and stored for up to 4 hours. • Discard unused portion. • Visually inspect for particulate matter and discoloration prior to administration. • One daily 10 mL dose should be added directly to at least 500 mL to 1000 mL, of intravenous dextrose, saline or similar infusion solutions. • After INFUVITE ADULT is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in INFUVITE ADULT, particularly A, D and riboflavin, are light sensitive. 2.3 Monitoring Vitamin Blood Levels Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time. 2.4 Drug Incompatibilities • INFUVITE ADULT is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, tetracycline HCl and chlorothiazide sodium. • Folic acid is unstable in the presence of calcium salts such as calcium gluconate. • Vitamin A and thiamine in INFUVITE ADULT may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfate. • Do not add INFUVITE ADULT directly to intravenous fat emulsions. • Consult appropriate references for additional listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion when needed. If incompatibilities are identified, avoid admixture or Y-site administration with vitamin solutions. 3 DOSAGE FORMS AND STRENGTHS INFUVITE ADULT Single Dose: is an injection for intravenous administration consisting of two vials labeled Vial 1 (5 mL) and Vial 2 (5 mL). For the vitamin strengths [see Description (11)]. Reference ID: 5474648 INFUVITE ADULT Pharmacy Bulk Package: is an injection for intravenous administration consisting of two vials labeled Vial 1 (50 mL) and Vial 2 (50 mL Fill in 100 mL Vial). The mixed solution (100 mL) will provide ten 10 mL single doses. For the vitamin strengths [see Description (11)]. Vial 1 (Single Dose and Pharmacy Bulk Package) is supplied as clear, yellow to orange liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and a white flip-off. Vial 2 (Single Dose and Pharmacy Bulk Package) is supplied as clear, colorless to pale yellow liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and a deep purple flip-off. 4 CONTRAINDICATIONS INFUVITE ADULT is contraindicated in patients who have • An existing hypervitaminosis, or • A history of hypersensitivity due to any vitamins or excipients contained in this formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity INFUVITE ADULT contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solution, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. To prevent aluminum toxicity periodically monitor aluminum levels with prolonged parenteral administration of INFUVITE ADULT in patients with renal impairment. 5.2 Allergic Reactions to Thiamine Allergic reactions such as urticaria, shortness of breath, wheezing and angioedema have been reported following intravenous administration of thiamine, which is found in INFUVITE ADULT. There have been rare reports of anaphylactoid reactions following intravenous doses of thiamine. No fatal anaphylactoid reactions associated with INFUVITE ADULT have been reported. 5.3. Hypervitaminosis A Hypervitaminosis A, manifested by nausea, vomiting, headache, dizziness, blurred vision has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease, Therefore, supplementation of renal failure patients and patients with liver disease with vitamin A, an ingredient found in INFUVITE ADULT, should be undertaken with caution [see Use in Specific Populations (8.6 and 8.7)]. 5.4 Decreased Anticoagulant Effect of Warfarin INFUVITE ADULT contains Vitamin K, which may decrease the anticoagulant action of warfarin. In patients who are on warfarin anticoagulant therapy receiving INFUVITE ADULT monitor blood levels of prothrombin/INR to determine if dose of warfarin needs to be adjusted. 5.5 Interference with Diagnosis of Megaloblastic Anemia INFUVITE ADULT contains folic acid and cyanocobalamin which can mask serum deficiencies of folic acid and cyanocobalamin in patients with megaloblastic anemia. Avoid the use of INFUVITE ADULT in patients with suspected Reference ID: 5474648 or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. 5.6 Potential to Develop Vitamin Deficiencies or Excesses In patients receiving parenteral multivitamins such as with INFUVITE ADULT, blood concentration should be periodically monitored to determine if deficiencies or excesses are developing. INFUVITE ADULT may not correct long- standing specific vitamin deficiencies. The administration of additional therapeutic doses of specific vitamins may be required [see Dosage and Administration (2.3)]. 5.7 Interference with Urine Glucose Testing INFUVITE ADULT contains vitamin C which is also known as ascorbic acid. Ascorbic acid in the urine may cause false negative urine glucose results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other section of the labeling. • Allergic reactions to thiamine [see Warnings and Precautions (5.2)] • Hypervitaminosis A [see Warnings and Precautions (5.3)] The following adverse reactions have been identified during postapproval use of INFUVITE ADULT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: rash, erythema, pruritis CNS: headache, dizziness, agitation, anxiety Ophthalmic: diplopia 7 DRUG INTERACTIONS A number of interactions between vitamins and drugs have been reported. The following are examples of these types of interactions: 7.1 Drug Interactions Affecting Co-Administered Drugs Warfarin: Vitamin K, a component of INFUVITE ADULT, antagonizes the anticoagulant action of warfarin. In patients who are co-administered warfarin and INFUVITE ADULT, blood levels of prothrombin/INR should be monitored to determine if dose of warfarin needs to be adjusted [see Warnings and Precautions (5.4)]. Antibiotics: Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease antibiotic activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin: Ascorbic acid and riboflavin inactivate bleomycin in vitro, thus the activity of bleomycin may be reduced. Levodopa: Pyridoxine may increase the metabolism of levodopa (decrease blood levels of levodopa) and decrease its efficacy. Phenytoin: Folic acid may increase phenytoin metabolism and lower the serum concentration of phenytoin resulting in increased seizure activity. Methotrexate: Folic acid may decrease a patient’s response to methotrexate therapy. Reference ID: 5474648 7.2 Drug Interactions Affecting Vitamin Levels Hydralazine, Isoniazid: Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements. Phenytoin: Phenytoin may decrease serum folic acid concentrations. Chloramphenicol: In patients with pernicious anemia, the hematologic response to vitamin B12 therapy may be inhibited by chloramphenicol. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Administration of the approved recommended dose of INFUVITE ADULT in parental nutrition is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant patients should follow the U.S. Recommended Daily Allowances for pregnancy because their vitamin requirements may exceed those of nonpregnant patients. Deficiency of essential vitamins may result in adverse pregnancy outcomes (see Clinical Considerations). Animal reproduction studies have not been conducted with INFUVITE ADULT. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo-Fetal Risk Deficiency of essential vitamins has been associated with adverse pregnancy and fetal outcomes, such as maternal folic acid deficiency and an increased risk of neural tube defects. Therefore, parenteral nutrition with multiple vitamins injection should be considered if a pregnant woman’s nutritional requirements cannot be fulfilled by oral or enteral intake. 8.2 Lactation Risk Summary Multiple vitamins present in INFUVITE ADULT are also present in human milk. Administration of the approved recommended dose of INFUVITE ADULT In parental nutrition is not expected to cause harm to a breastfed infant. There is no information on the effects of INFUVITE ADULT on milk production. Lactating patients should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonlactating patients. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INFUVITE ADULT and any potential adverse effects on the breastfed child from INFUVITE ADULT or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in children below the age of 11 years have not been established. 8.5 Geriatric Use Safety and effectiveness for geriatric use have not been established. 8.6 Renal Impairment INFUVITE ADULT has not been studied in patients with renal impairment. Monitor renal function, calcium, phosphorus and vitamin A levels in patients with renal impairment [see Warnings and Precautions (5.1 and 5.3)]. 8.7 Hepatic Impairment INFUVITE ADULT has not been studied in patients with liver impairments. Monitor vitamin A level in patients with liver disease, high alcohol consumption [see Warnings and Precautions (5.3)]. Reference ID: 5474648 10 OVERDOSAGE Signs and symptoms of acute or chronic overdosage may be those of individual INFUVITE ADULT component toxicity. In post-marketed surveillance, overdosage with INFUVITE ADULT at two times the prescribed dose did not result in toxicity. 11 DESCRIPTION INFUVITE ADULT (multiple vitamins injection) is a sterile product consisting of two vials provided as a single dose or as a pharmacy bulk package, both intended for intravenous use for administration by intravenous infusion after dilution: INFUVITE ADULT Single Dose - two 5 mL single-dose vials labeled Vial 1 and Vial 2. INFUVITE ADULT Pharmacy Bulk Package - two vials – 1 each of Vial 1 (50 mL) and Vial 2 (50 mL Fill in 100 mL Vial). The mixed solution (100 mL) will provide ten 10 mL single doses. Each 5 mL of Vial 1 contains: Ascorbic acid (Vitamin C) 200 mg Vitamin A (as palmitate) 3,300 IU Vitamin D3* (cholecalciferol) 200 IU Thiamine (Vitamin B1) (as the hydrochloride) 6 mg Riboflavin (Vitamin B2) (as riboflavin 5-phosphate sodium) 3.6 mg Pyridoxine HCl (Vitamin B6) 6 mg Niacinamide 40 mg Dexpanthenol (as d-pantothenyl alcohol) 15 mg Vitamin E* (dl-α-tocopheryl acetate) 10 IU Vitamin K1* 150 mcg *Polysorbate 80 is used to water solubilize the oil-soluble vitamins A, D, E, and K. Inactive ingredients: 1.4% polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection. Each 5 mL of Vial 2 contains: Folic acid 600 mcg Biotin 60 mcg Vitamin B12 (cyanocobalamin) 5 mcg Inactive ingredients: 30% propylene glycol, citric acid and/or sodium citrate for pH adjustment, and water for injection. INFUVITE ADULT makes available a combination of important oil-soluble and water-soluble vitamins in an aqueous solution, formulated for incorporation into intravenous solutions. The liposoluble vitamins A, D, E, and K have been solubilized in an aqueous medium with polysorbate 80, permitting intravenous administration of these vitamins. Contains no more than 70 mcg/L of aluminum (combined Vials 1 and 2). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been performed with INFUVITE ADULT. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Reference ID: 5474648 INFUVITE ADULT (multiple vitamins injection) is supplied as follows: Vial 1 (Single Dose and Pharmacy Bulk Package) is supplied as clear, yellow to orange liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and a white flip-off. Vial 2 (Single Dose and Pharmacy Bulk Package) is supplied as clear, colorless to pale yellow liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and a deep purple flip-off. INFUVITE ADULT Single Dose: Carton contains total ten single-dose vials NDC 54643-5649-1 Five of Vial 1 (5 mL) NDC 54643-5657-1 Five of Vial 2 (5 mL) NDC 54643-5659-1 one Vial 1 plus one Vial 2 to be used for a single dose [see Dosage and Administration (2.1)]. INFUVITE ADULT Pharmacy Bulk Package: Carton contains total two vials NDC 54643-5650-2 One Vial 1 (50 mL) NDC 54643-5661-2 One Vial 2 (50 mL Fill in 100 mL Vial) NDC 54643-5663-2 Mix contents of Vial 1 with Vial 2 to provide 10 single doses [see Dosage and Administration (2.1)]. Storage and Handling Minimize exposure of INFUVITE ADULT to light because vitamins A, D and riboflavin are light sensitive. Store under refrigeration, 2°C to 8° C (36°F to 46° F). 17 PATIENT COUNSELING INFORMATION Instruct patients (if age appropriate) and caregivers: • To watch for signs of allergic reactions such as urticaria, shortness of breath, wheezing and angioedema since hypersensitivity reactions may occur to any of the vitamins or excipients contained in INFUVITE ADULT. • To watch for and immediately report nausea, vomiting, headache, dizziness, blurred vision, especially if patients have renal impairment, as these may be signs of hypervitaminosis A. • To report other adverse reactions such as rash, erythema, pruritus, headache, dizziness, agitation, anxiety, and diplopia. • That the patients on warfarin anticoagulant therapy will be monitored periodically with blood prothrombin/ INR levels to determine if their dose of warfarin needs to be adjusted. • About the significance of periodic monitoring of blood vitamin concentrations to determine if vitamin deficiencies or excesses are developing and the need to monitor renal function, calcium, phosphorus, aluminum and vitamin A levels in patients with renal impairment. • That INFUVITE ADULT should be avoided in patients with suspected or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. • That vitamin C (ascorbic acid) contained in INFUVITE ADULT may cause false negative urine glucose results. Manufactured for Sandoz Inc., Princeton, NJ 08540 Distributed by Baxter Healthcare Corporation Reference ID: 5474648 Deerfield, IL 60015 USA INFUVITE is a registered trademark of Sandoz Canada Inc. Reference ID: 5474648	custom-source	2025-02-12T15:46:33.429585	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021163s045lbl.pdf', 'application_number': 21163, 'submission_type': 'SUPPL ', 'submission_number': 45}
80,178	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INFUVITE PEDIATRIC safely and effectively. See full prescribing information for INFUVITE PEDIATRIC. INFUVITE PEDIATRIC (multiple vitamins injection), for intravenous use Initial U.S. Approval: 2001 --------------------------- INDICATIONS AND USAGE -------------------------- INFUVITE PEDIATRIC is a combination of vitamins indicated for the prevention of vitamin deficiency in pediatric patients up to 11 years of age receiving parenteral nutrition (1) ---------------------- DOSAGE AND ADMINISTRATION ---------------------- • INFUVITE PEDIATRIC is a combination product that contains the following vitamins: ascorbic acid, vitamin A, vitamin D, thiamine, riboflavin, pyridoxine, niacinamide, dexpanthenol, vitamin E, vitamin K1, folic acid, biotin, and vitamin B12 (2.1) • INFUVITE PEDIATRIC is for administration by intravenous infusion after dilution (2.1) • Recommended daily dosage is based on patient’s actual weight (2.2): o INFUVITE PEDIATRIC Single Dose:  Weight less than 1 kg: 1.2 mL of Vial 1 and 0.3 mL of Vial 2  Weight 1 kg to less than 3 kg: 2.6 mL of Vial 1 and 0.65 mL of Vial 2  Weight 3 kg or greater: 4 mL of Vial 1 and 1 mL of Vial 2 o INFUVITE PEDIATRIC Pharmacy Bulk Package:  Weight less than 1 kg: 1.5 mL of combined content of Vials 1 and 2  Weight 1 kg to less than 3 kg: 3.25 mL of combined content of Vials 1 and 2  Weight 3 kg or greater: 5 mL of combined content of Vials 1 and 2. • Supplemental vitamin A may be required for low-birth weight infants (2.2) • INFUVITE PEDIATRIC is supplied as a single dose and as a pharmacy bulk package: o Single Dose consists of two vials labeled Vial 1 and Vial 2. Add one daily dose of Vial 1 and one daily dose of Vial 2 directly to at least 100 mL of intravenous dextrose or saline solution prior to intravenous use (2.3) o Pharmacy Bulk Package consists of two vials labeled Vial 1 and Vial 2. Transfer contents of Vial 2 to contents of Vial 1. Then, take 1.5 mL, 3.25 mL, or 5 mL from mixture and add to at least 100 mL of intravenous dextrose or saline solution prior to intravenous use (2.3) • After dilution in an intravenous infusion, refrigerate resulting solution unless used immediately. Use solution within 24 hours after dilution (2.3) • Monitor blood vitamin concentrations (2.4) • See Full Prescribing Information for drug incompatibilities (2.5). --------------------- DOSAGE FORMS AND STRENGTHS -------------------- • INFUVITE PEDIATRIC single dose is an injection consisting of two vials labeled Vial 1 (4 mL) and Vial 2 (1 mL) (3) • INFUVITE PEDIATRIC pharmacy bulk package is an injection consisting of two vials labeled Vial 1 (40 mL fill in 50 mL) and Vial 2 (10 mL) (3) • See Full Prescribing Information for vitamin strengths (11) ------------------------------ CONTRAINDICATIONS ----------------------------- • Hypersensitivity to any of vitamins or excipients (4) • Existing hypervitaminosis (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Risk of Aluminum Toxicity: For at risk patients (renal failure or those with prolonged therapy), consider periodic monitoring of aluminum levels (5.1) • Allergic Reactions: To thiamine may occur (5.2) • Hypervitaminosis A: Patients with renal failure or liver disease may be at higher risk (5.3) • Decreased Anticoagulant Effect of Warfarin: Monitor INR (5.4, 7.1) • Interferes with Megaloblastic Anemia Diagnosis: Avoid during testing for this disorder (5.5) • Risk of Vitamin Deficiencies or Excesses: Monitor blood vitamin concentrations (5.6) • False Negative Urine Glucose Tests: Due to vitamin C (5.7) • Risk of Vitamin E Toxicity: Additional oral and parenteral vitamin E may result in elevated vitamin E blood concentrations in infants (5.8) • Low Vitamin A Levels: Monitor vitamin A levels (5.9) • Risk of E-Ferol Syndrome: Due to polysorbates (5.10) ------------------------------ ADVERSE REACTIONS ----------------------------- Adverse reactions have included anaphylaxis, rash, erythema, pruritis, headache, dizziness, agitation, anxiety, diplopia (6) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- Effect of INFUVITE PEDIATRIC on other drugs: • Antibiotics: Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin (7.1) • Bleomycin: Ascorbic acid and riboflavin may reduce the activity of bleomycin (7.1) • Levodopa: Pyridoxine may decrease blood levels of levodopa and levodopa efficacy may decrease (7.1) • Phenytoin: Folic acid may decrease phenytoin blood levels and increase risk of seizure activity (7.1) • Methotrexate: Folic acid may decrease response to methotrexate (7.1) Effects of other drugs on INFUVITE PEDIATRIC: • Hydralazine, Isoniazid: Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements (7.2). • Phenytoin: May decrease folic acid concentrations (7.2) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Pregnancy and Lactation: Pregnant and lactating patients should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant and nonlactating patients (8.1, 8.2) • Renal Impairment: Monitor renal function, calcium, phosphorus and vitamin A levels (8.6) • Hepatic Impairment: Monitor vitamin A levels (8.7) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 Reference ID: 5474648 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Dosage Information 2.3 Preparation and Administration Instructions 2.4 Monitoring Vitamin Blood Levels 2.5 Drug Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity 5.2 Allergic Reactions to Thiamine 5.3 Hypervitaminosis A 5.4 Decreased Anticoagulant Effect of Warfarin 5.5 Interference with Diagnosis of Megaloblastic Anemia 5.6 Potential to Develop Vitamin Deficiencies or Excesses 5.7 Interference with Urine Glucose Testing 5.8 Vitamin E Overdose in Infants Receiving Additional Vitamin E 5.9 Risk of Low Vitamin A Levels 5.10 Risk of E-Ferol Syndrome in Low-Birth Weight Infants 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Drug Interactions Affecting Co-Administered Drugs 7.2 Drug Interactions Affecting Vitamin Levels 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE INFUVITE PEDIATRIC is a combination of vitamins indicated for the prevention of vitamin deficiency in pediatric patients up to 11 years of age receiving parenteral nutrition. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions INFUVITE PEDIATRIC is a combination product that contains the following vitamins: ascorbic acid, vitamin A, vitamin D, thiamine, riboflavin, pyridoxine, niacinamide, dexpanthenol, vitamin E, vitamin K1, folic acid, biotin, and vitamin B12. INFUVITE PEDIATRIC is supplied as a single dose or as a pharmacy bulk package for intravenous use intended for administration by intravenous infusion after dilution: • INFUVITE PEDIATRIC Single Dose consists of two vials. A weight-based volume from each vial must be added directly to dextrose or saline solution prior to intravenous administration [see Dosage and Administration (2.2 and 2.3)]. • INFUVITE PEDIATRIC Pharmacy Bulk Package consists of two pharmacy bulk vials which must be mixed prior to use. The mixed solution will provide multiple daily doses which must be diluted prior to intravenous administration. Pharmacy bulk package of INFUVITE PEDIATRIC is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion [see Dosage and Administration (2.2 and 2.3)]. 2.2 Dosage Information The recommended daily dosage volume is based on the patient's actual weight: less than 1 kg, 1 kg to less than 3 kg, and 3 kg or greater. Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated or additional doses of individual vitamins. Supplemental vitamin A may be required for low-birth weight infants. Additional daily dosages of Vitamin E in infants are not recommended [see Warnings and Precautions (5.8)]. Reference ID: 5474648 INFUVITE PEDIATRIC Single Dose (see Table 1): One daily dose of Vial 1 (1.2 mL, 2.6 mL or 4 mL) and one daily dose of Vial 2 (0.3 mL, 0.65 mL or 1 mL) based on the patient’s weight are added directly to a specified volume of an intravenous fluid [see Dosage and Administration (2.3)] (see Table 1). Table 1: Recommended Weight-Based Dosage of INFUVITE PEDIATRIC Single-Dose Less than 1 kg 1 kg to less than 3 kg 3 kg or greater Daily Dosage Volume – Vial 1 1.2 mL 2.6 mL 4 mL Ascorbic acid (Vitamin C) 24 mg 52 mg 80 mg Vitamin A (as palmitate) 690 IU (equals 0.2 mg) 1495 IU (equals 0.5 mg) 2,300 IU (equals 0.7 mg) Vitamin D3 (cholecalciferol) 120 IU (equals 3 mcg) 260 IU (equals 7 mcg) 400 IU (equals 10 mcg) Thiamine (Vitamin B1) (as the hydrochloride) 0.4 mg 0.8 mg 1.2 mg Riboflavin (Vitamin B2) (as riboflavin 5-phosphate sodium) 0.4 mg 0.9 mg 1.4 mg Pyridoxine HCl (Vitamin B6) 0.3 mg 0.7 mg 1 mg Niacinamide 5.1 mg 11.1 mg 17 mg Dexpanthenol (as d-pantothenyl alcohol) 1.5 mg 3.3 mg 5 mg Vitamin E (dl-α-tocopheryl acetate) 2.1 IU (equals 2 mg) 4.6 IU (equals 5 mg) 7 IU (equals 7 mg) Vitamin K1 0.1 mg 0.1 mg 0.2 mg Daily Dosage Volume – Vial 2 0.3 mL 0.65 mL 1 mL Folic acid 42 mcg 91 mcg 140 mcg Biotin 6 mcg 13 mcg 20 mcg Vitamin B12 (cyanocobalamin) 0.3 mcg 0.7 mcg 1 mcg INFUVITE PEDIATRIC Pharmacy Bulk Package (see Table 2): The recommended daily dosage volume of combined content of vials 1 and 2 (1.5 mL, 3.25 mL or 5 mL) is based on the patient’s weight and then added directly to the specific volume of an intravenous fluid [see Dosage and Administration (2.3)]. Table 2: Recommended Weight-Based Dosage of INFUVITE PEDIATRIC Pharmacy Bulk Package Less than 1 kg 1 kg to less than 3 kg 3 kg or greater Daily Dosage Volume (combined contents of Vial 1 and Vial 2) 1.5 mL 3.25 mL 5 mL Ascorbic acid (Vitamin C) 24 mg 52 mg 80 mg Vitamin A (as palmitate) 690 IU (equals 0.2 mg) 1495 IU (equals 0.5 mg) 2,300 IU (equals 0.7 mg) Vitamin D3 (cholecalciferol) 120 IU (equals 3 mcg) 260 IU (equals 7 mcg) 400 IU (equals 10 mcg) Thiamine (Vitamin B1) (as the hydrochloride) 0.4 mg 0.8 mg 1.2 mg Riboflavin (Vitamin B2) (as riboflavin 5-phosphate sodium) 0.4 mg 0.9 mg 1.4 mg Pyridoxine HCl (Vitamin B6) 0.3 mg 0.7 mg 1 mg Niacinamide 5.1 mg 11.1 mg 17 mg Reference ID: 5474648 Dexpanthenol (as d-pantothenyl alcohol) 1.5 mg 3.3 mg 5 mg Vitamin E (dl-α-tocopheryl acetate) 2.1 IU (equals 2 mg) 4.6 IU (equals 5 mg) 7 IU (equals 7 mg) Vitamin K1 0.1 mg 0.1 mg 0.2 mg Folic acid 42 mcg 91 mcg 140 mcg Biotin 6 mcg 13 mcg 20 mcg Vitamin B12 (cyanocobalamin) 0.3 mcg 0.7 mcg 1 mcg 2.3 Preparation and Administration Instructions Do not administer INFUVITE PEDIATRIC as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and possible tissue irritation. INFUVITE PEDIATRIC Single Dose: • Use only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Add one weight-based dose of Vial 1 (1.2 mL, 2.6 mL or 4 mL) and one weight-based dose of Vial 2 (0.3 mL, 0.65 mL or 1 mL) directly to at least 100 mL of intravenous dextrose or saline solution. • Discard unused portion. • Visually inspect for particulate matter and discoloration prior to administration. • After INFUVITE PEDIATRIC is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in INFUVITE PEDIATRIC, particularly A, D and riboflavin, are light sensitive. INFUVITE PEDIATRIC Pharmacy Bulk Package: • Use only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Transfer the contents of Vial 2 (10 mL of solution) into the contents of Vial 1 (40 mL of solution). The mixed solution (50 mL) will provide thirty-three 1.5 mL single doses, fifteen 3.25 mL single doses or ten 5 mL single doses. • Each bulk vial closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. • Once the closure system has been penetrated, complete dispensing from the pharmacy bulk vial should be completed within 4 hours. The mixed solution may be refrigerated and stored for up to 4 hours. • Discard unused portion. • Visually inspect for particulate matter and discoloration prior to administration. • Add one dose directly to at least 100 mL of intravenous dextrose or saline solution for each patient. • After INFUVITE PEDIATRIC is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in INFUVITE PEDIATRIC, particularly A, D and riboflavin, are light sensitive. 2.4 Monitoring Vitamin Blood Levels Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time. Reference ID: 5474648 2.5 Drug Incompatibilities • INFUVITE PEDIATRIC is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, tetracycline HCl and chlorothiazide sodium. • Folic acid is unstable in the presence of calcium salts such as calcium gluconate. • Vitamin A and thiamine in INFUVITE PEDIATRIC may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfite. • Do not add INFUVITE PEDIATRIC directly to intravenous fat emulsions. • Consult appropriate references for additional listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion when needed. If incompatibilities are identified, avoid admixture or Y-site administration with vitamin solutions. 3 DOSAGE FORMS AND STRENGTHS INFUVITE PEDIATRIC Single Dose is an injection consisting of two single-dose vials labeled Vial 1 (4 mL) and Vial 2 (1 mL). For the vitamin strengths [see Dosage and Administration (2.2) and Description (11)]. INFUVITE PEDIATRIC Pharmacy Bulk Package is an injection consisting of two vials labeled Vial 1 (40 mL Fill in 50 mL Vial) and Vial 2 (10 mL). The mixed solution (50 mL) will provide thirty-three 1.5 mL single doses, fifteen 3.25 mL single doses or ten 5 mL single doses. For the vitamin strengths [see Dosage and Administration (2.2) and Description (11)]. Vial 1 (Single Dose and Pharmacy Bulk Package) is supplied as clear, yellow to orange liquid in amber glass vial, closed with a rubber stopper, clear aluminum seal and a blue flip-off. Vial 2 (Single Dose and Pharmacy Bulk Package) is supplied as clear, colorless to pale yellow liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and pink flip-off. 4 CONTRAINDICATIONS INFUVITE PEDIATRIC is contraindicated in patients who have: • An existing hypervitaminosis, or • A history of hypersensitivity to any vitamins or excipients contained in this formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Aluminum Toxicity INFUVITE PEDIATRIC contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration in pediatric patients with renal impairment. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solution, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. To prevent aluminum toxicity periodically monitor aluminum levels with prolonged parenteral administration of INFUVITE PEDIATRIC. 5.2 Allergic Reactions to Thiamine Allergic reactions such as urticaria, shortness of breath, wheezing and angioedema have been reported following intravenous administration of thiamine, which is found in INFUVITE PEDIATRIC. There have been rare reports of Reference ID: 5474648 anaphylaxis following intravenous doses of thiamine. No fatal anaphylaxis associated with INFUVITE PEDIATRIC has been reported. 5.3 Hypervitaminosis A Hypervitaminosis A, manifested by nausea, vomiting, headache, dizziness, blurred vision has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. Therefore, supplementation of renal failure patients and patients with liver disease with vitamin A, an ingredient found in INFUVITE PEDIATRIC, should be undertaken with caution [see Use in Specific Populations (8.6 and 8.7)]. Blood levels of Vitamin A should be monitored periodically. 5.4 Decreased Anticoagulant Effect of Warfarin INFUVITE PEDIATRIC contains Vitamin K which may decrease the anticoagulant action of warfarin. In patients who are on warfarin anticoagulant therapy receiving INFUVITE PEDIATRIC monitor blood levels of prothrombin/INR to determine if dose of warfarin needs to be adjusted. 5.5 Interference with Diagnosis of Megaloblastic Anemia INFUVITE PEDIATRIC contains folic acid and cyanocobalamin which can mask serum deficiencies of folic acid and cyanocobalamin in patients with megaloblastic anemia. Avoid the use of INFUVITE PEDIATRICS in patients with suspected or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. 5.6 Potential to Develop Vitamin Deficiencies or Excesses In patients receiving parenteral multivitamins such as with INFUVITE PEDIATRIC, blood vitamin concentrations should be periodically monitored to determine if vitamin deficiencies or excesses are developing. INFUVITE PEDIATRIC may not correct long-standing specific vitamin deficiencies. The administration of additional doses of specific vitamins may be required [see Dosage and Administration (2.2)]. 5.7 Interference with Urine Glucose Testing INFUVITE PEDIATRIC contains vitamin C which is also known as ascorbic acid. Ascorbic acid in the urine may cause false negative urine glucose results. 5.8 Vitamin E Overdose in Infants Receiving Additional Vitamin E Additional vitamin E supplementations of patients receiving INFUVITE PEDIATRIC may result in elevated blood concentrations of vitamin E and potential vitamin E toxicity in infants. Avoid additional oral or parental doses of vitamin E in infants. Daily dose of INFUVITE PEDIATRIC contains adequate concentrations of vitamin E required to achieve normal blood levels of vitamin E. 5.9 Risk of Low Vitamin A Levels Lower vitamin A concentrations may occur after administration of INFUVITE PEDIATRIC due to the adherence of Vitamin A to plastic. Monitor blood vitamin A concentrations periodically. Additional administration of therapeutic doses of vitamin A may be required, especially in low-birth weight infants. 5.10 Risk of E-Ferol Syndrome in Low-Birth Weight Infants E-Ferol syndrome manifested by thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis has been reported in low-birth weight infants following administration of polysorbates which are found in INFUVITE PEDIATRIC. No E-Ferol syndrome associated with INFUVITE PEDIATRIC has been reported. Reference ID: 5474648 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Allergic reactions to thiamine [see Warnings and Precautions (5.2)]. • Hypervitaminosis A [see Warnings and Precautions (5.3)] The following adverse reactions have been identified during postapproval use of INFUVITE PEDIATRIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: rash, erythema, pruritis CNS: headache, dizziness, agitation, anxiety Ophthalmic: diplopia 7 DRUG INTERACTIONS A number of interactions between vitamins and drugs have been reported. The following are examples of these types of interactions. 7.1 Drug Interactions Affecting Co-Administered Drugs Warfarin: Vitamin K, a component of INFUVITE PEDIATRIC, antagonizes the anticoagulant action of warfarin. In patients who are co-administered warfarin and INFUVITE PEDIATRIC, blood levels of prothrombin/INR should be monitored to determine if dose of warfarin needs to be adjusted [see Warnings and Precautions (5.4)]. Antibiotics: Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease antibiotic activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin: Ascorbic acid and riboflavin inactivate bleomycin in vitro, thus the activity of bleomycin may be reduced. Levodopa: Pyridoxine may increase the metabolism of levodopa (decrease blood levels of levodopa) and decrease its efficacy. Phenytoin: Folic acid may increase phenytoin metabolism and lower the serum concentration of phenytoin resulting in increased seizure activity. Methotrexate: Folic acid may decrease a patient’s response to methotrexate therapy. 7.2 Drug Interactions Affecting Vitamin Levels Hydralazine, Isoniazid: Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements. Phenytoin: Phenytoin may decrease serum folic acid concentrations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Administration of the approved recommended dose of INFUVITE PEDIATRIC in parental nutrition is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant patients should follow the U.S. Recommended Daily Allowances for pregnancy because their vitamin requirements may exceed those of nonpregnant patients. Deficiency of essential vitamins may result in adverse pregnancy outcomes (see Clinical Considerations). Animal reproduction studies have not been conducted with INFUVITE PEDIATRIC. Reference ID: 5474648 The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo-Fetal Risk Deficiency of essential vitamins has been associated with adverse pregnancy and fetal outcomes, such as maternal folic acid deficiency and an increased risk of neural tube defects. Therefore, parenteral nutrition with multiple vitamins injection should be considered if a pregnant patient’s nutritional requirements cannot be fulfilled by oral or enteral intake. 8.2 Lactation Risk Summary Multiple vitamins present in INFUVITE PEDIATRIC are also present in human milk. Administration of the approved recommended dose of Infuvite Pediatric in parental nutrition is not expected to cause harm to a breastfed infant. There is no information on the effects of Infuvite Pediatric on milk production. Lactating patients should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonlactating patients. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INFUVITE PEDIATRIC and any potential adverse effects on the breastfed child from INFUVITE PEDIATRIC or from the underlying maternal condition. 8.4 Pediatric Use INFUVITE PEDIATRIC is approved for the prevention of vitamin deficiency in pediatric patients up to 11 years old receiving parenteral nutrition. INFUVITE PEDIATRIC has not been studied in pediatric patients older than 11 years. INFUVITE PEDIATRIC contains aluminum that may be toxic for premature neonates. Aluminum levels should be monitored periodically during administration of INFUVITE PEDIATRIC to premature neonates [see Warnings and Precautions (5.1)]. Additional vitamin E supplementations of infants receiving INFUVITE PEDIATRIC may result in elevated blood concentrations of vitamin E and potential vitamin E toxicity [see Warnings and Precautions (5.8)]. E-Ferol syndrome has been reported in low-birth weight infants following administration of polysorbates which are found in INFUVITE PEDIATRIC. No E-Ferol syndrome associated with INFUVITE PEDIATRIC has been reported [see Warnings and Precautions (5.10)]. 8.6 Renal Impairment INFUVITE PEDIATRIC has not been studied in patients with renal impairment. Monitor renal function, calcium, phosphorus and vitamin A levels in patients with renal impairment [see Warnings and Precautions (5.1 and 5.3)]. 8.7 Hepatic Impairment INFUVITE PEDIATRIC has not been studied in patients with liver impairment. Monitor vitamin A levels in patients with liver disease [see Warnings and Precautions (5.3)]. 10 OVERDOSAGE Signs and symptoms of acute or chronic overdosage may be those of individual INFUVITE PEDIATRIC component toxicity. There is no clinical experience with INFUVITE PEDIATRIC overdosage. Reference ID: 5474648 11 DESCRIPTION INFUVITE PEDIATRIC (multiple vitamins injection) is a sterile product consisting of two vials provided as a single dose or as a pharmacy bulk package for intravenous use intended for administration by intravenous infusion after dilution: INFUVITE PEDIATRIC (multiple vitamins injection) supplied as single dose consists of: (a) Vial 1 (4 mL); and (b) Vial 2 (1 mL). Vial 1 will provide one daily dose of 1.2 mL, 2.6 mL or 4 mL and Vial 2 will provide one daily dose of 0.3 mL, 0.65 mL or 1 mL [see Dosage and Administration (2.2)]. INFUVITE PEDIATRIC (multiple vitamins injection) supplied as pharmacy bulk package consists of: (a) Vial 1 (40 mL Fill in 50 mL Vial); and (b) Vial 2 (10 mL). The mixed solution will provide many single doses [see Dosage and Administration (2.2)]. Each 4 mL of Vial 1 contains 10 vitamins and each 1 mL of Vial 2 contains 3 vitamins (see Table 3). Table 3: Ingredients In INFUVITE Pediatric Formulation Vial 1 Active Ingredient Quantity per 4 mL Ascorbic acid (Vitamin C) 80 mg Vitamin A (as palmitate) 2,300 IU (equals 0.7 mg) Vitamin D3* (cholecalciferol) 400 IU (equals 10 mcg) Thiamine (Vitamin B1) (as the hydrochloride) 1.2 mg Riboflavin (Vitamin B2) (as riboflavin 5-phosphate sodium) 1.4 mg Pyridoxine HCl (Vitamin B6) 1 mg Niacinamide 17 mg Dexpanthenol (as d-pantothenyl alcohol) 5 mg Vitamin E* (dl-α-tocopheryl acetate) 7 IU (equals 7 mg) Vitamin K1* 0.2 mg *Polysorbate 80 is used to water solubilize the oil-soluble vitamins A, D, E, and K. Inactive ingredients in 4 mL of Vial 1: 50 mg polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection. Vial 2 Active Ingredient Quantity per 1 mL Folic acid 140 mcg Biotin 20 mcg Vitamin B12 (cyanocobalamin) 1 mcg Inactive ingredients in 1 mL of Vial 2: 75 mg mannitol, citric acid and/or sodium citrate for pH adjustment and water for injection. INFUVITE PEDIATRIC (multiple vitamins injection) makes available a combination of oil-soluble and water-soluble vitamins in an aqueous solution, formulated for incorporation into intravenous solutions. The liposoluble vitamins A, D, E, and K have been solubilized in an aqueous medium with polysorbate 80, permitting intravenous administration of these vitamins. Reference ID: 5474648 INFUVITE PEDIATRIC contains no more than 30 mcg/L of aluminum (combined Vials 1 and 2). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been performed with INFUVITE PEDIATRIC. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied INFUVITE PEDIATRIC (multiple vitamins injection) is supplied as follows: Vial 1 (Single Dose and Pharmacy Bulk Package) is supplied as clear, yellow to orange liquid in amber glass vial, closed with a rubber stopper, clear aluminum seal and a blue flip-off. Vial 2 (Single Dose and Pharmacy Bulk Package) is supplied as clear, colorless to pale yellow liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and pink flip-off. INFUVITE PEDIATRIC Single Dose: Carton contains total ten single-dose vials NDC 54643-5646-1 Five of Vial 1 (4 mL) NDC 54643-5648-1 Five of Vial 2 (1 mL) NDC 54643-5651-1 one Vial 1 plus one Vial 2 to be used for a single dose [see Dosage and Administration (2.2 and 2.3)]. INFUVITE PEDIATRIC Pharmacy Bulk Package: Carton contains total two vials NDC 54643-5647-0 One Vial 1 (40 mL fill in 50 mL) NDC 54643-5653-0 One Vial 2 (10 mL) NDC 54643-5655-0 Mixed contents of Vial 2 with Vial 1 provide thirty-three 1.5 mL single doses, fifteen 3.25 mL single doses or 10 single 5 mL doses [see Dosage and Administration (2.2 and 2.3)]. Storage and Handling Minimize exposure of INFUVITE PEDIATRIC to light because vitamins A, D and riboflavin are light sensitive. Store under refrigeration 2°C to 8° C (36°F to 46° F). 17 PATIENT COUNSELING INFORMATION Instruct caregiver(s) and patients (if age appropriate): • To watch for signs of allergic reactions such as urticaria, shortness of breath, wheezing and angioedema since hypersensitivity reactions may occur to any of the vitamins or excipients contained in INFUVITE PEDIATRIC. • To watch for and immediately report nausea, vomiting, headache, dizziness, blurred vision, especially if patients have renal impairment, as these may be signs of hypervitaminosis A. • To report other adverse reactions that patients may experience such as rash, erythema, pruritus, headache, dizziness, agitation, anxiety, and diplopia. • Patients on warfarin anticoagulant therapy will be monitored periodically with blood prothrombin/ INR levels to determine if the dose of warfarin needs to be adjusted. Reference ID: 5474648 • About the significance of periodic monitoring of blood vitamin concentrations to determine if vitamin deficiencies or excesses are developing and the need to monitor renal function, calcium, phosphorus, aluminum and vitamin A levels in patients with renal impairment. • That INFUVITE PEDIATRIC should be avoided in patients with suspected or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies. • That vitamin C (ascorbic acid) contained in INFUVITE PEDIATRIC may cause false negative urine glucose results. Manufactured for Sandoz Inc., Princeton, NJ 08540 Distributed by Baxter Healthcare Corporation Deerfield, IL 60015 USA INFUVITE is a registered trademark of Sandoz Canada Inc. Reference ID: 5474648	custom-source	2025-02-12T15:46:33.672523	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021265s044lbl.pdf', 'application_number': 21265, 'submission_type': 'SUPPL ', 'submission_number': 44}
80,181	AmBisome® (amphotericin B) liposome for injection DESCRIPTION AmBisome® for Injection is a sterile, non-pyrogenic lyophilized product for intravenous infusion. Each vial contains amphotericin B 50 milligrams (mg), intercalated into a liposomal membrane consisting of alpha tocopherol approximately 0.64 mg; cholesterol 52 mg; distearoyl phosphatidylglycerol sodium salt 84 mg; hydrogenated soy phosphatidylcholine 213 mg, together with disodium succinate hexahydrate 27 mg; and sucrose 900 mg. AmBisome may also contain hydrochloric acid and/or sodium hydroxide as pH adjusters. Following reconstitution with Sterile Water for Injection, USP, the resulting pH of the suspension is between 5-6. AmBisome is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. AmBisome consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the AmBisome liposomes. AmBisome contains true liposomes that are less than 100 nm in diameter. A schematic depiction of the liposome is presented below. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Note: Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products. Amphotericin B is a macrocyclic, polyene, antifungal antibiotic produced from a strain of Streptomyces nodosus. Amphotericin B is designated chemically as: [1R- (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33 R,35S,36R,37S)]-33-[(3-Amino-3,6-dideoxy-β-D-mannopyranosyl)oxy]- 1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39- dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid (CAS No. 1397-89-3). Amphotericin B has a molecular formula of C47H73NO17 and a molecular weight of 924.09. The structure of amphotericin B is shown below: MICROBIOLOGY Mechanism of Action Amphotericin B, the active ingredient of AmBisome, acts by binding to the sterol component, ergosterol, of the cell membrane of susceptible fungi. It forms transmembrane channels leading to alterations in cell permeability through which monovalent ions (NA+, K+, H+, and Cl-) leak out of the cell resulting in cell death. While amphotericin B has a higher affinity for the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell leading to cytotoxicity. AmBisome, the liposomal preparation of amphotericin B, has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi. Resistance Mutants with decreased susceptibility to amphotericin B have been isolated from several fungal species after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Drug combination studies in vitro and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in vivo suggest that imidazoles may induce resistance to amphotericin B; however, the clinical relevance of drug resistance has not been established. Antimicrobial Activity AmBisome has shown in vitro activity comparable to amphotericin B against the following organisms: Aspergillus fumigatus, Aspergillus flavus, Candida albicans, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, and Blastomyces dermatitidis. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. CLINICAL PHARMACOLOGY Pharmacokinetics The assay used to measure amphotericin B in the serum after administration of AmBisome does not distinguish amphotericin B that is complexed with the phospholipids of AmBisome from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of AmBisome is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin B was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of 1 to 5 mg/kg/day AmBisome for 3 to 20 days. The pharmacokinetics of amphotericin B after administration of AmBisome is nonlinear such that there is a greater than proportional increase in serum concentrations with an increase in dose from 1 to 5 mg/kg/day. The pharmacokinetic parameters of total amphotericin B (mean ± SD) after the first dose and at steady state are shown in the table below. Pharmacokinetic Parameters of AmBisome Dose 1 mg/kg/day 2.5 mg/kg/day 5 mg/kg/day Day 1 n = 8 Last n = 7 1 n = 7 Last n = 7 1 n = 12 Last n = 9 Parameters Cmax (mcg/mL) 7.3 ± 3.8 12.2 ± 4.9 17.2 ± 7.1 31.4 ± 17.8 57.6 ± 21 83 ± 35.2 AUC0-24 (mcg•hr/mL) 27 ± 14 60 ± 20 65 ± 33 197 ± 183 269 ± 96 555 ± 311 t½ (hr) 10.7 ± 6.4 7 ± 2.1 8.1 ± 2.3 6.3 ± 2 6.4 ± 2.1 6.8 ± 2.1 Vss (L/kg) 0.44 ± 0.27 0.14 ± 0.05 0.40 ± 0.37 0.16 ± 0.09 0.16 ± 0.10 0.10 ± 0.07 Cl (mL/hr/kg) 39 ± 22 17 ± 6 51 ± 44 22 ± 15 21 ± 14 11 ± 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of AmBisome, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of AmBisome, the mean half-life was 100-153 hours. The long terminal elimination half- life is probably a slow redistribution from tissues. Steady state concentrations were generally achieved within 4 days of dosing. Although variable, mean trough concentrations of amphotericin B remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum. Metabolism The metabolic pathways of amphotericin B after administration of AmBisome are not known. Excretion The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of AmBisome has not been studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Special Populations Renal Impairment The effect of renal impairment on the disposition of amphotericin B after administration of AmBisome has not been studied. However, AmBisome has been successfully administered to patients with pre-existing renal impairment (see DESCRIPTION OF CLINICAL STUDIES). Hepatic Impairment The effect of hepatic impairment on the disposition of amphotericin B after administration of AmBisome is not known. Pediatric and Elderly Patients The pharmacokinetics of amphotericin B after administration of AmBisome in pediatric and elderly patients has not been studied; however, AmBisome has been used in pediatric and elderly patients (see DESCRIPTION OF CLINICAL STUDIES). Gender and Ethnicity The effect of gender or ethnicity on the pharmacokinetics of amphotericin B after administration of AmBisome is not known. INDICATIONS AND USAGE AmBisome is indicated for the following: • Empirical therapy for presumed fungal infection in febrile, neutropenic patients. • Treatment of Cryptococcal Meningitis in HIV-infected patients (see DESCRIPTION OF CLINICAL STUDIES). • Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate. • Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with AmBisome, relapse rates were high following initial clearance of parasites (see DESCRIPTION OF CLINICAL STUDIES). See DOSAGE AND ADMINISTRATION for recommended doses by indication. DESCRIPTION OF CLINICAL STUDIES Eleven clinical studies supporting the efficacy and safety of AmBisome were conducted. This clinical program included both controlled and uncontrolled studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda These studies, which involved 2,171 patients, included patients with confirmed systemic mycoses, empirical therapy, and visceral leishmaniasis. Nineteen hundred and forty-six (1946) episodes were evaluable for efficacy, of which 1,280 (302 pediatric and 978 adults) were treated with AmBisome. Three controlled empirical therapy trials compared the efficacy and safety of AmBisome to amphotericin B. One of these studies was conducted in a pediatric population, one in adults, and a third in patients aged 2 years or more. In addition, a controlled empirical therapy trial comparing the safety of AmBisome to Abelcet® (amphotericin B lipid complex) was conducted in patients aged 2 years or more. One controlled trial compared the efficacy and safety of AmBisome to amphotericin B in HIV patients with cryptococcal meningitis. One compassionate use study enrolled patients who had failed amphotericin B deoxycholate therapy or who were unable to receive amphotericin B deoxycholate because of renal insufficiency. Empirical Therapy in Febrile Neutropenic Patients Study 94-0-002, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of AmBisome (1.5-6 mg/kg/day) compared with amphotericin B deoxycholate (0.3-1.2 mg/kg/day) in the empirical treatment of 687 adult and pediatric neutropenic patients who were febrile despite having received at least 96 hours of broad spectrum antibacterial therapy. Therapeutic success required (a) resolution of fever during the neutropenic period, (b) absence of an emergent fungal infection, (c) patient survival for at least 7 days post therapy, (d) no discontinuation of therapy due to toxicity or lack of efficacy, and (e) resolution of any study-entry fungal infection. The overall therapeutic success rates for AmBisome and the amphotericin B deoxycholate were equivalent. Results are summarized in the following table. Note: The categories presented below are not mutually exclusive. Empirical Therapy in Febrile Neutropenic Patients: Randomized, Double-Blind Study in 687 Patients AmBisome 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Number of patients receiving at least one dose of study drug 343 344 Overall Success 171 (49.9%) 169 (49.1%) Fever resolution during neutropenic period 199 (58%) 200 (58.1%) No treatment-emergent fungal infection 300 (87.5%) 301 (87.7%) Survival through 7 days post study drug 318 (92.7%) 308 (89.5%) Study drug not prematurely discontinued due to toxicity or lack of efficacy* 294 (85.7%) 280 (81.4%) * 8 and 10 patients, respectively, were treated as failures due to premature discontinuation alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This therapeutic equivalence had no apparent relationship to the use of prestudy antifungal prophylaxis or concomitant granulocytic colony-stimulating factors. The incidence of mycologically-confirmed, and clinically-diagnosed, emergent fungal infections are presented in the following table. AmBisome and amphotericin B were found to be equivalent with respect to the total number of emergent fungal infections. Empirical Therapy in Febrile Neutropenic Patients: Emergent Fungal Infections AmBisome 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Number of patients receiving at least one dose of study drug 343 344 Mycologically-confirmed fungal infection 11 (3.2%) 27 (7.8%) Clinically-diagnosed fungal infection 32 (9.3%) 16 (4.7%) Total emergent fungal infections 43 (12.5%) 43 (12.5%) Mycologically-confirmed fungal infections at study entry were cured in 8 of 11 patients in the AmBisome group and 7 of 10 in the amphotericin B group. Study 97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of AmBisome (3 and 5 mg/kg/day) compared with amphotericin B lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. One hundred and sixty-six (166) patients received AmBisome (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72 hours of broad spectrum antibacterial therapy. The primary endpoint of this study was safety. The study was not designed to draw statistically meaningful conclusions related to comparative efficacy and, in fact, Abelcet is not labeled for this indication. Two supportive, prospective, randomized, open-label, comparative multi-center studies examined the efficacy of two dosages of AmBisome (1 and 3 mg/kg/day) compared to amphotericin B deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. These patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease. Study 104-10 enrolled adult patients (n = 134). Study 104-14 enrolled pediatric patients (n = 214). Both studies support the efficacy equivalence of AmBisome and amphotericin B as empirical therapy in febrile neutropenic patients. Treatment of Cryptococcal Meningitis in HIV-Infected Patients Study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of AmBisome at doses (3 and 6 mg/kg/day) compared with amphotericin B deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric HIV-positive patients (the pediatric patient received amphotericin B deoxycholate). Of the 267 treated patients, 86 received AmBisome 3 mg/kg/day, 94 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda received 6 mg/kg/day and 87 received amphotericin B deoxycholate; cryptococcal meningitis was documented by a positive CSF culture at baseline in 73, 85 and 76 patients, respectively. Patients received study drug once daily for an induction period of 11 to 21 days. Following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. For mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline CSF culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14 ± 4 days), and was defined as CSF culture conversion. Success rates at 2 weeks for AmBisome and amphotericin B deoxycholate are summarized in the following table: Success Rates at 2 Weeks (CSF Culture Conversion) Study 94-0-013 AmBisome 3 mg/kg/day AmBisome 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Success at Week 2 35/60 (58.3%) 97.5% CI* = -9.4%, +31% 36/75 (48%) 97.5% CI* = -18.8%, +19.8% 29/61 (47.5%) * 97.5% Confidence Interval for the difference between AmBisome and amphotericin B success rates. A negative value is in favor of amphotericin B. A positive value is in favor of AmBisome. Success at 10 weeks was defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10. Success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of AmBisome 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that AmBisome 3 mg/kg/day is comparable in efficacy to amphotericin B deoxycholate. The table also presents 10-week survival rates for patients treated in this study. Success Rates and Survival Rates at Week 10, Study 94-0-013 (see text for definitions) AmBisome 3 mg/kg/day AmBisome 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Success in patients with documented cryptococcal meningitis 27/73 (37%) 97.5% CI* = -33.7%, +2.4% 42/85 (49%) 97.5% CI* = -20.9%, +14.5% 40/76 (53%) Survival rates 74/86 (86%) 97.5% CI* = -13.8%, +8.9% 85/94 (90%) 97.5% CI* = -8.3%, +12.2% 77/87 (89%) * 97.5% Confidence Interval for the difference between AmBisome and amphotericin B rates. A negative value is in favor of amphotericin B. A positive value is in favor of AmBisome. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving AmBisome compared to amphotericin B deoxycholate (see ADVERSE REACTIONS section for details); therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin B formulations should be taken into consideration when selecting a patient treatment regimen. Treatment of Patients with Aspergillus Species, Candida Species and/or Cryptococcus Species Infections Refractory to Amphotericin B Deoxycholate, or in Patients Where Renal Impairment or Unacceptable Toxicity Precludes the Use of Amphotericin B Deoxycholate AmBisome was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. These patients either had fungal infections refractory to amphotericin B deoxycholate, were intolerant to the use of amphotericin B deoxycholate, or had pre-existing renal insufficiency. Patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. Clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis. Treatment of Visceral Leishmaniasis AmBisome was studied in patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed Leishmania infantum. Clinical studies have not provided conclusive data regarding efficacy against L. donovani or L. chagasi. AmBisome achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12-30 mg/kg were administered. Most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. While acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30-40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. Of the 21 immunocompromised patients studied, 17 were coinfected with HIV; approximately half of the HIV-infected patients had AIDS. The following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the Mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. Efficacy is expressed as both acute parasite clearance at the end of therapy (EOT) and as overall success (clearance with no relapse) during the follow-up period (F/U) of greater than 6 months for immunocompetent and immunocompromised patients: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda AmBisome Efficacy in Visceral Leishmaniasis Immunocompetent Patients No. of Patients Parasite (%) Clearance at EOT Overall Success (%) at F/U 87 86/87 (98.9) 83/86 (96.5) Immunocompromised Patients Regimen Total Dose Parasite (%) Clearance at EOT Overall Success (%) at F/U 100 mg/day X 21 days 29-38.9 mg/kg 10/10 (100) 2/10 (20) 4 mg/kg/day, days 1-5, and 10, 17, 24, 31, 38 40 mg/kg 8/9 (88.9) 0/7 (0) TOTAL 18/19 (94.7) 2/17 (11.8) When followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. While case reports have suggested there may be a role for long-term therapy to prevent relapses in HIV coinfected patients (Lopez-Dupla, et al. J Antimicrob Chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of AmBisome or of maintenance therapy with this drug among immunocompromised patients. CONTRAINDICATIONS AmBisome is contraindicated in those patients who have demonstrated or have a known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk. WARNINGS Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including AmBisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome. PRECAUTIONS General As with any amphotericin B-containing product the drug should be administered by medically trained personnel. During the initial dosing period, patients should be under close clinical observation. AmBisome has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium). Drug-Laboratory Interactions: Serum phosphate false elevation False elevations of serum phosphate may occur when samples from patients receiving AmBisome are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples. Drug Interactions No formal clinical studies of drug interactions have been conducted with AmBisome; however, the following drugs are known to interact with amphotericin B and may interact with AmBisome: Antineoplastic Agents Concurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with caution. Corticosteroids and Corticotropin (ACTH) Concurrent use of corticosteroids and ACTH may potentiate hypokalemia, which could predispose the patient to cardiac dysfunction. If used concomitantly, serum electrolytes and cardiac function should be closely monitored. Digitalis Glycosides Concurrent use may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored. Flucytosine Concurrent use of flucytosine may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Azoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Leukocyte Transfusions Acute pulmonary toxicity has been reported in patients simultaneously receiving intravenous amphotericin B and leukocyte transfusions. Other Nephrotoxic Medications Concurrent use of amphotericin B and other nephrotoxic medications may enhance the potential for drug-induced renal toxicity. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications. Skeletal Muscle Relaxants Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine) due to hypokalemia. When administered concomitantly, serum potassium levels should be closely monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of AmBisome. AmBisome has not been tested to determine its mutagenic potential. A Segment I Reproductive Study in rats found an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in the high-dose groups (10 and 15 mg/kg, doses equivalent to human doses of 1.6 and 2.4 mg/kg based on body surface area considerations). AmBisome did not affect fertility or days to copulation. There were no effects on male reproductive function. Pregnancy There have been no adequate and well-controlled studies of AmBisome in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small. Segment II studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species. In rats, the maternal non-toxic dose of AmBisome was estimated to be 5 mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of 1 to 5 mg/kg) and in rabbits, 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to 2 times the recommended human dose) of AmBisome experienced a higher rate of spontaneous abortions than did the control groups. AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved. Nursing Mothers Many drugs are excreted in human milk; however, it is not known whether AmBisome is excreted in human milk. Due to the potential for serious adverse reactions in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda breastfed infants, a decision should be made whether to discontinue nursing or whether to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric patients, age 1 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with AmBisome. In studies which included 302 pediatric patients administered AmBisome, there was no evidence of any differences in efficacy or safety of AmBisome compared to adults. Since pediatric patients have received AmBisome at doses comparable to those used in adults on a per kilogram body weight basis, no dosage adjustment is required in this population. Safety and effectiveness in pediatric patients below the age of one month have not been established (See DESCRIPTION OF CLINICAL STUDIES - Empirical Therapy in Febrile Neutropenic Patients and DOSAGE AND ADMINISTRATION). Elderly Patients Experience with AmBisome in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of AmBisome for this population. As with most other drugs, elderly patients receiving AmBisome should be carefully monitored. ADVERSE REACTIONS The following adverse events are based on the experience of 592 adult patients (295 treated with AmBisome and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with AmBisome and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. AmBisome and amphotericin B were infused over two hours. The incidence of common adverse events (incidence of 10% or greater) occurring with AmBisome compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table: Empirical Therapy Study 94-0-002 Common Adverse Events Adverse Event by Body System AmBisome N = 343 % Amphotericin B N = 344 % Body as a Whole Abdominal pain Asthenia Back pain Blood product transfusion reaction Chills Infection Pain 19.8 13.1 12 18.4 47.5 11.1 14 21.8 10.8 7.3 18.6 75.9 9.3 12.8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Event by Body System AmBisome N = 343 % Amphotericin B N = 344 % Sepsis 14 11.3 Cardiovascular System Chest pain Hypertension Hypotension Tachycardia 12 7.9 14.3 13.4 11.6 16.3 21.5 20.9 Digestive System Diarrhea Gastrointestinal hemorrhage Nausea Vomiting 30.3 9.9 39.7 31.8 27.3 11.3 38.7 43.9 Metabolic and Nutritional Disorders Alkaline phosphatase increased ALT (SGPT) increased AST (SGOT) increased Bilirubinemia BUN increased Creatinine increased Edema Hyperglycemia Hypernatremia Hypervolemia Hypocalcemia Hypokalemia Hypomagnesemia Peripheral edema 22.2 14.6 12.8 18.1 21 22.4 14.3 23 4.1 12.2 18.4 42.9 20.4 14.6 19.2 14 12.8 19.2 31.1 42.2 14.8 27.9 11 15.4 20.9 50.6 25.6 17.2 Nervous System Anxiety Confusion Headache Insomnia 13.7 11.4 19.8 17.2 11 13.4 20.9 14.2 Respiratory System Cough increased Dyspnea Epistaxis Hypoxia Lung disorder Pleural effusion Rhinitis 17.8 23 14.9 7.6 17.8 12.5 11.1 21.8 29.1 20.1 14.8 17.4 9.6 11 Skin and Appendages Pruritus Rash Sweating 10.8 24.8 7 10.2 24.4 10.8 Urogenital System Hematuria 14 14 AmBisome was well tolerated. AmBisome had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In pediatric patients (16 years of age or less) in this double-blind study, AmBisome compared to amphotericin B deoxycholate, had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with AmBisome and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate. The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with AmBisome 3 mg/kg, 81 patients were treated with AmBisome 5 mg/kg and 78 patients were treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized, double-blind, multi-center study in febrile, neutropenic patients. AmBisome and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms, regardless of relationship to study drug, are summarized in the following table: Empirical Therapy Study 97-0-034 Common Adverse Events Adverse Event by Body System AmBisome 3 mg/kg/day N = 85 % AmBisome 5 mg/kg/day N = 81 % Amphotericin B Lipid Complex 5 mg/kg/day N = 78 % Body as a Whole Abdominal pain Asthenia Chills/rigors Sepsis Transfusion reaction 12.9 8.2 40 12.9 10.6 9.9 6.2 48.1 7.4 8.6 11.5 11.5 89.7 11.5 5.1 Cardiovascular System Chest pain Hypertension Hypotension Tachycardia 8.2 10.6 10.6 9.4 11.1 19.8 7.4 18.5 6.4 23.1 19.2 23.1 Digestive System Diarrhea Nausea Vomiting 15.3 25.9 22.4 17.3 29.6 25.9 14.1 37.2 30.8 Metabolic and Nutritional Disorders Alkaline phosphatase increased Bilirubinemia BUN increased Creatinine increased Edema Hyperglycemia Hypervolemia Hypocalcemia Hypokalemia Hypomagnesemia 7.1 16.5 20 20 12.9 8.2 8.2 10.6 37.6 15.3 8.6 11.1 18.5 18.5 12.3 8.6 11.1 4.9 43.2 25.9 12.8 11.5 28.2 48.7 12.8 14.1 14.1 5.1 39.7 15.4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Event by Body System AmBisome 3 mg/kg/day N = 85 % AmBisome 5 mg/kg/day N = 81 % Amphotericin B Lipid Complex 5 mg/kg/day N = 78 % Liver function tests abnormal 10.6 7.4 11.5 Nervous System Anxiety Confusion Headache 10.6 12.9 9.4 7.4 8.6 17.3 9 3.8 10.3 Respiratory System Dyspnea Epistaxis Hypoxia Lung disorder 17.6 10.6 7.1 14.1 22.2 8.6 6.2 13.6 23.1 14.1 20.5 15.4 Skin and Appendages Rash 23.5 22.2 14.1 The following adverse events are based on the experience of 267 patients (266 adult patients and 1 pediatric patient) of whom 86 patients were treated with AmBisome 3 mg/kg, 94 patients were treated with AmBisome 6 mg/kg and 87 patients were treated with amphotericin B deoxycholate 0.7 mg/kg in Study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in HIV-positive patients. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table: Cryptococcal Meningitis Therapy Study 94-0-013 Common Adverse Events Adverse Event by Body System AmBisome 3 mg/kg/day N = 86 % AmBisome 6 mg/kg/day N = 94 % Amphotericin B 0.7 mg/kg/day N = 87 % Body as a Whole Abdominal pain Infection Procedural Complication 7 12.8 8.1 7.4 11.7 9.6 10.3 6.9 10.3 Cardiovascular System Phlebitis 9.3 10.6 25.3 Digestive System Anorexia Constipation Diarrhea Nausea Vomiting 14 15.1 10.5 16.3 10.5 9.6 14.9 16 21.3 21.3 11.5 20.7 10.3 25.3 20.7 Hemic and Lymphatic System Anemia Leukopenia Thrombocytopenia 26.7 15.1 5.8 47.9 17 12.8 43.7 17.2 6.9 Metabolic and Nutritional Disorders Bilirubinemia BUN increased 0 9.3 8.5 7.4 12.6 10.3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Event by Body System AmBisome 3 mg/kg/day N = 86 % AmBisome 6 mg/kg/day N = 94 % Amphotericin B 0.7 mg/kg/day N = 87 % Creatinine increased Hyperglycemia Hypocalcemia Hypokalemia Hypomagnesemia Hyponatremia Liver Function Tests Abnormal 18.6 9.3 12.8 31.4 29.1 11.6 12.8 39.4 12.8 17 51.1 48.9 8.5 4.3 43.7 17.2 13.8 48.3 40.2 9.2 9.2 Nervous System Dizziness Insomnia 7 22.1 8.5 17 10.3 20.7 Respiratory System Cough Increased 8.1 2.1 10.3 Skin and Appendages Rash 4.7 11.7 4.6 Infusion-Related Reactions In Study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion-related reaction was administered prior to the first dose of study drug (Day 1). AmBisome-treated patients had a lower incidence of infusion-related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients. The incidence of infusion-related reactions on Day 1 in pediatric and adult patients is summarized in the following table: Incidence of Day 1 Infusion-Related Reactions (IRR) By Patient Age Pediatric Patients (≤ 16 years of age) Adult Patients (> 16 years of age) AmBisome 3 mg/kg/day Amphotericin B 0.6 mg/kg/day AmBisome 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Total number of patients receiving at least one dose of study drug 48 47 295 297 Patients with fever* increase ≥ 1.0oC 6 (13%) 22 (47%) 52 (18%) 128 (43%) Patients with chills/rigors 4 (8%) 22 (47%) 59 (20%) 165 (56%) Patients with nausea 4 (8%) 4 (9%) 38 (13%) 31 (10%) Patients with vomiting 2 (4%) 7 (15%) 19 (6%) 21 (7%) Patients with other reactions 10 (21%) 13 (28%) 47 (16%) 69 (23%) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda * Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). Cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin B-treated patients as summarized in the following table: Incidence of Infusion-Related Cardiorespiratory Events Event AmBisome 3 mg/kg/day N = 343 Amphotericin B 0.6 mg/kg/day N = 344 Hypotension 12 (3.5%) 28 (8.1%) Tachycardia 8 (2.3%) 43 (12.5%) Hypertension 8 (2.3%) 39 (11.3%) Vasodilatation 18 (5.2%) 2 (0.6%) Dyspnea 16 (4.7%) 25 (7.3%) Hyperventilation 4 (1.2%) 17 (4.9%) Hypoxia 1 (0.3%) 22 (6.4%) The percentage of patients who received drugs either for the treatment or prevention of infusion-related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in AmBisome-treated patients compared with amphotericin B deoxycholate-treated patients. In the empirical therapy study 97-0-034, on Day 1, where no premedication was administered, the overall incidence of infusion-related events of chills/rigors was significantly lower for patients administered AmBisome compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each AmBisome group compared with the amphotericin B lipid complex group. The infusion- related event hypoxia was reported for 11.5% of amphotericin B lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day AmBisome and 1.2% of patients treated with 5 mg/kg per day AmBisome. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Incidence of Day 1 Infusion-Related Reactions (IRR) Chills/Rigors Empirical Therapy Study 97-0-034 AmBisome Amphotericin B lipid complex 5 mg/kg/day 3 mg/kg/day 5 mg/kg/day BOTH Total number of patients 85 81 166 78 Patients with Chills/Rigors (Day 1) 16 (18.8%) 19 (23.5%) 35 (21.1%) 62 (79.5%) Patients with other notable reactions: Fever (>1.0oC increase in temperature) 20 (23.5%) 16 (19.8%) 36 (21.7%) 45 (57.7%) Nausea 9 (10.6%) 7 (8.6%) 16 (9.6%) 9 (11.5%) Vomiting 5 (5.9%) 5 (6.2%) 10 (6%) 11 (14.1%) Hypertension 4 (4.7%) 7 (8.6%) 11 (6.6%) 12 (15.4%) Tachycardia 2 (2.4%) 8 (9.9%) 10 (6%) 14 (17.9%) Dyspnea 4 (4.7%) 8 (9.9%) 12 (7.2%) 8 (10.3%) Hypoxia 0 1 (1.2%) 1 (< 1%) 9 (11.5%) Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). Patients were not administered premedications to prevent infusion-related reactions prior to the Day 1 study drug infusion. In Study 94-0-013, a randomized, double-blind, multicenter trial comparing AmBisome and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion-related reactions were permitted. AmBisome- treated patients had a lower incidence of fever, chills/rigors and respiratory adverse events as summarized in the following table: Incidence of Infusion-Related Reactions Study 94-0-013 AmBisome 3 mg/kg/day AmBisome 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Total number of patients receiving at least one dose of study drug 86 94 87 Patients with fever increase of >1°C 6 (7%) 8 (9%) 24 (28%) Patients with chills/rigors 5 (6%) 8 (9%) 42 (48%) Patients with nausea 11 (13%) 13 (14%) 18 (20%) Patients with vomiting 14 (16%) 13 (14%) 16 (18%) Respiratory adverse events 0 1 (1%) 8 (9%) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with AmBisome administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within a few minutes after the start of infusion and disappeared rapidly when the infusion was stopped. The symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed. Toxicity and Discontinuation of Dosing In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the AmBisome group compared with the amphotericin B group. In addition, nearly three times as many patients administered amphotericin B required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion-related reaction compared with those administered AmBisome. In empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin B lipid complex group discontinued the study drug due to an adverse event than in the AmBisome groups. Less Common Adverse Events The following adverse events also have been reported in 2% to 10% of AmBisome- treated patients receiving chemotherapy or bone marrow transplantation, or who had HIV disease in six comparative, clinical trials: Body as a Whole Abdomen enlarged, allergic reaction, cellulitis, cell-mediated immunological reaction, face edema, graft-versus-host disease, malaise, neck pain, and procedural complication. Cardiovascular System Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing). Digestive System Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease. Hemic & Lymphatic System Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolic & Nutritional Disorders Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis. Musculoskeletal System Arthralgia, bone pain, dystonia, myalgia, and rigors. Nervous System Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor. Respiratory System Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis. Skin & Appendages Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash. Special Senses Conjunctivitis, dry eyes, and eye hemorrhage. Urogenital System Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage. Post-marketing Experience The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis. Clinical Laboratory Values The effect of AmBisome on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in Study 94-0-002. The frequency and magnitude of hepatic test abnormalities were similar in the AmBisome and amphotericin B groups. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda increasing 100% or more over pretreatment levels in adult patients, provided the peak creatinine concentration was > 1.2 mg/dL. Hypokalemia was defined as potassium levels ≤ 2.5 mmol/L any time during treatment. Incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and incidence of hypokalemia in the double-blind, randomized study were lower in the AmBisome group as summarized in the following table: Study 94-0-002 Laboratory Evidence of Nephrotoxicity AmBisome 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Total number of patients receiving at least one dose of study drug 343 344 Nephrotoxicity 64 (18.7%) 116 (33.7%) Mean peak creatinine 1.24 mg/dL 1.52 mg/dL Mean change from baseline in creatinine 0.48 mg/dL 0.77 mg/dL Hypokalemia 23 (6.7%) 40 (11.6%) The effect of AmBisome (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure: In empirical therapy study 97-0-034, the incidence of nephrotoxicity as measured by increases of serum creatinine from baseline was significantly lower for patients administered AmBisome (individual dose groups and combined) compared with amphotericin B lipid complex. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Incidence of Nephrotoxicity Empirical Therapy Study 97-0-034 AmBisome Amphotericin B lipid complex 5 mg/kg/day 3 mg/kg/day 5 mg/kg/day BOTH Total number of patients 85 81 166 78 Number with nephrotoxicity 1.5X baseline serum creatinine value 25 (29.4%) 21 (25.9%) 46 (27.7%) 49 (62.8%) 2X baseline serum creatinine value 12 (14.1%) 12 (14.8%) 24 (14.5%) 33 (42.3%) The following graph shows the average serum creatinine concentrations in the compassionate use study and shows that there is a drop from pretreatment concentrations for all patients, especially those with elevated (greater than 1.7 mg/dL) pretreatment creatinine concentrations. The incidence of nephrotoxicity in Study 94-0-013 comparative trial in cryptococcal meningitis was lower in the AmBisome groups as shown in the following table: Laboratory Evidence of Nephrotoxicity Study 94-0-013 AmBisome 3 mg/kg/day AmBisome 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Total number of patients receiving at least one dose of study drug 86 94 87 Number with Nephrotoxicity (%) 1.5X baseline serum creatinine 30 (35%) 44 (47%) 52 (60%) 2X baseline serum creatinine 12 (14%) 20 (21%) 29 (33%) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE The toxicity of AmBisome due to overdose has not been defined. Repeated daily doses up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients have been administered in clinical trials with no reported dose-related toxicity. Management If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Particular attention should be given to monitoring renal function. Hemodialysis or peritoneal dialysis do not appear to significantly affect the elimination of AmBisome. DOSAGE AND ADMINISTRATION AmBisome is not interchangeable or substitutable on a mg per mg basis with other amphotericin B products. Different amphotericin B products are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing. AmBisome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes. An in-line membrane filter may be used for the intravenous infusion of AmBisome, provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON. NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of AmBisome. If this is not feasible, AmBisome must be administered through a separate line. Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased. The recommended initial dose of AmBisome for each indication for adult and pediatric patients is as follows: Indication Dose (mg/kg/day) Empirical therapy 3 Systemic fungal infections: Aspergillus Candida Cryptococcus 3 - 5 Cryptococcal meningitis in HIV-infected patients (see DESCRIPTION OF CLINICAL STUDIES) 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events. Doses recommended for visceral leishmaniasis are presented below: Visceral Leishmaniasis Dose (mg/kg/day) Immunocompetent patients 3 (days 1 - 5) and 3 on days 14, 21 Immunocompromised patients 4 (days 1 - 5) and 4 on days 10, 17, 24, 31, 38 For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful. For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information, see DESCRIPTION OF CLINICAL STUDIES. Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning Reconstitution AmBisome must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of AmBisome containing 50 mg of amphotericin B are prepared as follows: Reconstitution 1. Aseptically add 12 mL of Sterile Water for Injection, USP to each AmBisome vial to yield a preparation containing 4 mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of AmBisome. 2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. AmBisome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed. Filtration and Dilution 3. Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted. 4. Withdraw this amount of reconstituted AmBisome into a sterile syringe. 5. Attach the 5 micron filter provided to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection (use only one filter per vial of AmBisome). 6. AmBisome must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS. STORAGE OF AMBISOME Unopened vials of lyophilized material are to be stored at temperatures up to 25°C (77°F). Storage of Reconstituted Product Concentrate The reconstituted product concentrate may be stored for up to 24 hours at 2°-8°C (36°- 46°F) following reconstitution with Sterile Water for Injection, USP. Do not freeze. Storage of Diluted Product Injection of AmBisome should commence within 6 hours of dilution with 5% Dextrose Injection. As with all parenteral drug products, the reconstituted AmBisome should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in AmBisome or in the materials specified for reconstitution and dilution. HOW SUPPLIED AmBisome for Injection is available as an individual carton (NDC 0469-3051-30). Each carton contains one pre-packaged, disposable sterile 5 micron filter. Rx only Marketed by: Astellas Pharma US, Inc. Northbrook, IL 60062 Manufactured by: Gilead Sciences, Inc. Foster City, CA 94404 AmBisome® is a registered trademark of Gilead Sciences, Inc. All other trademarks and registered trademarks are the property of their respective owners. Revised Month: xx/20xx 420840-AMB-USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda David Lewis Digitally signed by David Lewis Date: 11/04/2024 04:00:27PM GUID: 508da72000029f287fa31e664741b577 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:33.969319	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/050740Orig1s037Lbl.pdf', 'application_number': 50740, 'submission_type': 'SUPPL ', 'submission_number': 37}
80,183	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DELSTRIGO safely and effectively. See full prescribing information for DELSTRIGO. DELSTRIGO® (doravirine, lamivudine, and tenofovir disoproxil fumarate) tablets, for oral use Initial U.S. Approval: 2018 WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B (HBV) have been reported in people with concomitant HIV-1 and HBV who have discontinued lamivudine or tenofovir disoproxil fumarate (TDF), two of the components of DELSTRIGO. Closely monitor hepatic function in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.2) ---------------------------RECENT MAJOR CHANGES -------------------------- Warnings and Precautions, Severe Skin Reactions (5.1) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- DELSTRIGO is a three-drug combination of doravirine (a non nucleoside reverse transcriptase inhibitor [NNRTI]), lamivudine, and tenofovir disoproxil fumarate (both nucleoside analogue reverse transcriptase inhibitors) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: • with no antiretroviral treatment history, OR • to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------------- • Testing: Prior to or when initiating DELSTRIGO, test for HBV infection. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (2.1) • Recommended dosage: One tablet taken orally once daily with or without food in adults and pediatric patients weighing at least 35 kg. (2.2) • Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (2.3) • Dosage adjustment with rifabutin: Take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine 100 mg (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO. (2.4) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- • Tablets: 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate. (3) -------------------------------CONTRAINDICATIONS------------------------------ • DELSTRIGO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO. (4) • DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens. Discontinue DELSTRIGO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops, and closely monitor clinical status. (5.1) • New onset or worsening renal impairment: Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. Avoid administering DELSTRIGO with concurrent or recent use of nephrotoxic drugs. (5.3) • Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.5) • Monitor for Immune Reconstitution Syndrome. (5.6) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (incidence greater than or equal to 5%, all grades) are dizziness, nausea, and abnormal dreams. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ • Because DELSTRIGO is a complete regimen, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. (7.1) • Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. (4, 5.4, 7) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Testing When Initiating and During Treatment with DELSTRIGO 2.2 Recommended Dosage 2.3 Renal Impairment 2.4 Dosage Adjustment with Rifabutin 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Severe Skin Reactions 5.2 Severe Acute Exacerbation of Hepatitis B in people with concomitant HIV-1 and HBV 5.3 New Onset or Worsening Renal Impairment 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions 5.5 Bone Loss and Mineralization Defects 5.6 Immune Reconstitution Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with Other Antiretroviral Medications 7.2 Effect of Other Drugs on DELSTRIGO 7.3 Effect of DELSTRIGO on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Reference ID: 5475884 14 CLINICAL STUDIES 14.1 Clinical Trial Results in Adults with No Antiretroviral 16 17 HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION Treatment History 14.2 Clinical Trial Results in Virologically-Suppressed Adults 14.3 Clinical Trial Results in Pediatric Participants Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5475884 FULL PRESCRIBING INFORMATION WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) have been reported in people with concomitant HIV-1 and HBV who have discontinued lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue DELSTRIGO. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE DELSTRIGO® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: • with no prior antiretroviral treatment history, OR • to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Testing When Initiating and During Treatment with DELSTRIGO Prior to or when initiating DELSTRIGO, test patients for HBV infection [see Warnings and Precautions (5.2)]. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.3)]. 2.2 Recommended Dosage DELSTRIGO is a fixed-dose combination product containing 100 mg of doravirine (DOR), 300 mg of lamivudine (3TC), and 300 mg of TDF. The recommended dosage of DELSTRIGO in adults and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)]. 2.3 Renal Impairment Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. 2.4 Dosage Adjustment with Rifabutin If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine 100 mg (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO for the duration of rifabutin co-administration [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS DELSTRIGO film-coated tablets are yellow, oval-shaped tablets, debossed with the corporate logo and 776 on one side and plain on the other side. Each tablet contains 100 mg doravirine, 300 mg lamivudine, and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil). 3 Reference ID: 5475884 4 CONTRAINDICATIONS • DELSTRIGO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO [see Warnings and Precautions (5.4), Drug Interactions (7.2), and Clinical Pharmacology (12.3)]. These drugs include, but are not limited to, the following: - the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin - the androgen receptor inhibitor enzalutamide - the antimycobacterials rifampin, rifapentine - the cytotoxic agent mitotane - St. John’s wort (Hypericum perforatum) • DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. 5 WARNINGS AND PRECAUTIONS 5.1 Severe Skin Reactions Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens [see Adverse Reactions (6.2)]. Discontinue DELSTRIGO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Clinical status should be closely monitored, and appropriate therapy should be initiated. 5.2 Severe Acute Exacerbation of Hepatitis B in People with Concomitant HIV-1 and HBV All patients with HIV-1 should be tested for the presence of HBV before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in people with concomitant HIV-1 and HBV who have discontinued products containing lamivudine and/or TDF, and may occur with discontinuation of DELSTRIGO. Patients who are coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DELSTRIGO. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post- treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.3 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of DELSTRIGO. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients living with HIV with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. 4 Reference ID: 5475884 The lamivudine and TDF components of DELSTRIGO are primarily excreted by the kidney. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min as dose interval adjustment required for lamivudine and TDF cannot be achieved with the fixed-dose combination tablet [see Use in Specific Populations (8.6)]. 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of DELSTRIGO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7.2)]: • Loss of therapeutic effect of DELSTRIGO and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of a component of DELSTRIGO. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during DELSTRIGO therapy, review concomitant medications during DELSTRIGO therapy, and monitor for adverse reactions. 5.5 Bone Loss and Mineralization Defects Bone Mineral Density In clinical trials in adults living with HIV, TDF (a component of DELSTRIGO) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in participants receiving TDF. Clinical trials evaluating TDF in pediatric participants were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In participants 2 years to less than 18 years of age living with HIV, bone effects were similar to those observed in adult participants and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated pediatric participants living with HIV as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric participants 2 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients living with HIV who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF [see Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.3)]. 5 Reference ID: 5475884 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe Acute Exacerbation of Hepatitis B in people with concomitant HIV-1 and HBV [see Warnings and Precautions (5.2)] • New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)] • Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5)] • Immune Reconstitution Syndrome [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with No Antiretroviral Treatment History The safety assessment of DELSTRIGO is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials. A total of 747 participants received doravirine either as the single entity in combination with other antiretroviral drugs as background regimens (n=383) or as the fixed-dose DELSTRIGO (n=364), and a total of 747 participants were randomized to control arms. In DRIVE-AHEAD (Protocol 021), 728 adult participants received either DELSTRIGO (n=364) or EFV/FTC/TDF once daily (n=364). By Week 96, 3% in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication. Adverse reactions reported in greater than or equal to 5% of participants in any treatment group in DRIVE AHEAD are presented in Table 1. Table 1: Adverse Reactions (All Grades) Reported in ≥5%† of Participants in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 96) DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Dizziness 7% 32% Nausea 5% 7% Abnormal Dreams 5% 10% Headache 4% 5% 6 Reference ID: 5475884 Insomnia 4% 5% Diarrhea 4% 6% Somnolence 3% 7% Rash‡ 2% 12% Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. †No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥2% of participants treated with DELSTRIGO. ‡Rash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo papular, rash papular, rash pruritic. The majority (66%) of adverse reactions associated with DELSTRIGO occurred at severity Grade 1 (mild). Neuropsychiatric Adverse Events For DRIVE-AHEAD, the analysis of participants with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of participants who reported one or more neuropsychiatric adverse events was 24% and 57% in the DELSTRIGO and EFV/FTC/TDF groups, respectively. A statistically significantly lower proportion of DELSTRIGO-treated participants compared to EFV/FTC/TDF-treated participants reported neuropsychiatric adverse events by Week 48 in the three pre specified categories of dizziness, sleep disorders and disturbances, and altered sensorium. Table 2: DRIVE-AHEAD - Analysis of Participants with Neuropsychiatric Adverse Events (Week 48) DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Treatment Difference (DELSTRIGO - EFV/FTC/TDF) Estimate (95% CI)† Sleep disorders and disturbances‡ 12% 26% -13.5 (-19.1, -7.9) Dizziness 9% 37% -28.3 (-34.0, -22.5) Altered sensorium§ 4% 8% -3.8 (-7.6, -0.3) All causality and all grade events were included in the analysis. †The 95% CIs were calculated using Miettinen and Nurminen's method. Categories pre-specified for statistical testing were dizziness (p <0.001), sleep disorders and disturbances (p <0.001), and altered sensorium (p=0.033). ‡Predefined using MedDRA preferred terms including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism. §Predefined using MedDRA preferred terms including: altered state of consciousness, lethargy, somnolence, syncope. Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of participants, in the DELSTRIGO and EFV/FTC/TDF groups, respectively. In DRIVE-AHEAD through 48 weeks of treatment, the majority of participants who reported neuropsychiatric adverse events reported events that were mild to moderate in severity (97% [83/86] and 96% [198/207], in the DELSTRIGO and EFV/FTC/TDF groups, respectively) and the majority of participants reported these events in the first 4 weeks of treatment (72% [62/86] in the DELSTRIGO group and 86% [177/207] in the EFV/FTC/TDF group). Neuropsychiatric adverse events led to treatment discontinuation in 1% (2/364) and 1% (5/364) of participants in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of participants who 7 Reference ID: 5475884 reported neuropsychiatric adverse events through Week 4 was 17% (62/364) in the DELSTRIGO group and 49% (177/364) in the EFV/FTC/TDF group. At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. At Week 96, the prevalence of neuropsychiatric adverse events was 13% (47/364) in the DELSTRIGO group and 23% (82/364) in the EFV/FTC/TDF group. Laboratory Abnormalities The percentages of participants with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with DELSTRIGO or EFV/FTC/TDF in DRIVE-AHEAD are presented in Table 3. Table 3: Selected Laboratory Abnormalities Reported in Adult Participants with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 96) Laboratory Parameter Preferred Term (Unit)/Limit DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Blood Chemistry Total bilirubin (mg/dL) 1.1 - <1.6 x ULN 1.6 - <2.6 x ULN ≥2.6 x ULN 5% 2% 1% 0% 0% <1% Creatinine (mg/dL) >1.3 - 1.8 x ULN or Increase of >0.3 mg/dL above baseline >1.8 x ULN or Increase of ≥1.5 x above baseline 3% 3% 2% 2% Aspartate aminotransferase (IU/L) 2.5 - <5.0 x ULN ≥5.0 x ULN 3% 1% 3% 4% Alanine aminotransferase (IU/L) 2.5 - <5.0 x ULN ≥5.0 x ULN 4% 1% 4% 3% Alkaline phosphatase (IU/L) 2.5 - <5.0 x ULN ≥5.0 x ULN <1% 0% 1% <1% Lipase 1.5 - <3.0 x ULN ≥3.0 x ULN 6% 2% 4% 3% Creatine kinase (IU/L) 6.0 - <10.0 x ULN ≥10.0 x ULN 3% 4% 3% 6% Cholesterol, fasted (mg/dL) ≥300 mg/dL 1% <1% LDL cholesterol, fasted (mg/dL) ≥190 mg/dL <1% 2% Triglycerides, fasted (mg/dL) >500 mg/dL 1% 3% Each participant is only counted once per parameter at the highest toxicity grade. Only participants with a baseline value and at least one on-treatment value for a given laboratory parameter are included. ULN = Upper limit of normal range. Change in Lipids from Baseline For DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. Changes from baseline at Week 96 were similar to findings at Week 48. 8 Reference ID: 5475884 The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority of DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated. Table 4: Mean Change from Baseline in Fasting Lipids in Adult Participants with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 48) Laboratory Parameter Preferred Term DELSTRIGO Once Daily N=320 EFV/FTC/TDF Once Daily N=307 Difference Estimates (DELSTRIGO EFV/FTC/TDF) Baseline Change Baseline Change Difference (95% CI) LDL-Cholesterol (mg/dL) 91.7 -2.1 91.3 8.3 -10.2 (-13.8, -6.7) Non-HDL Cholesterol (mg/dL)* 114.7 -4.1 115.3 12.7 -16.9 (-20.8, -13.0) Total Cholesterol (mg/dL)† 156.8 -2.2 156.8 21.1 - Triglycerides (mg/dL)† 118.7 -12.0 122.6 21.6 - HDL-Cholesterol (mg/dL)† 42.1 1.8 41.6 8.4 - Participants on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=15 and EFV/FTC/TDF n=10). Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=3 and EFV/FTC/TDF n=8). p-value for the pre-specified hypothesis testing for treatment difference was <0.0001. †Not pre-specified for hypothesis testing. Adverse Reactions in Virologically-Suppressed Adults The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from 670 participants in the DRIVE-SHIFT trial (Protocol 024), a randomized, international, multicenter, open-label trial in which virologically-suppressed participants were switched from a baseline regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO. Overall, the safety profile in virologically-suppressed adult participants was similar to that in participants with no antiretroviral treatment history. Laboratory Abnormalities Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of participants in the immediate switch group experienced ALT and AST elevations of greater than 1.25 X ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent time patterns with regard to time to onset relative to switch were observed. One percent of participants had ALT or AST elevations greater than 5 X ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic, and not associated with bilirubin elevations. In comparison, 4% and 4% of participants in the delayed switch group experienced ALT and AST elevations of greater than 1.25 X ULN through 24 weeks on their baseline regimen. Change in Lipids from Baseline Changes from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in participants on a PI plus ritonavir-based regimen at baseline are shown in Table 5. The LDL and non-HDL comparisons were pre-specified, and the differences were statistically significant, showing superiority for an immediate switch to DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated. 9 Reference ID: 5475884 Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Participants on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24) Laboratory Parameter Preferred Term DELSTRIGO (Week 0-24) Once Daily N=244 PI+ritonavir (Week 0-24) Once Daily N=124 Difference Estimates Baseline Change Baseline Change Difference (95% CI) LDL-Cholesterol (mg/dL) 108.7 -16.3 110.5 -2.6 -14.5 (-18.9, -10.1) Non-HDL Cholesterol (mg/dL)* 138.6 -24.8 138.8 -2.1 -22.8 (-27.9, -17.7) Total Cholesterol (mg/dL)† 188.5 -26.1 187.4 -0.2 - Triglycerides (mg/dL)† 153.1 -44.4 151.4 -0.4 - HDL-Cholesterol (mg/dL)† 50.0 -1.3 48.5 1.9 - Participants on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13). Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=4 and PI+ritonavir n=2). p-value for the pre-specified hypothesis testing for treatment difference was <0.0001. †Not pre-specified for hypothesis testing. Adverse Reactions in Pediatric Participants The safety of DELSTRIGO was evaluated in 45 virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age living with HIV, through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) [see Clinical Studies (14.3)]. The safety profile in pediatric participants was similar to that in adults. There were no serious or Grade 3 or 4 adverse reactions. No participants discontinued due to an adverse event. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving doravirine-, lamivudine- or TDF-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Doravirine: Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) Lamivudine: Body as a Whole: redistribution/accumulation of body fat Endocrine and Metabolic: hyperglycemia General: Weakness Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy) Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbations of hepatitis B Hypersensitivity: anaphylaxis, urticaria Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis Skin: alopecia, pruritus 10 Reference ID: 5475884 --- TDF: Immune System Disorders: allergic reaction, including angioedema Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders: dyspnea Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT) Skin and Subcutaneous Tissue Disorders: rash Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions: asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. 7 DRUG INTERACTIONS 7.1 Concomitant Use with Other Antiretroviral Medications Because DELSTRIGO is a complete regimen for the treatment of HIV-1 infection, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. 7.2 Effect of Other Drugs on DELSTRIGO Co-administration of DELSTRIGO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce DELSTRIGO efficacy [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]. Co-administration of DELSTRIGO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. Table 6 shows the significant drug interactions with the components of DELSTRIGO. The drug interactions described are based on studies conducted with either DELSTRIGO or the components of DELSTRIGO as individual agents. 11 Reference ID: 5475884 Table 6: Drug Interactions with DELSTRIGO Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Androgen Receptors enzalutamide ↓ doravirine Co-administration is contraindicated with enzalutamide. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin ↓ doravirine Co-administration is contraindicated with these anticonvulsants. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Antimycobacterials rifampin† rifapentine ↓ doravirine Co-administration is contraindicated with rifampin or rifapentine. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. rifabutin† ↓ doravirine If DELSTRIGO is co-administered with rifabutin, one tablet of doravirine (PIFELTRO) should be taken approximately 12 hours after the dose of DELSTRIGO [see Dosage and Administration (2.4)]. Cytotoxic Agents mitotane ↓ doravirine Co-administration is contraindicated with mitotane. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Hepatitis C Antiviral Agents ledipasvir/sofosbuvir sofosbuvir/velpatasvir ↑ tenofovir Monitor for adverse reactions associated with TDF. Herbal Products St. John’s wort ↓ doravirine Co-administration is contraindicated with St. John’s wort. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Other Agents sorbitol ↓ lamivudine Co-administration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines. ↑ = increase, ↓ = decrease This table is not all-inclusive †The interaction between doravirine and the concomitant drug was evaluated in a clinical study. All other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways. Co-administration of DELSTRIGO with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, or methadone [see Clinical Pharmacology (12.3)]. 12 Reference ID: 5475884 No clinically significant changes in concentration were observed for tenofovir when co-administered with tacrolimus or entecavir [see Clinical Pharmacology (12.3)]. 7.3 Effect of DELSTRIGO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co- administered with doravirine: lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, or midazolam. No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, sofosbuvir, or tacrolimus in studies conducted in healthy participants. Lamivudine is not significantly metabolized by CYP enzymes nor does it inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur through these pathways [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There is insufficient prospective pregnancy data from the APR to adequately assess the risk of birth defects and miscarriage. Doravirine use in individuals during pregnancy has not been evaluated; however, lamivudine and TDF use during pregnancy has been evaluated in a limited number of individuals reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for lamivudine and TDF compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease- specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. No adverse developmental effects were observed when doravirine and TDF were administered separately at doses/exposures ≥8 (doravirine) and ≥14 (TDF) times those of the recommended human dose (RHD) of DELSTRIGO (see Data). Data Human Data Lamivudine: The APR has received a total of over 13,000 prospective reports with follow-up data of possible exposure to lamivudine-containing regimens; over 5,900 reports in the first trimester; over 5,600 reports in 13 Reference ID: 5475884 the second trimester; and over 1,800 reports in the third trimester. Birth defects occurred in 170 of 5,472 (3.1%, 95% CI: 2.7% to 3.6%) live births for lamivudine-containing regimens (first trimester exposure); and 218 of 7,513 (2.9%, 95% CI: 2.5% to 3.3%) live births for lamivudine-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between lamivudine and overall birth defects observed in the APR. TDF: The APR has received a total of over 7,000 prospective reports with follow-up data of possible exposure to tenofovir disoproxil-containing regimens; over 5,100 reports in the first trimester; over 1,300 reports in the second trimester; and over 600 reports in the third trimester. Birth defects occurred in 113 of 4,576 (2.5%, 95% CI: 2.0% to 3.0%) live births for TDF-containing regimens (first trimester exposure); and 51 of 1,965 (2.6%, 95% CI: 1.9% to 3.4%) live births for TDF-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between tenofovir and overall birth defects observed in the APR. Animal Data Doravirine: Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo- fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20. Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on GD 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine. TDF: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of harm to the fetus. 8.2 Lactation Risk Summary Based on limited published data, both lamivudine and tenofovir are present in human milk. It is unknown whether doravirine is present in human milk, but doravirine is present in the milk of lactating rats (see Data). It is not known whether DELSTRIGO or the components of DELSTRIGO affects human milk production, or has effects on the breastfed infant. Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV- 1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults. Data Doravirine: Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from GD 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14. 14 Reference ID: 5475884 8.4 Pediatric Use The safety and efficacy of DELSTRIGO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg [see Indications and Usage (1) and Dosage and Administration (2.2)]. Use of DELSTRIGO in this group is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, safety, and efficacy data from an open-label trial in virologically suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric participants were similar to that in adults, and there was no clinically significant difference in exposure for the components of DELSTRIGO. [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)]. Safety and efficacy of DELSTRIGO in pediatric patients weighing less than 35 kg have not been established. 8.5 Geriatric Use Clinical trials of doravirine, lamivudine, or TDF did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants. In general, caution should be exercised in the administration of DELSTRIGO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF, both components of DELSTRIGO, cannot be altered, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of DELSTRIGO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. DELSTRIGO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No data are available on overdose of DELSTRIGO in patients and there is no known specific treatment for overdose with DELSTRIGO. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Doravirine: There is no known specific treatment for overdose with doravirine. Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. TDF: TDF is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose. 11 DESCRIPTION DELSTRIGO is a fixed-dose combination, film-coated tablet, containing doravirine, lamivudine, and TDF for oral administration. 15 Reference ID: 5475884 Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine and is an HIV-1 nucleoside analogue reverse transcriptase inhibitor. TDF (a prodrug of tenofovir) is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo TDF is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir is an HIV-1 reverse transcriptase inhibitor. Each tablet contains 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium stearyl fumarate. The tablets are film coated with a coating material containing the following inactive ingredients: hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax. Doravirine: The chemical name for doravirine is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3 yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile. It has a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75. It has the following structural formula: Doravirine is practically insoluble in water. Lamivudine: The chemical name for lamivudine is (-)-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.26. It has the following structural formula: 16 Reference ID: 5475884 Lamivudine is soluble in water. TDF: The chemical name for TDF is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy] phosphinyl] methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10 P·C4H4O4 and a molecular weight of 635.52. It has the following structural formula: TDF is slightly soluble in water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action DELSTRIGO is a fixed-dose combination of the antiretroviral drugs doravirine, lamivudine, and TDF [see Microbiology (12.4)]. 12.2 Pharmacodynamics In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of doravirine in DELSTRIGO (in combination with FTC/TDF) in participants living with HIV with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Cardiac Electrophysiology At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of doravirine in DELSTRIGO does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Single-dose administration of one DELSTRIGO tablet to healthy participants provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus TDF tablets (300 mg). Doravirine pharmacokinetics are similar in healthy participants and participants living with HIV. Pharmacokinetic properties of the components of DELSTRIGO are provided in Table 7. Table 7: Pharmacokinetic Properties of the Components of DELSTRIGO Parameter Doravirine Lamivudine Tenofovir General Steady State Exposure AUC0-24 (mcg•h/mL) 16.1 (29)† 8.87 ± 1.83‡ 2.29 ± 0.69§ Cmax 0.962 (19)† 2.04 ± 0.54‡ 0.30 ± 0.09§ 17 Reference ID: 5475884 (mcg/mL) C24 (mcg/mL) 0.396 (63)† NA NA Absorption Absolute Bioavailability 64% 86% 25% Tmax (h) 2 NA 1 Effect of Food¶ AUC Ratio 1.10 (1.01, 1.20) 0.93 (0.84, 1.03) 1.27 (1.17, 1.37) Cmax Ratio 0.95 (0.80, 1.12) 0.81 (0.65, 1.01) 0.88 (0.74, 1.04) C24 Ratio 1.26 (1.13, 1.41) NA NA Distribution # Vdss 60.5 L 1.3 L/kg 1.3 L/kg Plasma Protein Binding 76% < 36% <0.7% Elimination t1/2 (h) 15 5-7 17 CL/F (mL/ min)* 106 (35.2) 398.5 ± 69.1 1,043.7 ± 115.4 CLrenal (mL/ min)* 9.3 (18.6) 199.7 ± 56.9 243.5 ± 33.3 Metabolism Primary Pathway(s) CYP3A Minor No CYP Metabolism Excretion Major route of elimination Metabolism Glomerular filtration and active tubular secretion Glomerular filtration and active tubular secretion Urine (unchanged) 6% 71% 70-80% Biliary/Fecal (unchanged) Minor NA NA Presented as geometric mean (%CV: geometric coefficient of variation) or mean ± SD. †Doravirine 100 mg once daily to participants living with HIV. ‡Lamivudine 300 mg once daily for 7 days to 60 healthy participants. §Single 300 mg dose of TDF to participants living with HIV in the fasted state. ¶Geometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1000 kcal, 50% fat. The effect of food is not clinically relevant. #Based on IV dose. Abbreviations: NA=not available; AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax=time to Cmax; Vdss=apparent volume of distribution at steady state; t1/2=elimination half-life; CL/F=apparent clearance; CLrenal = renal clearance Specific Populations In adults, no clinically significant differences in the pharmacokinetics of certain DELSTRIGO components were observed based on age ≥65 years (for doravirine), sex (for doravirine, lamivudine, tenofovir), and race/ethnicity (for doravirine, lamivudine). The effects of age (≥65 years) on the pharmacokinetics of lamivudine and tenofovir, and the effect of race on the pharmacokinetics of tenofovir are unknown. Patients with Renal Impairment Doravirine: No clinically significant difference in the pharmacokinetics of doravirine were observed in participants with mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault). Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis. Lamivudine: The AUC∞, Cmax, and half-life of lamivudine increased and CL/F decreased to a clinically significant extent with diminishing renal function (CLcr 111 to < 10 mL/min). 18 Reference ID: 5475884 TDF: A clinically significant increase in the Cmax and AUC of tenofovir was observed in participants with CLcr < 50 mL/min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Doravirine: No clinically significant difference in the pharmacokinetics of doravirine was observed in participants with moderate hepatic impairment (Child-Pugh score B) compared to participants without hepatic impairment. Doravirine has not been studied in participants with severe hepatic impairment (Child- Pugh score C). Lamivudine: No clinically significant differences in lamivudine pharmacokinetics were observed with diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. TDF: No clinically significant differences in tenofovir pharmacokinetics were observed between participants with any degree of hepatic impairment and unimpaired participants. Pediatric Patients Mean doravirine exposures were similar in 54 pediatric participants aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO. Exposures of lamivudine and tenofovir in pediatric participants following the administration of DELSTRIGO were similar to those in adults following administration of lamivudine and tenofovir (Table 8). For pediatric participants weighing ≥ 35 kg and < 45 kg who receive doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0-24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0-24 and Cmax increases are not considered clinically significant. Table 8: Steady State Pharmacokinetics for Doravirine, Lamivudine, and Tenofovir Following Administration of Doravirine or DELSTRIGO in Pediatric Participants Living with HIV Aged 12 to Less than 18 Years and Weighing at Least 35 kg Parameter Doravirine† Lamivudine‡ Tenofovir‡ AUC0-24 (mcg•h/mL) 16.4 (24) 11.3 (28) 2.55 (14) Cmax (mcg/mL) 1.03 (16) 2.1 (24) 0.293 (37) C24 (mcg/mL) 0.379 (42) NA NA Presented as geometric mean (%CV: geometric coefficient of variation) †From population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg) ‡From intensive PK analysis (n=10) Abbreviations: NA=not applicable; AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours Drug Interaction Studies DELSTRIGO is a complete regimen for the treatment of HIV-1 infection; therefore, DELSTRIGO is not recommended to be administered with other HIV-1 antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. The drug interaction trials described were conducted with doravirine, lamivudine and/or TDF, as single entities; no drug interaction trials have been conducted using the combination of doravirine, lamivudine, and TDF. No clinically relevant drug interactions were observed between doravirine, lamivudine, and TDF. 19 Reference ID: 5475884 Doravirine: Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (Cmax, AUC, and C24) of doravirine are summarized in Table 9. A single doravirine 100 mg dose was administered in these studies unless otherwise noted. Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug Co-administered Drug Regimen of Co- administered Drug N Geometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00) AUC Cmax C24 Azole Antifungal Agents ketoconazole† 400 mg QD 10 3.06 (2.85, 3.29) 1.25 (1.05, 1.49) 2.75 (2.54, 2.98) Antimycobacterials rifampin 600 mg QD 10 0.12 (0.10, 0.15) 0.43 (0.35, 0.52) 0.03 (0.02, 0.04) rifabutin 300 mg QD 12 0.50 (0.45, 0.55) 0.99 (0.85, 1.15) 0.32 (0.28, 0.35) 300 mg QD‡ 15 1.03 (0.94, 1.14) 0.97 (0.87, 1.08) 0.98 (0.88, 1.10) HIV Antiviral Agents ritonavir†,§ 100 mg BID 8 3.54 (3.04, 4.11) 1.31 (1.17, 1.46) 2.91 (2.33, 3.62) efavirenz 600 mg QD¶ 17 0.38 (0.33, 0.45) 0.65 (0.58, 0.73) 0.15 (0.10, 0.23) 600 mg QD# 17 0.68 (0.58, 0.80) 0.86 (0.77, 0.97) 0.50 (0.39, 0.64) CI = confidence interval; QD = once daily; BID = twice daily AUC0-∞ for single-dose, AUC0-24 for once daily. †Changes in doravirine pharmacokinetic values are not clinically relevant. ‡Doravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. §A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. ¶The first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. #14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, ritonavir, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. Lamivudine: Trimethoprim/Sulfamethoxazole: Co-administration of TMP/SMX with lamivudine resulted in an increase of 43% ±23% (mean ±SD) in lamivudine AUC∞, a decrease of 29% ±13% in lamivudine oral clearance, and a decrease of 30% ±36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by co-administration with lamivudine. 20 Reference ID: 5475884 Sorbitol (Excipient): Co-administration of lamivudine with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol resulted in dose-dependent decreases of 14%, 32%, and 36% in the AUC∞; and 28%, 52%, and 55% in the Cmax of lamivudine, respectively. TDF: No clinically significant changes in exposure were observed for tenofovir when co-administered with tacrolimus or entecavir. No clinically significant changes in exposure were observed for the following drugs when co-administered with tenofovir: tacrolimus, entecavir, methadone, or ethinyl estradiol/norgestimate. 12.4 Microbiology Mechanism of Action Doravirine: Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC50) of doravirine for RNA-dependent DNA polymerization of recombinant wild- type HIV-1 RT in a biochemical assay was 12.2±2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ. Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5´-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Lamivudine triphosphate (3TC-TP) is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ. TDF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral Activity in Cell Culture Doravirine: Doravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells and a median EC50 value for HIV-1 subtype B primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM. The antiviral activity of doravirine was not antagonistic when combined with lamivudine and TDF. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and peripheral blood mononuclear cells (PBMCs) using standard susceptibility assays. EC50 values were in the range of 3 to 15,000 nM (1,000 nM = 230 ng per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells. TDF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 21 Reference ID: 5475884 values for tenofovir were in the range of 40-8,500 nM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 500-2,200 nM). Resistance In Cell Culture Doravirine: Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, or F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. Lamivudine: Lamivudine-resistant variants of HIV-1 have been selected in cell culture and in participants treated with lamivudine. Genotypic analysis showed that substitutions M184I or V cause resistance to lamivudine. TDF: HIV-1 isolates selected by tenofovir in cell culture expressed a K65R substitution in HIV-1 RT and showed a 2–4 -fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir. In Clinical Trials Clinical Trial Results in Adults with No Antiretroviral Treatment History Doravirine: In the doravirine treatment arm of the DRIVE-AHEAD trial (n=364) through 96 weeks, 10 participants showed the emergence of doravirine resistance-associated substitutions among 24 (42%) participants in the resistance analysis subset (participants with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: V90V/G, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F, and Y318Y/S. Six of the 10 participants with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and all of them had a greater than 100-fold reduction in doravirine susceptibility (range >103 to >211). The other 4 virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364) through Week 96, 15 participants showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) participants in the resistance analysis subset. Lamivudine and TDF: In a pooled analysis of antiretroviral-naïve participants who received doravirine, lamivudine, and TDF, genotyping was performed on plasma HIV-1 isolates from all participants with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure or at time of early study drug discontinuation. Genotypic resistance developed in 8 evaluable participants who received DOR/3TC/TDF through Week 96. The resistance–associated substitutions that emerged were RT M41L (n=1), A62A/V (n=1), K65R (n=2), T69T/A (n=1), V75V/I (n=1), and M184V (n=5). In comparison, genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable participants who received EFV/FTC/TDF in DRIVE AHEAD; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or V (n=5), and K219K/E (n=1). Clinical Trial Results in Virologically-Suppressed Adults In the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2)], there were 6 participants in the immediate switch group (n=447) and 2 participants in the delayed switch group (n=209) who met the protocol-defined virologic failure criteria (confirmed HIV-1 RNA ≥ 50 copies/mL). Two of the 6 virologic failure participants in 22 Reference ID: 5475884 the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir during treatment with DELSTRIGO. One of the two virologic failure participants in the delayed switch group who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen. Cross-Resistance No significant cross-resistance has been demonstrated between doravirine-resistant HIV-1 variants and lamivudine/emtricitabine or tenofovir or between lamivudine or tenofovir-resistant variants and doravirine. Doravirine: Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the 6 virologic failure participants who developed doravirine phenotypic resistance, all had phenotypic resistance to efavirenz and nevirapine, 4 had phenotypic resistance to rilpivirine, and 4 had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure participants phenotypically resistant to efavirenz, 2 (18%) had decreased susceptibility to doravirine (18- and 36-fold). The treatment-emergent doravirine resistance-associated substitution Y318F did not confer reduced susceptibility to efavirenz, etravirine, or rilpivirine. A panel of 96 diverse clinical isolates containing NNRTI resistance-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine. Lamivudine: Cross-resistance has been observed among NRTIs. The M184I/V lamivudine resistance- associated substitution confers resistance to abacavir, didanosine and emtricitabine. Lamivudine also has reduced susceptibility against the K65R substitution. TDF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some patients living with HIV treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. The K70E substitution selected clinically by TDF results in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 isolates from patients (n=20) whose HIV-1 expressed a mean of 3 zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Participants whose virus expressed an RT L74V substitution without zidovudine resistance-associated substitutions (n=8) had reduced response to TDF. Limited data are available for patients whose virus expressed a Y115F substitution (n=3), Q151M substitution (n=2), or T69 insertion (n=4) in HIV-1 RT, all of whom had a reduced response in clinical trials. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Doravirine: Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the RHD. 23 Reference ID: 5475884 TDF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the RHD. At the high dose in female mice, liver adenomas were increased at exposures 16 times of that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the RHD. Mutagenesis Doravirine: Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. TDF: TDF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice. Impairment of Fertility Doravirine: There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to the highest dose tested. Systemic exposures (AUC) to doravirine were approximately 7 times the exposure in humans at the RHD. Lamivudine: In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring. TDF: There were no effects on fertility, mating performance or early embryonic development when TDF was administered to male rats at a dose equivalent to 10 times the RHD based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats. 14 CLINICAL STUDIES 14.1 Clinical Trial Results in Adults with No Antiretroviral Treatment History The efficacy of DELSTRIGO is based on the analyses of 96-week data from a randomized, multicenter, double-blind, active controlled Phase 3 trial (DRIVE-AHEAD, NCT02403674) in participants living with HIV with no antiretroviral treatment history (n=728). Participants were randomized and received at least 1 dose of either DELSTRIGO or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of participants was 31 years, 15% were female, 52% were Non-White, 3% had hepatitis B or C coinfection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm3; these characteristics were similar between treatment groups. Week 96 outcomes for DRIVE-AHEAD are provided in Table 10. Mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 238 and 223 cells/mm3, respectively. 24 Reference ID: 5475884 Table 10: Virologic Outcome in DRIVE-AHEAD at Week 96 in HIV-1 Adult Participants with No Antiretroviral Treatment History Outcome DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 HIV-1 RNA <50 copies/mL 77% 74% Treatment Difference (95% CI) 3.8% (-2.4%, 10.0%) HIV-1 RNA ≥ 50 copies/mL† 15% 12% No Virologic Data at Week 96 Window Discontinued study due to AE or Death‡ Discontinued study for Other Reasons§ On study but missing data in window 7% 3% 4% 1% 14% 8% 5% 1% Proportion (%) of Participants With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic Category Gender Male Female 78% (N = 305) 75% (N = 59) 73% (N = 311) 75% (N = 53) Race White Non-White 80% (N = 176) 76% (N = 188) 74% (N = 170) 74% (N = 194) Ethnicity¶ Hispanic or Latino Not Hispanic or Latino 81% (N = 126) 76% (N = 238) 77% (N = 119) 72% (N = 239) Baseline HIV-1 RNA (copies/mL) ≤100,000 copies/mL >100,000 copies/mL 80% (N = 291) 67% (N = 73) 77% (N = 282) 62% (N = 82) CD4+ T-cell Count (cells/mm3) ≤200 cells/mm3 >200 cells/mm3 59% (N = 44) 80% (N = 320) 70% (N = 46) 74% (N = 318) Viral Subtype¶ Subtype B Subtype Non-B 80% (N = 232) 73% (N = 130) 72% (N = 253) 77% (N = 111) The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. †Includes participants who discontinued study drug or study before Week 96 for lack or loss of efficacy and participants with HIV-1 RNA equal to or above 50 copies/mL in the Week 96 window. ‡Includes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 96 window. §Other reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by participant. ¶Does not include participants whose ethnicity or viral subtypes were unknown. 14.2 Clinical Trial Results in Virologically-Suppressed Adults The efficacy of switching from a baseline regimen consisting of two NRTIs in combination with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO was evaluated in a randomized, open-label trial (DRIVE-SHIFT, NCT02397096), in virologically-suppressed adults living with HIV. Participants must have been virologically-suppressed (HIV-1 RNA <50 copies/mL) on their baseline 25 Reference ID: 5475884 regimen for at least 6 months prior to trial entry, with no history of virologic failure. Participants were randomized to either switch to DELSTRIGO at baseline [n = 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to DELSTRIGO [n = 223, Delayed Switch Group (DSG)]. At baseline, the median age of participants was 43 years, 16% were female, and 24% were Non-White, 21% were of Hispanic or Latino ethnicity, 3% had hepatitis B and/or C virus co-infection, 17% had a history of AIDS, 96% had CD4+ T-cell count greater than or equal to 200 cells/mm3, 70% were on a regimen containing a PI plus ritonavir, 24% were on a regimen containing an NNRTI, 6% were on a regimen containing elvitegravir plus cobicistat, and 1% were on a regimen containing a PI plus cobicistat; these characteristics were similar between treatment groups. Virologic outcome results are shown in Table 11. Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Participants Who Switched to DELSTRIGO Outcome DELSTRIGO Once Daily ISG Week 48 N=447 Baseline Regimen DSG Week 24 N=223 HIV-1 RNA ≥ 50 copies/mL 2% 1% ISG-DSG, Difference (95% CI)†,‡ 0.7% (-1.3%, 2.6%) HIV-1 RNA <50 copies/mL 91% 95% No Virologic Data Within the Time Window Discontinued study due to AE or Death§ Discontinued study for Other Reasons¶ On study but missing data in window 8% 3% 4% 0 4% <1% 4% 0 Proportion (%) of Participants With HIV-1 RNA <50 copies/mL by Baseline and Demographic Category Age (years) <50 ≥50 90% (N = 320) 94% (N = 127) 95% (N = 157) 94% (N = 66) Gender Male Female 91% (N = 372) 91% (N = 75) 94% (N = 194) 100% (N = 29) Race White Non-White 90% (N = 344) 93% (N = 103) 95% (N = 168) 93% (N = 55) Ethnicity Hispanic or Latino Not Hispanic or Latino 88% (N = 99) 91% (N = 341) 91% (N = 45) 95% (N = 175) CD4+ T-cell Count (cells/mm3) <200 cells/mm3 ≥200 cells/mm3 85% (N = 13) 91% (N = 426) 75% (N = 4) 95% (N = 216) Baseline Regimen# PI plus either ritonavir or cobicistat 90% (N = 316) 94% (N = 156) 26 Reference ID: 5475884 I I elvitegravir plus cobicistat or NNRTI 93% (N = 131) 96% (N = 67) *Includes participants who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and participants with HIV-1 RNA ≥50 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG †The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. ‡Assessed using a non-inferiority margin of 4%. §Includes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window. ¶Other reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by participant. #Baseline Regimen = PI plus either ritonavir or cobicistat (specifically atazanavir, darunavir, or lopinavir), or elvitegravir plus cobicistat, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs. 14.3 Clinical Trial Results in Pediatric Participants The efficacy of DELSTRIGO was evaluated in cohort 2 of an open-label, single-arm 2-cohort trial in pediatric participants 12 to less than 18 years of age living with HIV (IMPAACT 2014 (Protocol 027), NCT03332095). In cohort 1, virologically-suppressed participants (n=9) received a single 100 mg dose of doravirine followed by intensive PK sampling. In cohort 2, virologically-suppressed participants (n=43) were switched to DELSTRIGO and treatment-naïve participants (n=2) were started on DELSTRIGO. In cohort 2, at baseline the median age of participants was 15 years (range: 12 to 17), the median weight was 52 kg (range: 45 to 80), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm3 (range 84 to 1397). After switching to DELSTRIGO, 95% (41/43) of virologically-suppressed participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naïve participants achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naïve participant met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir was detected. 16 HOW SUPPLIED/STORAGE AND HANDLING Each DELSTRIGO tablet contains 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil), is yellow, oval-shaped, film-coated, and is debossed with the corporate logo and 776 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-5007-01) and silica gel desiccants, and is closed with a child-resistant closure. Store DELSTRIGO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccants. Store DELSTRIGO at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Skin Reactions Inform patients that severe skin reactions including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with DELSTRIGO. Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking DELSTRIGO and seek medical attention if a painful rash with mucosal involvement develops [see Warnings and Precautions (5.1)]. 27 Reference ID: 5475884 Severe Acute Exacerbation of Hepatitis B in people with concomitant HIV-1 and HBV Inform patients that severe acute exacerbations of hepatitis B have been reported in people with concomitant HIV-1 and HBV who have discontinued lamivudine or TDF and may occur with discontinuation of DELSTRIGO [see Warnings and Precautions (5.2)]. Advise patients not to discontinue DELSTRIGO without first informing their healthcare provider. Drug Interactions Inform patients that DELSTRIGO may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7)]. For patients concomitantly receiving rifabutin, take one tablet of doravirine (PIFELTRO) 100 mg approximately 12 hours after the dose of DELSTRIGO [see Dosage and Administration (2.4)]. New Onset or Worsening Renal Impairment Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF. Advise patients to avoid DELSTRIGO with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDS) [see Warnings and Precautions (5.3)]. Bone Loss and Mineralization Defects Inform patients that decreases in bone mineral density have been observed with the use of TDF, a component of DELSTRIGO. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.5)]. Immune Reconstitution Syndrome Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.6)]. Dosing Instructions Advise patients to take DELSTRIGO every day at a regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance. If a patient forgets to take DELSTRIGO, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to DELSTRIGO [see Use in Specific Populations (8.1)]. Lactation Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. 28 Reference ID: 5475884 Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2018-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk1439a-t-XXXXr00X 29 Reference ID: 5475884 Patient Information DELSTRIGO® (del-STREE-go) (doravirine, lamivudine, and tenofovir disoproxil fumarate) tablets What is the most important information I should know about DELSTRIGO? DELSTRIGO can cause serious side effects, including: Worsening of hepatitis B virus infection (HBV). If you have Human Immunodeficiency Virus-1 (HIV-1) and HBV infection, your HBV infection may get worse (flare-up) if you stop taking DELSTRIGO. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Your healthcare provider will test you for HBV infection before you start treatment with DELSTRIGO. • Do not run out of DELSTRIGO. Refill your prescription or talk to your healthcare provider before your DELSTRIGO is all gone. • Do not stop taking DELSTRIGO without first talking to your healthcare provider. If you stop taking DELSTRIGO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking DELSTRIGO. For more information about side effects, see “What are the possible side effects of DELSTRIGO?” What is DELSTRIGO? DELSTRIGO is a prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults and children who weigh at least 77 pounds (35 kg): • who have not received HIV-1 medicines in the past, or • to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). DELSTRIGO contains the prescription medicines doravirine, lamivudine and tenofovir disoproxil fumarate. It is not known if DELSTRIGO is safe and effective in children who weigh less than 77 pounds (35 kg). Who should not take DELSTRIGO? Do not take DELSTRIGO if you take any of the following medicines: • carbamazepine • rifampin • oxcarbazepine • rifapentine • phenobarbital • mitotane • phenytoin • St. John’s wort • enzalutamide Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. If you have taken any of the medicines in the past 4 weeks, talk to your healthcare provider or pharmacist before starting treatment with DELSTRIGO. Do not take DELSTRIGO if you have ever had an allergic reaction to lamivudine. What should I tell my healthcare provider before treatment with DELSTRIGO? Before treatment with DELSTRIGO, tell your healthcare provider about all of your medical conditions, including if you: • have hepatitis B virus infection Reference ID: 5475884 • have kidney problems • have bone problems, including a history of bone fractures • are pregnant or plan to become pregnant. It is not known if DELSTRIGO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with DELSTRIGO. Pregnancy Registry: There is a pregnancy registry for people who take DELSTRIGO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. • are breastfeeding or plan to breastfeed. Two of the medicines in DELSTRIGO (lamivudine and tenofovir) can pass into your breast milk. Doravirine may pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with DELSTRIGO: o the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection. o the HIV-1 virus may become harder to treat if your baby has HIV-1 infection. o your baby may get side effects from DELSTRIGO. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. • Some medicines interact with DELSTRIGO. Keep a list of your medicines to show your healthcare provider and pharmacist. • Tell your healthcare provider if you have taken rifabutin in the past 4 weeks. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with DELSTRIGO. • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DELSTRIGO with other medicines. How should I take DELSTRIGO? • Take DELSTRIGO every day exactly as your healthcare provider tells you to take it. • Take DELSTRIGO 1 time each day, at about the same time every day. • DELSTRIGO is usually taken by itself (without other HIV-1 medicines). • If you take the medicine rifabutin during treatment with DELSTRIGO, your healthcare provider will also prescribe an additional dose of doravirine for you. You may not have enough doravirine in your blood if you take rifabutin during treatment with DELSTRIGO. Carefully follow your healthcare provider’s instructions about when to take doravirine and how much to take. This is usually 1 tablet of doravirine about 12 hours after your last dose of DELSTRIGO. • Take DELSTRIGO with or without food. • Do not change your dose or stop taking DELSTRIGO without talking to your healthcare provider. Stay under a healthcare provider’s care when taking DELSTRIGO. • It is important that you do not miss or skip doses of DELSTRIGO. • If you miss a dose of DELSTRIGO, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of DELSTRIGO at the same time. • If you have any questions, call your healthcare provider or pharmacist. • If you take too much DELSTRIGO, call your healthcare provider or go to the nearest hospital emergency room right away. • When your DELSTRIGO supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to DELSTRIGO and become harder to treat. Reference ID: 5475884 What are the possible side effects of DELSTRIGO? DELSTRIGO may cause serious side effects, including: • See “What is the most important information I should know about DELSTRIGO?” • Severe skin reactions have happened in people treated with DELSTRIGO. Call your healthcare provider right away if you develop a rash during treatment with DELSTRIGO. Stop taking DELSTRIGO and get medical help right away if you develop a painful rash with any of the following symptoms: fever, blisters or sores in the mouth, blisters or peeling of the skin, or redness or swelling of the eyes (conjunctivitis). • New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with DELSTRIGO. Your healthcare provider may tell you to stop taking DELSTRIGO if you develop new or worse kidney problems. • Bone problems can happen in some people who take DELSTRIGO. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones. Tell your healthcare provider if you have any of the following symptoms during treatment with DELSTRIGO: bone pain that does not go away or worsening bone pain, pain in your arms, legs, hands or feet, broken (fractured) bones, or muscle pain or weakness. These may be symptoms of a bone or kidney problem. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. The most common side effects of DELSTRIGO include dizziness, nausea, and abnormal dreams. These are not all of the possible side effects of DELSTRIGO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. How should I store DELSTRIGO? • Store DELSTRIGO tablets at room temperature between 68°F to 77°F (20°C to 25°C). • Keep DELSTRIGO in the original bottle. • Do not take the tablets out of the bottle to store in another container, such as a pill box. • Keep the bottle tightly closed to protect DELSTRIGO from moisture. • The DELSTRIGO bottle contains desiccants to help keep your medicine dry (protect it from moisture). Keep the desiccants in the bottle. Do not eat the desiccants. Keep DELSTRIGO and all medicines out of the reach of children. General information about the safe and effective use of DELSTRIGO. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use DELSTRIGO for a condition for which it was not prescribed. Do not give DELSTRIGO to other people, even if they have the same symptoms that you have. It may harm them. You can ask Reference ID: 5475884 your pharmacist or healthcare provider for information about DELSTRIGO that is written for healthcare professionals. What are the ingredients in DELSTRIGO? Active ingredients: doravirine, lamivudine, and tenofovir disoproxil fumarate. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating contains hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax. Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2018-XXXX Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. usppi-mk1439a-t-XXXXr00X For more information, go to www.DELSTRIGO.com or call 1-877-888-4231. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5475884	custom-source	2025-02-12T15:46:34.582782	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/210807s013lbl.pdf', 'application_number': 210807, 'submission_type': 'SUPPL ', 'submission_number': 13}
80,182	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PIFELTRO safely and effectively. See full prescribing information for PIFELTRO. PIFELTRO® (doravirine) tablets, for oral use Initial U.S. Approval: 2018 ---------------------------RECENT MAJOR CHANGES -------------------------- Warnings and Precautions, Severe Skin Reactions (5.1) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- PIFELTRO, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: • with no prior antiretroviral treatment history, OR • to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------------- • Recommended dosage: One tablet taken orally once daily with or without food in adults and pediatric patients weighing at least 35 kg. (2.1) • Dosage adjustment with rifabutin: One tablet taken twice daily (approximately 12 hours apart). (2.2) ---------------------DOSAGE FORMS AND STRENGTHS -------------------- • Tablets: 100 mg doravirine. (3) -------------------------------CONTRAINDICATIONS------------------------------ • PIFELTRO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO. (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens. Discontinue PIFELTRO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops, and closely monitor clinical status. (5.1) • Monitor for Immune Reconstitution Syndrome. (5.3) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (incidence greater than or equal to 5%, all grades) are nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . -------------------------------DRUG INTERACTIONS------------------------------ Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. (4, 5.2, 7) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Dosage Adjustment with Rifabutin 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Severe Skin Reactions 5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions 5.3 Immune Reconstitution Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on PIFELTRO 7.2 Effect of PIFELTRO on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Clinical Trial Results in Adults with No Antiretroviral Treatment History 14.2 Clinical Trial Results in Virologically-Suppressed Adults 14.3 Clinical Trial Results in Pediatric Participants 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5475856 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE PIFELTRO® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: • with no prior antiretroviral treatment history; OR • to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage regimen of PIFELTRO in adults and pediatric patients weighing at least 35 kg is one 100 mg tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)]. 2.2 Dosage Adjustment with Rifabutin If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart) for the duration of rifabutin co-administration [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS PIFELTRO film-coated tablets are white, oval-shaped tablets, debossed with the corporate logo and 700 on one side and plain on the other side. Each tablet contains 100 mg doravirine. 4 CONTRAINDICATIONS PIFELTRO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO [see Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. These drugs include, but are not limited to, the following: • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin • the androgen receptor inhibitor enzalutamide • the antimycobacterials rifampin, rifapentine • the cytotoxic agent mitotane • St. John’s wort (Hypericum perforatum) 5 WARNINGS AND PRECAUTIONS 5.1 Severe Skin Reactions Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens [see Adverse Reactions (6.2)]. Discontinue PIFELTRO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Clinical status should be closely monitored, and appropriate therapy should be initiated. 5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of PIFELTRO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of PIFELTRO and possible development of resistance [see Dosage and Administration (2.2), Contraindications (4) and Drug Interactions (7.1)]. 2 Reference ID: 5475856 See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PIFELTRO therapy, review concomitant medications during PIFELTRO therapy, and monitor for adverse reactions. 5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Immune Reconstitution Syndrome [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with No Antiretroviral Treatment History The safety assessment of PIFELTRO used in combination with other antiretroviral agents is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)). In DRIVE-FORWARD, 766 adult participants received either PIFELTRO 100 mg (n=383) or darunavir 800 mg + ritonavir 100 mg (DRV+r) (n=383) once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC). By Week 96, 2% in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication. In DRIVE-AHEAD, 728 adult participants received either DELSTRIGO [doravirine (DOR)/3TC/TDF] (n=364) or efavirenz (EFV)/FTC/TDF once daily (n=364). By Week 96, 3% in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication. Adverse reactions reported in greater than or equal to 5% of participants in any treatment group in DRIVE FORWARD and DRIVE-AHEAD are presented in Table 1. Table 1: Adverse Reactions (All Grades) Reported in ≥5%† of Participants in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96) DRIVE-FORWARD DRIVE-AHEAD PIFELTRO +2 NRTIs‡ Once Daily N=383 DRV+r +2 NRTIs‡ Once Daily N=383 DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Nausea 7% 8% 5% 7% 3 Reference ID: 5475856 Headache 6% 3% 4% 5% Fatigue 6% 3% 4% 4% Diarrhea 6% 13% 4% 6% Abdominal Pain 5% 2% 1% 2% Dizziness 3% 2% 7% 32% Rash 2% 3% 2% 12% Abnormal Dreams 1% <1% 5% 10% Insomnia 1% 2% 4% 5% Somnolence 0% <1% 3% 7% Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. †No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥ 2% of participants treated with doravirine. ‡NRTI = nucleoside reverse transcriptase inhibitor. NRTIs = FTC/TDF or ABC/3TC. Fatigue: includes fatigue, asthenia, malaise Abdominal Pain: includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort Rash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular The majority (77%) of adverse reactions associated with doravirine occurred at severity Grade 1 (mild). Neuropsychiatric Adverse Events For DRIVE-AHEAD, the analysis of participants with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of participants who reported one or more neuropsychiatric adverse events was 24% and 57% in the DELSTRIGO and EFV/FTC/TDF groups, respectively. A statistically significantly lower proportion of DELSTRIGO-treated participants compared to EFV/FTC/TDF-treated participants reported neuropsychiatric adverse events by Week 48 in the three pre specified categories of dizziness, sleep disorders and disturbances, and altered sensorium. Table 2: DRIVE-AHEAD - Analysis of Participants with Neuropsychiatric Adverse Events (Week 48) DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Treatment Difference DELSTRIGO - EFV/FTC/TDF Estimate (95% CI)† Sleep disorders and disturbances‡ 12% 26% -13.5 (-19.1, -7.9) Dizziness 9% 37% -28.3 (-34.0, -22.5) Altered sensorium§ 4% 8% -3.8 (-7.6, -0.3) All causality and all grade events were included in the analysis. †The 95% CIs were calculated using Miettinen and Nurminen's method. Categories pre-specified for statistical testing were dizziness (p <0.001), sleep disorders and disturbances (p <0.001), and altered sensorium (p=0.033). ‡Predefined using MedDRA preferred terms, including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism. §Predefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, syncope. 4 Reference ID: 5475856 Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of participants, in the DELSTRIGO and EFV/FTC/TDF groups, respectively. In DRIVE-AHEAD through 48 weeks of treatment, the majority of participants who reported neuropsychiatric adverse events reported events that were mild to moderate in severity (97% [83/86] and 96% [198/207], in the DELSTRIGO and EFV/FTC/TDF groups, respectively) and the majority of participants reported these events in the first 4 weeks of treatment (72% [62/86] in the DELSTRIGO group and 86% [177/207] in the EFV/FTC/TDF group). Neuropsychiatric adverse events led to treatment discontinuation in 1% (2/364) and 1% (5/364) of participants in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of participants who reported neuropsychiatric adverse events through Week 4 was 17% (62/364) in the DELSTRIGO group and 49% (177/364) in the EFV/FTC/TDF group. At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. At Week 96, the prevalence of neuropsychiatric adverse events was 13% (47/364) in the DELSTRIGO group and 23% (82/364) in the EFV/FTC/TDF group. Laboratory Abnormalities The percentages of participants with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with PIFELTRO or DRV+r in DRIVE-FORWARD, or DELSTRIGO or EFV/FTC/TDF in DRIVE-AHEAD are presented in Table 3. Table 3: Selected Laboratory Abnormalities Reported in Adult Participants with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96) DRIVE-FORWARD DRIVE-AHEAD Laboratory Parameter Preferred Term (Unit)/Limit PIFELTRO +2 NRTIs Once Daily N=383 DRV+r +2 NRTIs Once Daily N=383 DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Blood Chemistry Total bilirubin (mg/dL) 1.1 - < 1.6 x ULN 1.6 - <2.6 x ULN ≥2.6 x ULN 6% 2% <1% 2% <1% 0% 5% 2% 1% 0% 0% <1% Creatinine (mg/dL) >1.3 - 1.8 x ULN or Increase of >0.3 mg/dL above baseline >1.8 x ULN or Increase of ≥1.5 x above baseline 4% 4% 6% 4% 3% 3% 2% 2% Aspartate aminotransferase (IU/L) 2.5 - <5.0 x ULN ≥5.0 x ULN 5% 2% 4% 2% 3% 1% 3% 4% Alanine aminotransferase (IU/L) 2.5 - <5.0 x ULN ≥5.0 x ULN 4% 2% 2% 3% 4% 1% 4% 3% Alkaline phosphatase (IU/L) 2.5 - <5.0 x ULN ≥5.0 x ULN <1% 0% 1% <1% <1% 0% 1% <1% Lipase 1.5 - <3.0 x ULN ≥3.0 x ULN 7% 3% 6% 4% 6% 2% 4% 3% Creatine kinase (IU/L) 6.0 - <10.0 x ULN ≥10.0 x ULN 3% 5% 3% 6% 3% 4% 3% 6% Cholesterol, fasted (mg/dL) ≥300 mg/dL 0% 1% 1% <1% LDL cholesterol, fasted (mg/dL) ≥190 mg/dL <1% 4% <1% 2% 5 Reference ID: 5475856 I I I I Triglycerides, fasted (mg/dL) >500 mg/dL 1% 2% 1% 3% Each participant is only counted once per parameter at the highest toxicity grade. Only participants with a baseline value and at least one on-treatment value for a given laboratory parameter are included. ULN = Upper limit of normal range. Note: NRTIs = FTC/TDF or ABC/3TC. Change in Lipids from Baseline For DRIVE-FORWARD and DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. Changes from baseline at Week 96 were similar to those seen at Week 48. The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority for doravirine for both parameters. The clinical benefit of these findings has not been demonstrated. Table 4: Mean Change from Baseline in Fasting Lipids in Adult Participants with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48) DRIVE-FORWARD PIFELTRO +2 NRTIs Once Daily N=320 DRV+r +2 NRTIs Once Daily N=311 Laboratory Parameter Preferred Term Baseline Change Baseline Change Difference Estimates (95% CI) LDL-Cholesterol (mg/dL) 91.4 -4.6 92.3 9.5 -14.4 (-18.0, -10.8) Non-HDL Cholesterol (mg/dL)* 113.6 -5.4 114.5 13.7 -19.4 (-23.4, -15.4) Total Cholesterol (mg/dL)† 157.2 -1.4 157.8 18.0 - Triglycerides (mg/dL)† 111.0 -3.1 113.7 24.5 - HDL-Cholesterol (mg/dL)† 43.6 4.0 43.3 4.3 - DRIVE-AHEAD DELSTRIGO Once Daily N=320 EFV/FTC/TDF Once Daily N=307 Laboratory Parameter Preferred Term Baseline Change Baseline Change Difference Estimates (95% CI) LDL-Cholesterol (mg/dL)* 91.7 -2.1 91.3 8.3 -10.2 (-13.8, -6.7) Non-HDL Cholesterol (mg/dL)* 114.7 -4.1 115.3 12.7 -16.9 (-20.8, -13.0) Total Cholesterol (mg/dL)† 156.8 -2.2 156.8 21.1 - Triglycerides (mg/dL)† 118.7 -12.0 122.6 21.6 - HDL-Cholesterol (mg/dL)† 42.1 1.8 41.6 8.4 - Participants on lipid-lowering agents at baseline were excluded from these analyses (in DRIVE-FORWARD: PIFELTRO n=12 and DRV+r n=14; in DRIVE-AHEAD: DELSTRIGO n=15 and EFV/FTC/TDF n=10). Participants initiating a lipid-lowering agent post- baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (in DRIVE-FORWARD: PIFELTRO n=6 and DRV+r n=4; in DRIVE-AHEAD: DELSTRIGO n=3 and EFV/FTC/TDF n=8). p-values for the pre-specified hypothesis testing for treatment difference were <0.0001 in both DRIVE-FORWARD and DRIVE AHEAD. †Not pre-specified for hypothesis testing. 6 Reference ID: 5475856 Adverse Reactions in Virologically-Suppressed Adults The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from 670 participants in the DRIVE-SHIFT trial (Protocol 024), a randomized, international, multicenter, open-label trial in which virologically-suppressed participants were switched from a baseline regimen consisting of two NRTIs in combination with a protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or a non-nucleoside reverse transcriptase inhibitor (NNRTI) to DELSTRIGO. Overall, the safety profile in virologically-suppressed adult participants was similar to that in participants with no antiretroviral treatment history. Laboratory Abnormalities Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of participants in the immediate switch group experienced ALT and AST elevations greater than 1.25 X ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent patterns with regard to time to onset relative to switch were observed. One percent of participants had ALT or AST elevations greater than 5 X ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic and not associated with bilirubin elevations. In comparison, 4% and 4% of participants in the delayed switch group experienced ALT and AST elevations of greater than 1.25 X ULN through 24 weeks on their baseline regimen. Change in Lipids from Baseline Changes from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in participants on a PI plus ritonavir-based regimen at baseline are shown in Table 5. The LDL and non-HDL comparisons were pre-specified, and the differences were statistically significant, showing superiority for an immediate switch to DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated. Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Participants on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24) Laboratory Parameter Preferred Term DELSTRIGO (Week 0-24) Once Daily N=244 PI+ritonavir (Week 0-24) Once Daily N=124 Difference Estimates Baseline Change Baseline Change Difference (95% CI) LDL-Cholesterol (mg/dL) 108.7 -16.3 110.5 -2.6 -14.5 (-18.9, -10.1) Non-HDL Cholesterol (mg/dL)* 138.6 -24.8 138.8 -2.1 -22.8 (-27.9, -17.7) Total Cholesterol (mg/dL)† 188.5 -26.1 187.4 -0.2 - Triglycerides (mg/dL)† 153.1 -44.4 151.4 -0.4 - HDL-Cholesterol (mg/dL)† 50.0 -1.3 48.5 1.9 - Participants on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13). Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=4 and PI+ritonavir n=2). p-value for the pre-specified hypothesis testing for treatment difference was <0.0001. †Not pre-specified for hypothesis testing. Adverse Reactions in Pediatric Participants The safety of doravirine as a component of DELSTRIGO was evaluated in 45 virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age living with HIV through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) [see Clinical Studies (14.3)]. The safety profile in pediatric participants was similar to that in adults. There were no serious or Grade 3 or 4 adverse reactions. No participants discontinued due to an adverse event. 7 Reference ID: 5475856 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving doravirine-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on PIFELTRO Co-administration of PIFELTRO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce PIFELTRO efficacy [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)]. Co-administration of PIFELTRO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. Table 6 shows significant drug interactions with PIFELTRO. Table 6: Drug Interactions with PIFELTRO Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Androgen Receptors enzalutamide ↓ doravirine Co-administration is contraindicated with enzalutamide. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin ↓ doravirine Co-administration is contraindicated with these anticonvulsants. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. Antimycobacterials rifampin† rifapentine ↓ doravirine Co-administration is contraindicated with rifampin or rifapentine. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. rifabutin† ↓ doravirine Increase PIFELTRO dosage to one tablet twice daily when co-administered with rifabutin [see Dosage and Administration (2.2)]. Cytotoxic Agents mitotane ↓ doravirine Co-administration is contraindicated with mitotane. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. HIV Antiviral Agents efavirenz† etravirine nevirapine ↓ doravirine Use with efavirenz, etravirine, or nevirapine is not recommended. Herbal Products St. John’s wort ↓ doravirine Co-administration is contraindicated with St. John’s wort. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. ↑ = increase, ↓ = decrease This table is not all inclusive. †The interaction between PIFELTRO and the concomitant drug was evaluated in a clinical study. All other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways. 8 Reference ID: 5475856 No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone [see Clinical Pharmacology (12.3)]. 7.2 Effect of PIFELTRO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co- administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary No adequate human data are available to establish whether or not PIFELTRO poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures ≥8 times the exposure in humans at the recommended human dose (RHD) of PIFELTRO (see Data). The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Data Animal Data Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo- fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20. 8.2 Lactation Risk Summary It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Doravirine is present in the milk of lactating rats (see Data). Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant in a breastfed infant similar to those seen in adults. 9 Reference ID: 5475856 --- Data Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from GD 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14. 8.4 Pediatric Use The safety and efficacy of PIFELTRO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg [see Indications and Usage (1) and Dosage and Administration (2.1)]. Use of PIFELTRO in this group is supported by evidence from adequate and well-controlled trials in adults and an open-label trial in virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age. The safety, efficacy, and exposure of doravirine in these pediatric participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)]. Safety and efficacy of PIFELTRO in pediatric patients weighing less than 35 kg have not been established. 8.5 Geriatric Use Clinical trials of PIFELTRO did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants. In general, caution should be exercised in the administration of PIFELTRO in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No dosage adjustment of PIFELTRO is required in patients with mild, moderate, or severe renal impairment. PIFELTRO has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of PIFELTRO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PIFELTRO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION PIFELTRO is a film-coated tablet containing doravirine for oral administration. Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Each tablet contains 100 mg of doravirine as the active ingredient. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film coated with a coating material containing the following inactive ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax. The chemical name for doravirine is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3 yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile. It has a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75. It has the following structural formula: 10 Reference ID: 5475856 Doravirine is practically insoluble in water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doravirine is an antiretroviral drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of PIFELTRO, (in combination with FTC/TDF) in participants living with HIV with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Cardiac Electrophysiology At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of PIFELTRO, doravirine does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Doravirine pharmacokinetics are similar in healthy participants and participants living with HIV. Doravirine pharmacokinetics are provided in Table 7. Table 7: Pharmacokinetic Properties of Doravirine Parameter Doravirine General Steady State Exposure,† AUC0-24 (mcg•h/mL) 16.1 (29) Cmax (mcg/mL) 0.962 (19) C24 (mcg/mL) 0.396 (63) Time to Steady State (Days) 2 Accumulation Ratio 1.2 to 1.4 Absorption Absolute Bioavailability 64% Tmax (h) 2 Effect of Food‡ AUC Ratio 1.16 (1.06, 1.26) Cmax Ratio 1.03 (0.89, 1.19) C24 Ratio 1.36 (1.19, 1.55) Distribution Vdss (L)§ 60.5 Plasma Protein Binding 76% 11 Reference ID: 5475856 Elimination t1/2 (h) 15 CL/F (mL/min)† 106 (35.2) CLrenal (mL/min)† 9.3 (18.6) Metabolism Primary Pathway(s) CYP3A Excretion Major Route of Elimination Metabolism Urine (unchanged) 6% Biliary/Fecal (unchanged) Minor Doravirine 100 mg once daily to participants living with HIV †Presented as geometric mean (%CV: geometric coefficient of variation) ‡Geometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1,000 kcal, 50% fat. The effect of food is not clinically relevant. §Based on IV dose Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax time to Cmax; Vdss= volume of distribution at steady state, t1/2=elimination half-life; CL/F=apparent clearance; CLrenal=apparent renal clearance Specific Populations In adults, no clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, or severe hepatic impairment (Child-Pugh C) is unknown. Patients with Renal Impairment In a study comparing 8 participants with severe renal impairment to 8 participants without renal impairment, the single dose exposure of doravirine was 43% higher in participants with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis [see Use in Specific Populations (8.6)]. Patients with Hepatic Impairment No clinically significant difference in the pharmacokinetics of doravirine was observed in participants with moderate hepatic impairment (Child-Pugh score B) compared to participants without hepatic impairment. Doravirine has not been studied in participants with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7)]. Pediatric Patients Mean doravirine exposures were similar in 54 pediatric participants aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO (Table 8). For pediatric participants weighing ≥ 35 kg and < 45 kg who received doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0 24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0-24 and Cmax increases are not considered clinically significant. 12 Reference ID: 5475856 Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in Pediatric Participants Living with HIV Aged 12 to Less than 18 Years and Weighing at Least 35 kg Parameter Doravirine† AUC0-24 (mcg•h/mL) 16.4 (24) Cmax (mcg/mL) 1.03 (16) C24 (mcg/mL) 0.379 (42) Presented as geometric mean (%CV: geometric coefficient of variation) †From population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg) Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours Drug Interaction Studies Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (Cmax, AUC, and C24) of doravirine are summarized in Table 9. A single doravirine 100 mg dose was administered in these studies unless otherwise noted. Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug Co-administered Drug Regimen of Co- administered Drug N Geometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00) AUC Cmax C24 Azole Antifungal Agents ketoconazole† 400 mg QD 10 3.06 (2.85, 3.29) 1.25 (1.05, 1.49) 2.75 (2.54, 2.98) Antimycobacterials rifampin 600 mg QD 10 0.12 (0.10, 0.15) 0.43 (0.35, 0.52) 0.03 (0.02, 0.04) rifabutin 300 mg QD 12 0.50 (0.45, 0.55) 0.99 (0.85, 1.15) 0.32 (0.28, 0.35) 300 mg QD‡ 15 1.03 (0.94, 1.14) 0.97 (0.87, 1.08) 0.98 (0.88, 1.10) HIV Antiviral Agents ritonavir†,§ 100 mg BID 8 3.54 (3.04, 4.11) 1.31 (1.17, 1.46) 2.91 (2.33, 3.62) efavirenz 600 mg QD¶ 17 0.38 (0.33, 0.45) 0.65 (0.58, 0.73) 0.15 (0.10, 0.23) 600 mg QD# 17 0.68 (0.58, 0.80) 0.86 (0.77, 0.97) 0.50 (0.39, 0.64) CI = confidence interval; QD = once daily; BID = twice daily AUC0-∞ for single-dose, AUC0-24 for once daily. †Changes in doravirine pharmacokinetic values are not clinically relevant. ‡Doravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. §A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. ¶The first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. #14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 13 Reference ID: 5475856 Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, ritonavir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. 12.4 Microbiology Mechanism of Action Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC50) of doravirine for RNA-dependent DNA polymerization of recombinant wild- type HIV-1 RT in a biochemical assay was 12.2±2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral Activity in Cell Culture Doravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells and a median EC50 value for HIV-1 subtype B primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM. Antiviral Activity in Combination with other HIV Antiviral Agents The antiviral activity of doravirine in cell culture was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4 fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, or F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. In Clinical Trials Clinical Trial Results in Adults with No Antiretroviral Treatment History In the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747) through Week 96, 13 participants showed the emergence of doravirine resistance-associated substitutions in their HIV among 36 (36%) participants in the resistance analysis subset (participants with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: V90G/I, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F and Y318Y/S. Eight of 13 (62%) participants with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and most of them had at least a 100-fold reduction in doravirine susceptibility (range >95- to >211–fold reduction in doravirine susceptibility). The other 5 virologic failures who had only amino acid mixtures of NNRTI resistance 14 Reference ID: 5475856 substitutions showed doravirine phenotypic fold-changes of less than 2-fold. Of the 36 participants in the resistance analysis subset, 10 participants (28%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, emtricitabine, lamivudine, or tenofovir) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials. The resistance-associated substitutions that emerged were RT M41L (n=1), A62A/V (n=1), K65R (n=2), T69T/A (n=1), V75V/I (n=1), and M184I or V (n=7). In the DRV/r treatment arm of the DRIVE-FORWARD trial (n=383) through Week 96, no participants showed the emergence of darunavir resistance-associated substitutions among 15 participants with resistance data and 2 of the participants had emergent genotypic or phenotypic resistance to lamivudine or tenofovir. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364) through Week 96, 15 participants showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) participants in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable participants; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or V (n=5), and K219K/E (n=1). Clinical Trial Results in Virologically-Suppressed Adults In the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2)], there were 6 participants in the immediate switch group (n=447) and 2 participants in the delayed switch group (n=209) who met the protocol-defined virologic failure criteria (confirmed HIV-1 RNA ≥ 50 copies/mL). Two of the 6 virologic failure participants in the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir during treatment with DELSTRIGO. One of the two virologic failure participants in the delayed switch group who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen. Cross-Resistance Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance- associated substitutions can confer cross-resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the 8 virologic failure participants who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 4 had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure participants in DRIVE-AHEAD phenotypically resistant to efavirenz, 2 (18%) had decreased susceptibility to doravirine (18- and 36-fold). The treatment-emergent doravirine resistance-associated substitution Y318F did not confer reduced susceptibility to efavirenz, etravirine, or rilpivirine. A panel of 96 diverse clinical isolates containing NNRTI resistance-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. 15 Reference ID: 5475856 Mutagenesis Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. Impairment of fertility There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD. 14 CLINICAL STUDIES 14.1 Clinical Trial Results in Adults with No Antiretroviral Treatment History The efficacy of PIFELTRO is based on the analyses of 96-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials (DRIVE-FORWARD, NCT02275780 and DRIVE-AHEAD, NCT02403674) in participants living with HIV with no antiretroviral treatment history (n=1494). In DRIVE-FORWARD, 766 participants were randomized and received at least 1 dose of either PIFELTRO once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of participants was 33 years, 16% were female, 27% were Non-White, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC, and 87% received FTC/TDF; these characteristics were similar between treatment groups. In DRIVE-AHEAD, 728 participants were randomized and received at least 1 dose of either DELSTRIGO (DOR/3TC/TDF) or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of participants was 31 years, 15% were female, 52% were Non-White, 3% had hepatitis B or C co-infection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T- cell count greater than 200 cells/mm3; these characteristics were similar between treatment groups. Week 96 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 10. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. In DRIVE-FORWARD, the mean CD4+ T-cell counts in the PIFELTRO and DRV+r groups increased from baseline by 224 and 207 cells/mm3, respectively. In DRIVE-AHEAD, the mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 238 and 223 cells/mm3, respectively. 16 Reference ID: 5475856 Table 10: Virologic Outcome in DRIVE-FORWARD and DRIVE-AHEAD at Week 96 in HIV-1 Adults with No Antiretroviral Treatment History Outcome DRIVE-FORWARD DRIVE-AHEAD PIFELTRO + 2 NRTIs Once Daily N=383 DRV+r + 2 NRTIs Once Daily N=383 DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 HIV-1 RNA <50 copies/mL 72% 65% 77% 74% Treatment Differences (95% CI) 7.5% (1.0%, 14.1%) 3.8% (-2.4%, 10.0%) HIV-1 RNA ≥ 50 copies/mL† 17% 20% 15% 12% No Virologic Data at Week 96 Window Discontinued study due to AE or Death‡ Discontinued study for Other Reasons§ On study but missing data in window 11% 2% 7% 2% 15% 4% 9% 3% 7% 3% 4% 1% 14% 8% 5% 1% Proportion (%) of Participants With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic Category Gender Male Female 72% (N = 319) 73% (N = 64) 67% (N = 326) 54% (N = 57) 78% (N = 305) 75% (N = 59) 73% (N = 311) 75% (N = 53) Race White Non-White 78% (N = 280) 58% (N = 103) 68% (N = 280) 57% (N = 102) 80% (N = 176) 76% (N = 188) 74% (N = 170) 74% (N = 194) Ethnicity¶ Hispanic or Latino Not Hispanic or Latino 76% (N = 93) 71% (N = 284) 63% (N = 86) 66% (N = 290) 81% (N = 126) 76% (N = 238) 77% (N = 119) 72% (N = 239) NRTI Background Therapy FTC/TDF ABC/3TC 71% (N = 333) 80% (N = 50) 64% (N = 335) 67% (N = 48) - - - - Baseline HIV-1 RNA (copies/mL) ≤100,000 copies/mL >100,000 copies/mL 75% (N = 300) 61% (N = 83) 66% (N = 309) 59% (N = 73) 80% (N = 291) 67% (N = 73) 77% (N = 282) 62% (N = 82) CD4+ T-cell Count (cells/mm3) ≤200 cells/mm3 >200 cells/mm3 62% (N = 42) 74% (N = 341) 51% (N = 67) 68% (N = 316) 59% (N = 44) 80% (N = 320) 70% (N = 46) 74% (N = 318) Viral Subtype¶ Subtype B Subtype Non-B 71% (N = 266) 75% (N = 117) 66% (N = 272) 62% (N = 111) 80% (N = 232) 73% (N = 130) 72% (N = 253) 77% (N = 111) The 95% CIs for the treatment differences were calculated using stratum-adjusted Mantel-Haenszel method. †Includes participants who discontinued study drug or study before Week 96 for lack or loss of efficacy and participants with HIV-1 RNA equal to or above 50 copies/mL in the Week 96 window. ‡Includes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 96 window. §Other Reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by participant. ¶Does not include participants whose ethnicity or viral subtypes were unknown. 17 Reference ID: 5475856 Note: NRTIs = FTC/3TC or ABC/3TC. 14.2 Clinical Trial Results in Virologically-Suppressed Adults The efficacy of switching from a baseline regimen consisting of two NRTIs in combination with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO was evaluated in a randomized, open-label trial (DRIVE-SHIFT, NCT02397096), in virologically-suppressed adults living with HIV. Participants must have been virologically-suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure. Participants were randomized to either switch to DELSTRIGO at baseline (n = 447, Immediate Switch Group (ISG)), or stay on their baseline regimen until Week 24, at which point they switched to DELSTRIGO (n = 223, Delayed Switch Group (DSG)). At baseline, the median age of participants was 43 years, 16% were female, and 24% were Non-White, 21% were of Hispanic or Latino ethnicity, 3% had hepatitis B and/or C virus co-infection, 17% had a history of AIDS, 96% had CD4+ T-cell count greater than or equal to 200 cells/mm3, 70% were on a regimen containing a PI plus ritonavir, 24% were on a regimen containing an NNRTI, 6% were on a regimen containing elvitegravir plus cobicistat, and 1% were on a regimen containing a PI plus cobicistat; these characteristics were similar between treatment groups. Virologic outcome results are shown in Table 11. Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Participants Who Switched to DELSTRIGO Outcome DELSTRIGO Once Daily ISG Week 48 N=447 Baseline Regimen DSG Week 24 N=223 HIV-1 RNA ≥ 50 copies/mL 2% 1% ISG-DSG, Difference (95% CI) †,‡ 0.7% (-1.3%, 2.6%) HIV-1 RNA <50 copies/mL 91% 95% No Virologic Data Within the Time Window Discontinued study due to AE or Death§ Discontinued study for Other Reasons¶ On study but missing data in window 8% 3% 4% 0 4% <1% 4% 0 Proportion (%) of Participants With HIV-1 RNA <50 copies/mL by Baseline and Demographic Category Age (years) < 50 ≥ 50 Gender Male Female 90% (N = 320) 94% (N = 127) 91% (N = 372) 91% (N = 75) 95% (N = 157) 94% (N = 66) 94% (N = 194) 100% (N = 29) Race White Non-White 90% (N = 344) 93% (N = 103) 95% (N = 168) 93% (N = 55) Ethnicity Hispanic or Latino Not Hispanic or Latino 88% (N = 99) 91% (N = 341) 91% (N = 45) 95% (N = 175) 18 Reference ID: 5475856 CD4+ T-cell Count (cells/mm3) <200 cells/mm3 ≥200 cells/mm3 85% (N = 13) 91% (N = 426) 75% (N = 4) 95% (N = 216) Baseline Regimen# PI plus either ritonavir or cobicistat elvitegravir plus cobicistat or NNRTI 90% (N=316) 93% (N=131) 94% (N=156) 96% (N=67) *Includes participants who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and participants with HIV-1 RNA ≥50 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG. †The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. ‡Assessed using a non-inferiority margin of 4%. §Includes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window. ¶Other reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by participant. #Baseline Regimen = PI plus either ritonavir or cobicistat (specifically atazanavir, darunavir, or lopinavir), or elvitegravir plus cobicistat, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs. 14.3 Clinical Trial Results in Pediatric Participants The efficacy of DELSTRIGO (DOR/3TC/TDF) was evaluated in cohort 2 of an open-label, single-arm 2 cohort trial in pediatric participants 12 to less than 18 years of age living with HIV (IMPAACT 2014 (Protocol 027), NCT03332095). In cohort 1, virologically-suppressed participants (n=9) received a single 100 mg dose of PIFELTRO followed by intensive PK sampling. In cohort 2, virologically-suppressed participants (n=43) were switched to DELSTRIGO and treatment-naïve participants (n=2) were started on DELSTRIGO. In cohort 2, at baseline the median age of participants was 15 years (range: 12 to 17), the median weight was 52 kg (range: 45 to 80), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm3 (range 84 to 1397). After switching to DELSTRIGO, 95% (41/43) of virologically-suppressed participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naïve participants achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naïve participant met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir was detected. 16 HOW SUPPLIED/STORAGE AND HANDLING Each PIFELTRO tablet contains 100 mg of doravirine, is white, oval-shaped and film-coated, and is debossed with the corporate logo and 700 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-3069-01) with silica gel desiccant and is closed with a child-resistant closure. Store PIFELTRO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. Store PIFELTRO at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). 19 Reference ID: 5475856 Severe Skin Reactions Inform patients that severe skin reactions including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with PIFELTRO. Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking PIFELTRO and seek medical attention if a painful rash with mucosal involvement develops [see Warnings and Precautions (5.1)]. Drug Interactions Inform patients that PIFELTRO may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort [see Contraindications (4), Warnings and Precautions (5.2), and Drug Interactions (7.1)]. For patients concomitantly receiving rifabutin, take one tablet of PIFELTRO twice daily (approximately 12 hours apart) [see Dosage and Administration (2.2)]. Immune Reconstitution Syndrome Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.3)]. Dosing Instructions Advise patients to take PIFELTRO every day at a regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance. If a patient forgets to take PIFELTRO, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to PIFELTRO [see Use in Specific Populations (8.1)]. Lactation Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1– positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2018-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk1439-t-XXXXr00X 20 Reference ID: 5475856 Patient Information PIFELTRO® (pih-FEL-tro) (doravirine) tablets What is PIFELTRO? PIFELTRO is a prescription medicine that is used together with other HIV-1 medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and children who weigh at least 77 pounds (35 kg): • who have not received HIV-1 medicines in the past, or • to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if PIFELTRO is safe and effective in children who weigh less than 77 pounds (35 kg). Who should not take PIFELTRO? Do not take PIFELTRO if you take any of the following medicines: • carbamazepine • rifampin • oxcarbazepine • rifapentine • phenobarbital • mitotane • phenytoin • St. John’s wort • enzalutamide Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. If you have taken any of the medicines in the past 4 weeks, talk to your healthcare provider or pharmacist before starting treatment with PIFELTRO. What should I tell my healthcare provider before treatment with PIFELTRO? Before treatment with PIFELTRO, tell your healthcare provider about all of your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if PIFELTRO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with PIFELTRO. Pregnancy Registry: There is a pregnancy registry for people who take PIFELTRO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. • are breastfeeding or plan to breastfeed. PIFELTRO may pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with PIFELTRO: o the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection. o the HIV-1 virus may become harder to treat if your baby has HIV-1 infection. o your baby may get side effects from PIFELTRO. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. • Some medicines interact with PIFELTRO. Keep a list of your medicines to show your healthcare provider and pharmacist. • Tell your healthcare provider if you have taken rifabutin in the past 4 weeks. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with PIFELTRO. Reference ID: 5475856 • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take PIFELTRO with other medicines. How do I take PIFELTRO? • Take PIFELTRO every day exactly as your healthcare provider tells you to take it. • Take PIFELTRO 1 time each day, at about the same time every day. • If you take the medicine rifabutin during treatment with PIFELTRO, take PIFELTRO 2 times each day, about 12 hours apart, as prescribed by your healthcare provider. You may not have enough doravirine in your blood if you take rifabutin during treatment with PIFELTRO. • Take PIFELTRO with or without food. • Do not change your dose or stop taking PIFELTRO without talking to your healthcare provider. Stay under a healthcare provider’s care when taking PIFELTRO. • It is important that you do not miss or skip doses of PIFELTRO. • If you miss a dose of PIFELTRO, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of PIFELTRO at the same time. • If you have any questions, call your healthcare provider or pharmacist. • When your PIFELTRO supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to PIFELTRO and become harder to treat. What are the possible side effects of PIFELTRO? PIFELTRO can cause serious side effects, including: • Severe skin reactions have happened in people treated with PIFELTRO. Call your healthcare provider right away if you develop a rash during treatment with PIFELTRO. Stop taking PIFELTRO and get medical help right away if you develop a painful rash with any of the following symptoms: fever, blisters or sores in the mouth, blisters or peeling of the skin, or redness or swelling of the eyes (conjunctivitis). • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. The most common side effects of PIFELTRO include: • nausea • diarrhea • dizziness • stomach (abdominal) pain • headache • abnormal dreams • tiredness These are not all of the possible side effects of PIFELTRO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. How should I store PIFELTRO? • Store PIFELTRO tablets at room temperature between 68°F to 77°F (20°C to 25°C). • Keep PIFELTRO in the original bottle. • Do not take the tablets out of the bottle to store in another container, such as a pill box. Reference ID: 5475856 • Keep the bottle tightly closed to protect PIFELTRO from moisture. • The PIFELTRO bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant. Keep PIFELTRO and all medicines out of the reach of children. General information about the safe and effective use of PIFELTRO. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PIFELTRO for a condition for which it was not prescribed. Do not give PIFELTRO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PIFELTRO that is written for healthcare professionals. What are the ingredients in PIFELTRO? Active ingredient: doravirine. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet film coating contains hypromellose, lactose monohydrate, titanium dioxide and triacetin. The coated tablets are polished with carnauba wax. Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2018-XXXX Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. usppi-mk1439-t-XXXXr00X For more information, go to www.PIFELTRO.com or call 1-877-888-4231. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5475856	custom-source	2025-02-12T15:46:34.688111	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/210806s011lbl.pdf', 'application_number': 210806, 'submission_type': 'SUPPL ', 'submission_number': 11}
80,189	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LIVMARLI safely and effectively. See full prescribing information for LIVMARLI. LIVMARLI® (maralixibat) oral solution Initial U.S. Approval: 2021 ------------------------------RECENT MAJOR CHANGES----------------------- Indications and Usage (1) 3/2024 Dosage and Administration (2) 3/2024 Dosage and Administration (2.1, 2.2) 7/2024 Contraindications (4) 3/2024 Warnings and Precautions (5.1) 3/2024 Warnings and Precautions (5.2) 3/2024 Warnings and Precautions (5.3) 3/2024 Warnings and Precautions (5.4) 7/2024 -----------------------------INDICATIONS AND USAGE-------------------------- LIVMARLI is an ileal bile acid transporter (IBAT) inhibitor indicated for: • the treatment of cholestatic pruritus in patients 3 months of age and older with Alagille syndrome (ALGS). (1.1) • the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC). (1.2) Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of bile salt export pump (BSEP) protein. (14.2) ------------------------DOSAGE AND ADMINISTRATION---------------------- • Treatment of ALGS: Use LIVMARLI Oral Solution 9.5 mg/mL. The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before a meal in the morning. (2.1) Starting dose is 190 mcg/kg orally once daily, and should be increased to 380 mcg/kg once daily after one week, as tolerated and not to exceed a maximum daily dose of 28.5 mg. (2.1) • Treatment of PFIC: Use LIVMARLI Oral Solution 19 mg/mL. The recommended dosage is 570 mcg/kg twice daily. (2.2) Starting dose is 285 mcg/kg orally once daily in the morning and should be increased to 285 mcg/kg twice daily, 428 mcg/kg twice daily, and then to 570 mcg/kg twice daily, as tolerated and not to exceed a maximum daily dose of 38 mg. (2.2) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Oral solution: • 9.5 mg of maralixibat per mL: treatment of ALGS (3) • 19 mg of maralixibat per mL: treatment of PFIC (3) -------------------------------CONTRAINDICATIONS------------------------------ Patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Hepatotoxicity: Obtain baseline liver tests and monitor patients frequently for the first 6 to 8 months after starting therapy, and as clinically indicated thereafter during treatment. If liver test abnormalities or signs of clinical hepatitis occur, consider dose reduction or treatment interruption. For persistent or recurrent liver test abnormalities relative to baseline, discontinue LIVMARLI. Monitor patients with compensated cirrhosis frequently. Permanently discontinue LIVMARLI if hepatic decompensation event occurs. (5.1) • Gastrointestinal Adverse Reactions: Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or abdominal pain, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. Consider stopping LIVMARLI treatment if diarrhea or abdominal pain persists and no alternate etiology is identified. (5.2) • Fat-Soluble Vitamin (FSV) Deficiency: Obtain baseline levels and monitor during treatment. Supplement if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, consider discontinuing LIVMARLI treatment. (5.3) Fracture: Consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels. Bleeding: Interrupt treatment with LIVMARLI. Treatment can be restarted if the FSV deficiency is corrected and bleeding has resolved. • Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 years of Age): Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue if toxicity is suspected. (5.4) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (≥5%) are: • ALGS: diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, and bone fractures. (6.1) • PFIC: diarrhea, fat soluble vitamin deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mirum Pharmaceuticals at 1-855-MRM-4YOU or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ • Bile Acid Sequestrants: Modify LIVMARLI administration schedule. (7.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Treatment of Cholestatic Pruritus in Patients with Alagille Syndrome 1.2 Treatment of Cholestatic Pruritus in Patients with Progressive Familial Intrahepatic Cholestasis 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Alagille Syndrome 2.2 Recommended Dosage for Progressive Familial Intrahepatic Cholestasis 2.3 Missed Dose 2.4 Important Administration Instructions 2.5 Dosage Modification for Management of Adverse Events 2.6 Administration Modification for Drug Interaction 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Gastrointestinal Adverse Reactions 5.3 Fat-Soluble Vitamin (FSV) Deficiency 5.4 Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age) 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on LIVMARLI 7.2 Effects of LIVMARLI on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Alagille Syndrome 14.2 Progressive Familial Intrahepatic Cholestasis 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5475379 1 2 FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE 1.1 Treatment of Cholestatic Pruritus in Patients with Alagille Syndrome LIVMARLI® is indicated for the treatment of cholestatic pruritus in patients 3 months of age and older with Alagille syndrome (ALGS). 1.2 Treatment of Cholestatic Pruritus in Patients with Progressive Familial Intrahepatic Cholestasis LIVMARLI is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC). Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of bile salt export pump (BSEP) protein [see Clinical Studies (14.2)]. DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Alagille Syndrome Use LIVMARLI Oral Solution 9.5 mg/mL for the treatment of ALGS. The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before a meal in the morning. Start dosing at 190 mcg/kg administered orally once daily; after one week, increase to 380 mcg/kg once daily, as tolerated. The maximum daily dose should not exceed 28.5 mg (3 mL) per day. Refer to the dosing by weight guidelines presented in Table 1. Reference ID: 5475379 Table 1: 9.5 mg/mL Solution for Patients with ALGS: Volume per Dose (mL) by Weight Patient Weight (kg) Days 1-7 (190 mcg/kg once daily) Beginning Day 8 (380 mcg/kg once daily) 9.5 mg/mL Solution (for ALGS) Volume per Dose (mL) 5 to 6 0.1 0.2 7 to 9 0.15 0.3 10 to 12 0.2 0.45 13 to 15 0.3 0.6 16 to 19 0.35 0.7 20 to 24 0.45 0.9 25 to 29 0.5 1 30 to 34 0.6 1.25 35 to 39 0.7 1.5 40 to 49 0.9 1.75 50 to 59 1 2.25 60 to 69 1.25 2.5 70 or higher 1.5 3 2.2 Recommended Dosage for Progressive Familial Intrahepatic Cholestasis Use LIVMARLI Oral Solution 19 mg/mL for the treatment of PFIC. The two strengths of LIVMARLI, 9.5 mg/mL and 19 mg/mL, should not be substituted for one another when treating PFIC patients. Special attention should be given to the accurate calculation of the dose volume of LIVMARLI. This is especially important for pediatric patients less than 5 years old as LIVMARLI oral solution contains the excipient propylene glycol (364.5 mg/mL) [see Warnings and Precautions (5.4) and Overdosage (10)]. The recommended dosage is 570 mcg/kg twice daily 30 minutes before a meal. The starting dose is 285 mcg/kg orally once daily in the morning, and should be increased to 285 mcg/kg twice daily, 428 mcg/kg twice daily, and then to 570 mcg/kg twice daily, as tolerated. The maximum daily dose should not exceed 38 mg (2 mL) per day. Refer to the dosing by weight guidelines presented in Table 2. Reference ID: 5475379 Table 2: 19 mg/mL Solution for Patients with PFIC: Volume per Dose (mL) by Weight Patient Weight (kg) 285 mcg/kg (once daily titrated to twice daily) 428 mcg/kg (twice daily) 570 mcg/kg (twice daily as tolerated) 19 mg/mL Solution (for PFIC) Volume per Dose (mL) 5 0.1 0.1 0.15 6 to 7 0.1 0.15 0.2 8 0.1 0.2 0.25 9 0.15 0.2 0.25 10 to 12 0.15 0.25 0.3 13 to 15 0.2 0.3 0.4 16 to 19 0.25 0.4 0.5 20 to 24 0.3 0.5 0.6 25 to 29 0.4 0.6 0.8 30 to 34 0.45 0.7 0.9 35 to 39 0.6 0.8 1 40 to 49 0.6 0.9 1 50 to 59 0.8 1 1 60 or higher 0.9 1 1 2.3 Missed Dose For once daily dosing: If a dose is missed, it should be taken as soon as possible within 12 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 12 hours, the dose can be omitted and the original dosing schedule resumed. For twice daily dosing: If a dose is missed, it should be taken as soon as possible within 6 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 6 hours, the dose can be omitted and the original dosing schedule resumed. 2.4 Important Administration Instructions Administer LIVMARLI 30 minutes before a meal [see Clinical Pharmacology (12.3)]. A calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dosing dispenser) will be provided by the pharmacy to measure and deliver the prescribed dose accurately. After opening the LIVMARLI bottle, store below 30°C (86°F) and discard any remaining LIVMARLI after 100 days. 2.5 Dosage Modification for Management of Adverse Events Establish the baseline pattern of variability of liver tests prior to starting LIVMARLI, so that potential signs of liver injury can be identified. Monitor liver tests (e.g., ALT [alanine aminotransferase], AST [aspartate aminotransferase], TB [total bilirubin]), DB [direct bilirubin], and International Normalized Ratio [INR]) during treatment with LIVMARLI. Reduce the dosage or interrupt LIVMARLI if new onset liver test abnormalities occur. Once the liver test abnormalities either return back to baseline values or stabilize at a new baseline value, consider restarting LIVMARLI at the last tolerated dose, and increase the dose as tolerated. Consider discontinuing LIVMARLI permanently if liver test Reference ID: 5475379 3 4 5 abnormalities recur or symptoms consistent with clinical hepatitis are observed [see Warnings and Precautions (5.1)]. LIVMARLI has not been studied in patients with hepatic decompensation. Discontinue LIVMARLI permanently if a patient experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). 2.6 Administration Modification for Drug Interaction Bile Acid Binding Resins Administer LIVMARLI at least 4 hours before or 4 hours after administering the bile acid binding resins [see Drug Interactions (7.1)] when used concomitantly. DOSAGE FORMS AND STRENGTHS Oral solution: • 9.5 mg of maralixibat per mL (for treatment of ALGS) as a clear, colorless to yellow solution. • 19 mg of maralixibat per mL (for treatment of PFIC) as a clear, colorless to yellow solution. CONTRAINDICATIONS LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy) [see Warnings and Precautions (5.1)]. WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity LIVMARLI treatment is associated with a potential for drug-induced liver injury. In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died. In the ALGS trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred. Most abnormalities included elevations in ALT, AST, and/or TB/DB. One patient whose TB was elevated at baseline discontinued LIVMARLI after 28 weeks due to increased TB above baseline. Four patients had ALT increases that led to dose modification (n=1), dose interruption (n=2), or permanent discontinuation (n=2) of LIVMARLI during the long-term, open-label extension period [see Adverse Reactions (6.1)]. Obtain baseline liver tests because some ALGS and PFIC patients have abnormal liver tests at baseline. Monitor patients frequently for the first 6 to 8 months after starting therapy and as clinically indicated thereafter during treatment with LIVMARLI. Monitor for elevations in liver tests, for the development of liver-related adverse reactions, and for physical signs of hepatic decompensation. If liver test abnormalities or signs of clinical hepatitis occur in the absence of other causes, consider dose reduction or treatment interruption. Permanently discontinue LIVMARLI if a patient experiences the following: • persistent or recurrent liver test abnormalities, or Reference ID: 5475379 • upon rechallenge, signs and symptoms consistent with clinical hepatitis, or • a hepatic decompensation event. The safety and effectiveness of LIVMARLI have not been established in patients with decompensated cirrhosis. Monitor patients with compensated cirrhosis frequently and discontinue LIVMARLI if hepatic decompensation occurs. LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events [see Contraindications (4)]. 5.2 Gastrointestinal Adverse Reactions Diarrhea and abdominal pain were reported as the most common adverse reactions in patients treated with LIVMARLI [see Adverse Reactions (6.1)]. Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or abdominal pain, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. Consider stopping LIVMARLI treatment if diarrhea or abdominal pain persists and no alternate etiology is identified. Monitor for dehydration due to diarrhea and treat promptly. LIVMARLI was not evaluated in PFIC patients with chronic diarrhea requiring intravenous fluids. When diarrhea or abdominal pain resolves, restart LIVMARLI at the last tolerated dose and increase the dose as tolerated. Consider stopping LIVMARLI treatment if they recur upon re-challenge with LIVMARLI. 5.3 Fat Soluble Vitamin (FSV) Deficiency LIVMARLI may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and K (measured using INR levels). ALGS and PFIC patients can have FSV deficiency at baseline and are frequently supplemented with FSV. In ALGS patients in Trial 1, treatment-emergent FSV deficiency was reported in 3 (10%) patients during 48 weeks of treatment. In PFIC patients in Trial 2, treatment-emergent FSV deficiency (assessed biochemically) was reported in 13 (28%) of LIVMARLI-treated patients versus 16 (35%) of placebo-treated patients during 26 weeks of treatment. Bone Fracture Treatment-emergent bone fracture events have been observed more frequently with LIVMARLI- treated patients compared to placebo-treated patients [see Adverse Reactions (6.1)]. If fracture occurs, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels. Bleeding If bleeding occurs, interrupt treatment with LIVMARLI. LIVMARLI can be restarted if FSV deficiency is corrected and bleeding has resolved. Obtain serum FSV levels prior to initiation of LIVMARLI and monitor the levels periodically during treatment, along with any clinical manifestations of FSV deficiency. Supplement with FSV if FSV deficiency is diagnosed. Consider discontinuing LIVMARLI if FSV deficiency persists or worsens despite adequate FSV supplementation. If complications of FSV deficiency occur, such as fracture or bleeding, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels. Reference ID: 5475379 6 5.4 Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age) LIVMARLI contains propylene glycol. Patients less than 5 years of age are at highest risk for propylene glycol toxicity, and a safe level for propylene glycol exposure with repeated administration has not been established for pediatric patients less than 5 years of age. When LIVMARLI is administered at the dose (380 mcg/kg once daily) for treatment of cholestatic pruritus in patients with ALGS, the exposure to propylene glycol will be 14.6 mg/kg/day. When LIVMARLI is administered at the dose (570 mcg/kg twice daily) for treatment of cholestatic pruritus in patients with PFIC, the exposure to propylene glycol will be 21.9 mg/kg/day. The total daily intake of propylene glycol from all sources should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of potential propylene glycol toxicity, including hemolysis, hyperosmolarity with anion gap metabolic acidosis, acute kidney injury, and CNS toxicity. Discontinue LIVMARLI if propylene glycol toxicity is suspected [see Overdosage (10)]. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)] • Fat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ALGS: In the Alagille syndrome clinical development program, which includes five clinical studies comprising 86 patients, patients received doses of LIVMARLI up to 760 mcg/kg per day with a median duration of exposure of 32.3 months (range: 0.03 – 60.9 months). In Trial 1, the 4-week placebo control period occurred after 18 weeks of LIVMARLI treatment. In two supportive studies that included long-term open-label extensions, only 13 weeks of placebo-controlled treatment occurred which evaluated doses lower than 380 mcg/kg/day. The majority of LIVMARLI exposure in the development program occurred without a placebo control in open-label trial extensions. The most common adverse reactions (≥5%) for ALGS patients treated with LIVMARLI are presented in Table 3 below. Treatment interruptions or dose reductions occurred in 5 (6%) patients due to diarrhea, abdominal pain, or vomiting. Table 3: Adverse Reactions Occurring in ≥ 5% of Patients Treated with LIVMARLI in the ALGS Clinical Development Program LIVMARLI (n=86) Adverse Reaction Any Grade n (%) Number of events per 100 person-years1 Diarrhea 48 (55.8%) 41.6 Abdominal pain* 46 (53.5%) 38.6 Vomiting 35 (40.7%) 19.8 Reference ID: 5475379 Nausea 7 (8.1%) 2.9 Fat-Soluble Vitamin deficiency* 22 (25.6%) 11.1 Transaminases increased (ALT, AST)* 16 (18.6%) 6.9 Bone Fractures* 8 (9.3%) 3.3 *Terms were defined as: Fat-Soluble Vitamin deficiency includes: A, D, E, or K deficiency, or INR increase Abdominal Pain includes: abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper Transaminases increased includes: ALT abnormal, ALT increased, AST abnormal, AST increased Bone Fracture includes: tibia fracture, rib fracture, hand fracture, humerus fracture, pathological fracture, forearm fracture, clavicle fracture 1 Exposure adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this adverse reaction per patient Liver Test Abnormalities Increase in Transaminases In a pooled analysis of patients with ALGS (N=86) administered LIVMARLI, increases in hepatic transaminases (ALT) were observed. Seven (8.1%) patients discontinued LIVMARLI due to ALT increases. Three (3.5%) patients had a decrease in dose or interruption of LIVMARLI in response to ALT increases. In the majority of cases, the elevations resolved or improved after discontinuation or dose modification of LIVMARLI. In some cases, the elevations resolved or improved without change in LIVMARLI dosing. Increases to more than three times baseline in ALT occurred in 26% of patients treated with LIVMARLI and increases to more than five times baseline occurred in 3%. AST increases to more than three times baseline occurred in 16% of patients treated with LIVMARLI, and an increase to more than five times baseline occurred in one patient. Elevations in transaminases were asymptomatic and not associated with bilirubin elevations or other laboratory abnormalities. Increases in Bilirubin Four (4.6%) patients in the pooled analysis experienced bilirubin increases above baseline, and LIVMARLI was subsequently withdrawn in two of these patients, who had elevated bilirubin at baseline. PFIC: In Trial 2, which enrolled 93 patients, 47 patients received doses of LIVMARLI up to 570 mcg/kg BID, with a median duration of exposure of 6 months (range: 0.3-6.7 months). The most common adverse reactions (≥5%) for PFIC patients treated with LIVMARLI at a rate greater than placebo are presented in Table 4 below. Diarrhea was the most frequent adverse reaction; the majority of episodes were mild and transient with a median duration of 5.5 days. Nineteen (40.4%) LIVMARLI-treated subjects had diarrhea greater than or equal to 7 days. Placebo-treated subjects had a median duration of 3 days of diarrhea and two subjects (4.3%) experienced diarrhea with a duration greater than or equal to 7 days. There were no severe events reported. The majority of abdominal pain events were mild based on AE grading, and associated with concurrent diarrhea. One LIVMARLI-treated patient with an event of mild diarrhea discontinued treatment. Treatment interruptions or dose reductions occurred in 3 (6.4%) LIVMARLI-treated patients due to diarrhea or abdominal pain. No placebo-treated subjects discontinued treatment or had dose reductions or interruptions due to diarrhea. Table 4: Adverse Reactions (any grade) Occurring in ≥5% and at a Rate Greater Than Placebo in Patients Treated with LIVMARLI in the PFIC Trial Reference ID: 5475379 Adverse Reaction (Any Grade) Placebo n=46 LIVMARLI n=47 Diarrhea 9 (19.6%) 27 (57.4%) Abdominal pain† 7 (15.2%) 13 (27.7%) Transaminases increased (ALT or AST) † 3 (6.5%) 8 (17%) Hematochezia or rectal hemorrhage 1 (2.2%) 4 (8.5%) Bone Fractures† 0 3 (6.4%) †Terms were defined as: Abdominal Pain includes: abdominal pain, abdominal pain upper, abdominal distension Transaminases increased includes: Hypertransaminasaemia, ALT abnormal, ALT increased, AST abnormal, AST increased, Transaminases increased, Hepatic enzyme increased. Bone Fracture includes: upper limb fracture, lower limb fracture, radius fracture, ulna fracture, femur fracture, foot fracture Hepatotoxicity LIVMARLI treatment is associated with a potential for drug-induced liver injury. In PFIC patients in Trial 2, treatment-emergent elevations of liver tests or worsening of liver tests, relative to baseline values, and hepatic decompensation events were observed. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI; one patient received 570 mcg/kg twice daily and the second patient required dose interruption and reduction. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died. Biliary Complications In the placebo-controlled portion of Trial 2, two LIVMARLI-treated patients developed cholangitis or cholecystitis within 3-weeks of drug discontinuation (after 84 days and 130 days after initiating LIVMARLI treatment, respectively). Four LIVMARLI-treated patients developed cholecystitis or cholangitis in the open-label extension portion of Trial 2; the average time to onset was 281 days. Bone Fracture In PFIC patients in Trial 2, treatment-emergent bone fracture events were observed. Three receiving LIVMARLI experienced bone fractures relative to none in placebo-treated patients. The median time to onset of fractures was 73 days. Two LIVMARLI-treated patients developed bone fractures in the open-label portion of Trial 2, with average time to onset of fracture was 204 days. Bleeding In PFIC patients in Trial 2, treatment-emergent events of hematochezia (4 [8.5%] versus 1 [2.2%]), decrease in hemoglobin greater than or equal to 2 grams/dL from baseline (8 [17%] versus 1 [2.2%]), were reported more frequently in LIVMARLI-treated patients relative to placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LIVMARLI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: hematemesis, liver transplant, post-endoscopy hemorrhage, post-liver biopsy hemorrhage Reference ID: 5475379 General disorders and administration site conditions: drug ineffective Injury, poisoning and procedural complications: off label use Investigations: gamma-glutamyltransferase increased Nervous system disorders: intracranial hemorrhage 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on LIVMARLI Bile Acid Binding Resins Bile acid binding resins may bind to maralixibat in the gut. Administer LIVMARLI at least 4 hours before or 4 hours after administration of bile acid binding resins (e.g., cholestyramine, colesevelam, or colestipol). 7.2 Effects of LIVMARLI on Other Drugs OATP2B1 substrates Maralixibat is an OATP2B1 inhibitor based on in vitro studies. A decrease in the oral absorption of OATP2B1 substrates (e.g., statins) due to OATP2B1 inhibition in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates (e.g. statins) as needed [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Maternal use at the recommended clinical dose of LIVMARLI is not expected to result in measurable fetal exposure because systemic absorption following oral administration is low [see Clinical Pharmacology (12.3)]. Maralixibat may inhibit the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3) and Clinical Considerations]. In animal reproduction studies, no developmental effects were observed (see Data). The estimated background risk of major birth defects for ALGS is higher than the general population because ALGS is an autosomal dominant condition. The background risk of miscarriage for ALGS is unknown. The background risk of birth defects and miscarriage for PFIC is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Maralixibat may inhibit the absorption of fat-soluble vitamins (FSV). Monitor for FSV deficiency and supplement as needed. Increased supplementation of FSVs may be needed during pregnancy [see Warnings and Precautions (5.3)]. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 1000 mg/kg/day (approximately 3300 to 12000 times the maximum recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with up to Reference ID: 5475379 250 mg/kg/day (approximately 1200 to 4700 times the maximum recommended dose based on AUC) during the period of organogenesis. No effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with up to 750 mg/kg/day during organogenesis through lactation. Maternal systemic exposure to maralixibat at the maximum dose tested was approximately 2500 to 9400 times the maximum recommended dose based on AUC. 8.2 Lactation Risk Summary LIVMARLI has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to LIVMARLI at the recommended dose [see Clinical Pharmacology (12.3)]. There are no data on the presence of LIVMARLI in human milk, the effects on the breastfed infant, or the effects on milk production. Patients with ALGS or PFIC can have FSV deficiency as part of their disease. Maralixibat may reduce absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. Monitor FSV levels and supplement FSV intake, if FSV deficiency is observed during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s need for LIVMARLI and any potential adverse effects on the breastfed child from LIVMARLI or from the underlying maternal condition. 8.4 Pediatric Use ALGS The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in Alagille syndrome have been established in pediatric patients aged 3 months of age and older. Use of LIVMARLI in this population is supported by evidence from a study of patients 1 to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by a 4 week placebo-controlled randomized withdrawal period and a subsequent 26-week open-label treatment period. Additional safety information was obtained from four studies in patients up to 21 years of age (N=55) [see Adverse Reactions (6) and Clinical Studies (14.1)]. Use of LIVMARLI in patients 3 to <12 months of age is supported by an open-label, multicenter study of LIVMARLI which showed a similar safety, tolerability and pharmacokinetic profile to patients with ALGS >12 months of age. The safety and effectiveness of LIVMARLI have not been established in patients with ALGS less than 3 months of age. PFIC The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in PFIC have been established in pediatric patients aged 12 months of age and older. Use of LIVMARLI in this population is supported by evidence from Trial 2 in patients 1 to <18 years of age that included 26 weeks of placebo-controlled safety and efficacy data [see Adverse Reactions (6) and Clinical Studies (14.2)]. The 19 mg/mL formulation of LIVMARLI should be used in patients with PFIC in order to minimize exposure to excipients, including propylene glycol. Patients less than 5 years of age are at highest risk for propylene glycol toxicity. The total daily intake of propylene glycol from all sources should be considered for managing the risk of propylene glycol toxicity [see Warnings and Precautions (5.4)]. The safety and effectiveness of LIVMARLI have not been established in patients with PFIC younger than 12 months of age. 8.5 Geriatric Use The safety and effectiveness of LIVMARLI for the treatment of pruritus in ALGS or PFIC in adult patients, 65 years of age and older, have not been established. Reference ID: 5475379 8.6 Hepatic impairment Clinical studies of LIVMARLI included ALGS or PFIC patients with impaired hepatic function at baseline. The efficacy and safety in ALGS or PFIC patients with clinically significant portal hypertension and in patients with decompensated cirrhosis have not been established. LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events [see Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.1), and Clinical Studies (14)]. 10 OVERDOSAGE Single doses of maralixibat up to 500 mg, approximately 18-fold higher than the recommended dose, have been administered in healthy adults and were tolerated without a meaningful increase in adverse effects when compared to lower doses. If an overdose occurs, discontinue LIVMARLI, monitor the patient for any signs and symptoms and institute general supportive measures if needed. LIVMARLI contains propylene glycol as an excipient. In cases of suspected overdose, monitor for signs of propylene glycol toxicity, including hemolysis, hyperosmolarity with anion gap metabolic acidosis, acute kidney injury, and CNS toxicity. Discontinue LIVMARLI if propylene glycol toxicity is suspected. 11 DESCRIPTION LIVMARLI (maralixibat) oral solution is an ileal bile acid transporter (IBAT) inhibitor. Maralixibat is present as a chloride salt with the chemical name 1-[[4-[[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino) 2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1 azoniabicyclo[2.2.2]octane chloride. The molecular formula of maralixibat chloride is C40H56ClN3O4S with a molecular weight of 710.42. It has the following chemical structure: LIVMARLI is supplied in a multiple-dose bottle containing 9.5 mg of maralixibat per mL (equivalent to 10 mg of maralixibat chloride per mL), or containing 19 mg of maralixibat per mL (equivalent to 20 mg of maralixibat chloride per mL). The oral solution contains the following inactive ingredients: edetate disodium, grape flavor, propylene glycol, purified water, and sucralose. The pH of the oral solution is 3.8 – 4.8. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Maralixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum. Reference ID: 5475379 Pruritus is a common symptom in patients with ALGS or PFIC and the pathophysiology of pruritus in patients with ALGS or PFIC is not completely understood. Although the complete mechanism by which maralixibat improves pruritus in ALGS or PFIC patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids [see Clinical Pharmacology (12.2)]. 12.2 Pharmacodynamics ALGS In Trial 1, pediatric patients with ALGS were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period [see Clinical Studies (14.1)]. At baseline, serum bile acids were highly variable among patients ranging from 20 to 749 µmol/L and mean (SD) serum bile acid level was 283 (210.6) µmol/L. Serum bile acid levels decreased from baseline in the majority of patients as early as at Week 12 and the reduction in serum bile acids was generally maintained for the treatment period. PFIC In Trial 2, pediatric patients with PFIC were administered LIVMARLI 570 mcg/kg or placebo twice daily for up to 22 weeks after an initial 4–6-week dose escalation period [see Clinical Studies (14.2)]. At baseline, serum bile acids concentrations were highly variable among patients ranging from 4 to 504 µmol/L and mean (SD) serum bile acid level was 253 (136) µmol/L. Serum bile acid concentrations decreased from baseline in the majority of patients as early as at Week 2; while the concentrations fluctuated, the reduction in serum bile acids was generally maintained for the treatment period. 12.3 Pharmacokinetics Because of the low systemic absorption of maralixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended dose. Concentrations of maralixibat in the pediatric ALGS and PFIC patients were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples. Following single oral administration of maralixibat in healthy adults at doses ranging from 1 mg to 500 mg, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg and PK parameters could not be reliably estimated. Following a single dose administration of 30 mg under fasted condition, median Tmax was 0.75 and mean (SD) Cmax and AUClast were 1.65 (1.10) ng/ml and 3.43 (2.13) ng·h/mL, respectively. Absorption Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses. Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in a dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg. No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once-daily. Effect of Food Concomitant administration of a high-fat meal with a single oral dose of maralixibat decreased both the rate and extent of absorption. AUC and Cmax of maralixibat values in the fed state were 64.8% to 85.8% lower relative to oral administration of 30 mg in fasted conditions. The effect of food on the Reference ID: 5475379 changes of systemic exposures to maralixibat is not clinically significant [see Dosage and Administration (2.1, 2.3)]. Distribution Maralixibat shows high binding (91%) to human plasma proteins in vitro. Elimination Following a single oral dose of 30 mg maralixibat in healthy adults, the mean half-life (t1/2) was 1.6 hours. Metabolism No maralixibat metabolites have been detected in plasma. Three minor metabolites, accounting for <3% of maralixibat-associated fecal radioactivity in total, were identified following oral administration of [14C]maralixibat. Excretion Fecal excretion was found to be the major route of elimination. Following a single oral dose of 5 mg 14C-maralixibat, 73% of the dose was excreted in the feces with 0.066% excreted in the urine. 94% of the fecal excretion was as unchanged maralixibat. Specific Populations Patients with Renal Impairment The pharmacokinetics of maralixibat were not studied in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis. Drug Interaction Studies Effect of Other Drugs on Maralixibat Maralixibat is not a substrate of the drug transporters MDR1 (P-gp), BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant drug products are not predicted to affect the disposition of maralixibat. Effect of Maralixibat on Other Drugs In vitro, maralixibat did not induce CYP isoforms 1A2, 2B6, or 3A4, nor inhibit CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations. Maralixibat inhibits CYP3A4 in vitro, however clinically relevant effects on the pharmacokinetics of CYP3A4 substrates are unlikely. In vitro, maralixibat did not inhibit the transporters MDR1 (P-gp), BCRP, OAT1, OAT3, OATP1B1, OATP1B3, PEPT1, OCT1, OCT2, OCT3, OCTN1, OCTN2, MRP2, MATE1, or MATE2-K at clinically relevant concentrations. Maralixibat inhibits the drug transporter OATP2B1 in vitro, which can potentially result in reduced absorption of drugs that rely on OATP2B1-mediated uptake in the GI tract. In clinical studies coadministration of 4.75 mg maralixibat (once daily in the morning) with daily doses of either simvastatin, or lovastatin in the evening, did not have a clinically relevant effect on the pharmacokinetics of these statins and their metabolites. Coadministration of 4.75 mg maralixibat did not affect pharmacokinetics of atorvastatin. However, the effect of maralixibat on the pharmacokinetics of OATP2B1 substrates at higher doses has not been evaluated in a clinical study. 12.5 Pharmacogenomics PFIC is a heterogenous disease caused by homozygous or compound heterozygous variants, with different PFIC subtypes occurring in the general population. PFIC1 is caused by variants in the Reference ID: 5475379 aminophospholipid flippase (ATP8B1) gene, which encodes the Familial Intrahepatic Cholestasis 1 (FIC1) protein, while PFIC2 results from variants in the ABCB11 gene, which encodes the Bile Salt Export Pump (BSEP) protein. PFIC2 is further categorized into BSEP subgroups based on specific variants. The BSEP-1 subgroup includes patients with at least one p.D482G (c.1445A>G) or p.E297G (c.890A>G) variant, BSEP-2 includes patients with at least one missense variant other than p.D482G or p.E297G (non BSEP-1), and BSEP-3 includes patients with variants that are predicted to encode a non-functional protein. PFIC3 is caused by variants in the ABCB4 gene, which encodes multidrug resistance protein 3 (MDR3). PFIC4 is caused by variants in the tight junction protein 2 gene (TJP2), which encodes TJP2. PFIC6 is caused by variants in myosin 5B (MYO5B), which encodes MYO5B. Patients can be clinically diagnosed with PFIC without a known pathogenic variant. PFIC2 is the most common subtype accounting for 37-90% of patients with PFIC. The prevalence of BSEP-1, BSEP-2, and BSEP-3 subgroups are approximately 27.3%, 51.5%, and 21.2%, respectively, based on data from a global consortium characterizing the natural history of severe BSEP deficiency. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride. Mutagenesis Maralixibat chloride was negative in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (rat bone marrow micronucleus) assays. Impairment of Fertility No effects on fertility were observed in female rats treated orally with up to 2000 mg/kg/day or in male rats treated orally with up to 750 mg/kg/day. 14 CLINICAL STUDIES 14.1 Alagille Syndrome The efficacy of LIVMARLI was assessed in Trial 1 (NCT02160782), which consisted of an 18-week open-label treatment period; a 4-week randomized, double-blind, placebo-controlled drug-withdrawal period; a subsequent 26-week open-label treatment period; and a long-term open-label extension period. Thirty-one pediatric ALGS patients with cholestasis and pruritus were enrolled, with 90.3% of patients receiving at least one medication to treat pruritus at study entry. All patients had JAGGED1 mutation. Patients were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period; two patients discontinued treatment during this first 18 weeks of open-label treatment. The 29 patients who completed the open-label treatment phase were then randomized to continue treatment with LIVMARLI or receive matching placebo during the 4 week drug withdrawal period at Weeks 19-22 (n=16 placebo, n=13 LIVMARLI). All 29 patients completed the randomized, blinded drug withdrawal period; subsequently, patients received open- label LIVMARLI at 380 mcg/kg once daily for an additional 26 weeks. Randomized patients had a median age of 5 years (range: 1 to 15 years) and 66% were male. The baseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid Reference ID: 5475379 levels 280 (213) µmol/L, AST 158 (68) U/L, ALT 179 (112) U/L, Gamma Glutamyl Transferase (GGT) 498 (399) U/L, and TB 5.6 (5.4) mg/dL. Given the patients’ young age, a single-item observer-reported outcome was used to measure patients’ pruritus symptoms as observed by their caregiver twice daily (once in the morning and once in the evening) on the Itch Reported Outcome Instrument (ItchRO[Obs]). Pruritus symptoms were assessed on a 5-point ordinal response scale, with scores ranging from 0 (none observed or reported) to 4 (very severe). Patients were included in Trial 1 if their average pruritus score was greater than 2.0 (moderate) in the 2 weeks prior to baseline. The average of the worst daily ItchRO(Obs) pruritus scores was computed for each week. For randomized patients, the mean (SD) at baseline (pre-treatment) was 3.1 (0.5) and the mean (SD) at Week 18 (pre-randomized withdrawal period) was 1.4 (0.9). On average, patients administered LIVMARLI for 22 weeks maintained pruritus reduction whereas those in the placebo group who were withdrawn from LIVMARLI after Week 18 returned to baseline pruritus scores by Week 22. Results from the placebo-controlled period are presented in Table 5. After re-entering the open-label treatment phase, both randomized treatment groups had similar mean pruritus scores by Week 28, the first week placebo patients received the full dosage of LIVMARLI after withdrawal. These observer-rated pruritus results are supported by similar results on patient-rated pruritus in patients 5 years of age and older who were able to self-report their itching severity. Table 5: Weekly Average of Worst Daily ItchRO(Obs) Pruritus Severity Scores in Trial 1 Maralixibat (N=13) Placebo (N=16) Mean Difference Week 22, Mean (95% CI) 1.6 (1.1, 2.1) 3.0 (2.6, 3.5) Change from Week 18 to Week 22, Mean (95% CI) 0.2 (-0.3, 0.7) 1.6 (1.2, 2.1) -1.4 (-2.1, -0.8) Results based on an analysis of covariance model with treatment group and Week 18 average worst daily pruritus score as covariates 14.2 Progressive Familial Intrahepatic Cholestasis The efficacy of LIVMARLI was assessed in Trial 2 (NCT03905330), a 26-week randomized, placebo-controlled trial. Efficacy was evaluated in 64 patients with documented molecular diagnosis of PFIC with presence of biallelic known pathogenic variants; this included 31 non-truncated PFIC2 patients (i.e., excluding patients with BSEP3) and 33 patients with PFIC1 (n=13), PFIC3 (n=9), PFIC4 (n=7), or PFIC6 (n=4) [see Clinical Pharmacology (12.5)]. Additional patients with BSEP3 (n=9), prior surgical diversion (n=8), heterozygous subjects (n=2), or no variants associated with cholestasis (n=8) were included for evaluation in a supplemental cohort [see Adverse Reactions (6.1)]. Patients were randomized to receive maralixibat orally 570 mcg/kg (n=33) or placebo (n=31) twice daily. 53% of pediatric patients were females. Most patients were on stable ursodeoxycholic acid (89.1%) or rifampicin (51.6%) therapy at baseline. The baseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid levels 263 (143) μmol/L, AST 113 (82) U/L, ALT 107 (87) U/L, and TB 4.1 (4.1) mg/dL, DB 3.0 (3.1) mg/dL. Given the patients’ young age, a single-item observer-reported outcome was used to measure patients’ pruritus symptoms as observed by their caregiver twice daily (once in the morning and once in the evening) on the Itch Reported Outcome Instrument (ItchRO[Obs]). Pruritus symptoms were assessed on a 5-point ordinal response scale, with scores ranging from 0 (none observed or Reference ID: 5475379 reported) to 4 (very severe). Patients were included in Trial 2 if their average pruritus score was greater than or equal to 1.5 in the 4 weeks prior to baseline. Table 6 presents the results of the comparison between LIVMARLI and placebo on the mean change in the average morning ItchRO(Obs) severity score between baseline and Weeks 15–26. For the outcome summarized over Weeks 15-26, the average morning ItchRO(Obs) severity score for each patient was calculated by: (Step 1) averaging the morning scores within a week; (Step 2) averaging 4 weekly morning scores to yield a single 4-week score; and finally (Step 3) averaging the three 4-week average morning scores (Weeks 15-18, Weeks 19-22, Weeks 23-26). The baseline average itching scores for each patient was calculated by averaging the morning ItchRO(Obs) score obtained in Step 2 across the 4 weeks prior to the first dose of the study. Patients treated with LIVMARLI demonstrated greater improvement in pruritus compared with placebo. Table 6: Average Morning ItchRO(Obs) Pruritus Severity Scores in Trial 2 Maralixibat (N=33) Placebo (N=31) Baseline Mean 2.9 2.7 Change from baseline to Weeks 15-26a Mean (95% CI) -1.8 (-2.2, -1.4) -0.6 (-1.0, -0.2) Mean difference from Placebo (95% CI) p-value -1.2 (-1.7, -0.7) <0.0001 aResults based on least squares means from an analysis of a mixed-effect model for repeated measures (MMRM). Model adjusts for treatment group, visit, treatment group-by-visit interaction, baseline 4-week average morning ItchRO(Obs) severity score, baseline score-by-visit interaction, and PFIC type. Figure 1 displays the means (95% confidence intervals) of patients’ average morning ItchRO(Obs) severity scores in each treatment group for each 4-6 week time period. Figure 1. Mean of the Average Morning ItchRO(Obs) Pruritus Severity Scores Over Time in PFIC 1, 2, 3, 4, and 6 Reference ID: 5475379 _,._ LIVMARLI ··• ·· Placebo Baseline Weeks 1-6 Weeks 7-1 o Weeks 11-14 Weeks 15-1 8 Weeks 19-22 Weeks 23-26 Note: Figure 1 presents least squares mean (95% CI) estimates from a mixed model for repeated measures (MMRM) with observed value as the dependent variable and fixed categorical effects of treatment group, time period, treatment-by-time period interaction, and PFIC type. Although the number of patients with BSEP3 in Trial 2 were limited, improvement in pruritus was not observed in 5 patients with BSEP3 who received LIVMARLI compared to 4 patients with BSEP3 who received placebo for 26 weeks. 16 HOW SUPPLIED/STORAGE AND HANDLING Oral Solution LIVMARLI is a clear, colorless to yellow oral solution. ALGS: 9.5 mg per mL • Each amber plastic bottle contains LIVMARLI oral solution at a concentration of 9.5 mg per mL. • One 30 mL amber plastic bottle: NDC 79378-110-01 PFIC: 19 mg per mL • Each amber plastic bottle contains LIVMARLI oral solution at a concentration of 19 mg per mL. • One 30 mL amber plastic bottle: NDC 79378-111-01 Storage and Handling Store unopened LIVMARLI between 20°C and 25°C (68°F and 77°F), excursion permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. After opening the LIVMARLI bottle, store below 30°C (86°F) and discard any remaining LIVMARLI after 100 days [see Dosage and Administration (2.4)]. Reference ID: 5475379 17 PATIENT COUNSELING INFORMATION Advise the patient or their caregiver(s) to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Administration Instructions Advise patients or their caregivers(s) to: • Take LIVMARLI 30 minutes prior to a meal once or twice daily as prescribed using a calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.1, 2.2 2.4)]. • Take LIVMARLI at least 4 hours before or 4 hours after taking a bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)]. • Store the opened bottle below 30⁰C (86⁰F). Discard any unused LIVMARLI 100 days after opening the bottle [see How Supplied/Storage and Handling (16)]. Hepatotoxicity Advise patients or their caregiver(s) that liver tests should be obtained before starting LIVMARLI and periodically during LIVMARLI therapy. Inform patients or their caregiver(s) of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury. Instruct patients or their caregiver(s) to immediately report any signs or symptoms of severe liver injury to their healthcare provider [see Warnings and Precautions (5.1)]. Gastrointestinal Adverse Reactions Advise patients or their caregiver(s) to notify their healthcare provider if they experience a new onset or worsening of gastrointestinal symptoms (abdominal pain, vomiting, bloody stool, and diarrhea) [see Warnings and Precautions (5.2)]. Fat Soluble Vitamin (FSV) Deficiency Advise patients or their caregiver(s) that INR (for vitamin K) and serum levels of vitamins A, D, E will be obtained before starting treatment and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3)]. Inform patients or their caregiver(s) that they may bleed more easily, may bleed longer, or have a bone fracture. Advise patients or their caregiver(s) to call their healthcare provider for any signs or symptoms of bleeding or report any fractures. Rx only Manufactured for: Mirum Pharmaceuticals, Inc. 989 E. Hillsdale Blvd., Suite 300 Foster City, CA 94404 © 2024 Mirum Pharmaceuticals, Inc. LIVMARLI® is a trademark of Mirum Pharmaceuticals, Inc. LB00155v3 Reference ID: 5475379	custom-source	2025-02-12T15:46:35.103929	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214662s011lbl.pdf', 'application_number': 214662, 'submission_type': 'SUPPL ', 'submission_number': 11}
80,184	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DANZITEN safely and effectively. See full prescribing information for DANZITEN. DANZITEN (nilotinib) tablets, for oral use Initial U.S. Approval: 2007 WARNING: QT PROLONGATION and SUDDEN DEATHS See full prescribing information for complete boxed warning.  Nilotinib prolongs the QT interval. Prior to DANZITEN administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. (5.3) Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments. (5.3, 5.4, 5.8, 5.12)  Sudden deaths have been reported in patients receiving nilotinib. (5.4) Do not administer DANZITEN to patients with hypokalemia, hypomagnesemia, or long QT syndrome. (4, 5.3)  Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. (7.1, 7.2) ---------------------------INDICATIONS AND USAGE---------------------------- DANZITEN is a kinase inhibitor indicated for the treatment of:  Adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. (1.1)  Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. (1.2) -----------------------DOSAGE AND ADMINISTRATION--------------------  To avoid medication errors and overdosage or under dosage, note that DANZITEN may have different strengths and dosages than other nilotinib products and may not be substitutable with other nilotinib products on a milligram per milligram basis. (2.1)  Recommended Adult Dose: • Newly diagnosed Ph+ CML-CP: 142 mg orally twice daily. • Resistant or intolerant Ph+ CML-CP and CML-AP: 190 mg orally twice daily. (2.2)  See Dosage and Administration for full dosing instructions and dose- reduction instructions for toxicity. (2.4, 2.5, 2.6, 2.7, 2.8, 2.9)  Reduce starting dose in patients with baseline hepatic impairment. (2.8)  Eligible newly diagnosed adult patients with Ph+ CML-CP who have received DANZITEN for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received DANZITEN for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. (2.3, 2.4, 5.16) --------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 71 mg, and 95 mg (3) ------------------------------CONTRAINDICATIONS---------------------------- DANZITEN is contraindicated in patients with hypokalemia, hypomagnesemia, o r long QT syndrome. (4) --------------------------WARNINGS AND PRECAUTIONS----------------------  Substitution with Other Nilotinib Products and Risk of Medication Errors: DANZITEN (nilotinib) tablets may not be substitutable with other nilotinib products, including other nilotinib tablets, on a milligram per milligram basis. Confirm that the intended nilotinib product is being prescribed and dispensed. (5.1)  Myelosuppression: Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. (5.2)  Cardiac and Arterial Vascular Occlusive Events: Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during DANZITEN therapy. (5.5)  Pancreatitis and Elevated Serum Lipase: Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis. (5.6)  Hepatotoxicity: Monitor hepatic function tests monthly or as clinically indicated. (5.7)  Electrolyte Abnormalities: DANZITEN can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating DANZITEN and monitor periodically during therapy. (5.8)  Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with DANZITEN. (5.9)  Hemorrhage: Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage a s needed. (5.10)  Fluid Retention: Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. (5.13)  Effects on Growth and Development in Pediatric Patients: Growth retardation has been reported in pediatric patients treated with nilotinib. Monitor growth and development in pediatric patients. (5.14)  Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.15, 8.1, 8.3)  Treatment Discontinuation: Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. (5.16) -------------------------------ADVERSE REACTIONS------------------------------- The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult patients are nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia, and anemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------------DRUG INTERACTIONS------------------------------  Strong CYP3A Inhibitors: Avoid concomitant use with DANZITEN or reduce DANZITEN dose if concomitant use cannot be avoided. (7.1)  Strong CYP3A Inducers: Avoid concomitant use with DANZITEN. (7.1)  Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. (7.1) ---------------------------USE IN SPECIFIC POPULATIONS--------------------  Lactation: Advise women not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Revised: 11/2024 Reference ID: 5475972 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: QT PROLONGATION and SUDDEN DEATHS 1 INDICATIONS AND USAGE 1.1 Adult Patients with Newly Diagnosed Ph+ CML-CP 1.2 Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP 2 DOSAGE AND ADMINISTRATION 2.1 Important Use and Administration Instructions 2.2 Recommended Dosage and Administration 2.3 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on DANZITEN 2.4 Reinitiation of Treatment in Patients Who Lose Molecular Response After Discontinuation of Therapy with DANZITEN 2.5 Dosage Modification for QT Interval Prolongation 2.6 Dosage Modifications for Myelosuppression 2.7 Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities 2.8 Recommended DANZITEN Dosage in Patients with Hepatic Impairment 2.9 Dosage Modification for Strong CYP3A4 Inhibitors 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Substitution with Other Nilotinib Products and Risk of Medication Errors 5.2 Myelosuppression 5.3 QT Prolongation 5.4 Sudden Deaths 5.5 Cardiac and Arterial Vascular Occlusive Events 5.6 Pancreatitis and Elevated Serum Lipase 5.7 Hepatotoxicity 5.8 Electrolyte Abnormalities 5.9 Tumor Lysis Syndrome 5.10 Hemorrhage 5.11 Total Gastrectomy 5.12 Monitoring Laboratory Tests 5.13 Fluid Retention 5.14 Effects on Growth and Development in Pediatric Patients: 5.15 Embryo-Fetal Toxicity 5.16 Monitoring of BCR-ABL Transcript Levels 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on DANZITEN 7.2 Drugs that Prolong the QT Interval 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Cardiac Disorders 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adult Newly Diagnosed Ph+ CML-CP 14.2 Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP 14.3 Treatment Discontinuation in Newly Diagnosed Ph+ CML-CP Patients Who Have Achieved a Sustained Molecular Response (MR4.5) 14.4 Treatment Discontinuation in Ph+ CML-CP Patients Who Have Achieved a Sustained Molecular Response (MR4.5) on DANZITEN Following Prior Imatinib Therapy 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5475972 FULL PRESCRIBING INFORMATION WARNING: QT PROLONGATION and SUDDEN DEATHS  Nilotinib prolongs the QT interval. Prior to DANZITEN administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies [see Warnings and Precautions (5.3)]. Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments [see Warnings and Precautions (5.3, 5.4, 5.8, 5.12)].  Sudden deaths have been reported in patients receiving nilotinib [see Warnings and Precautions (5.4)]. Do not administer DANZITEN tablets to patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Contraindications (4), Warnings and Precautions (5.3)].  Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors [see Drug Interactions (7.1, 7.2)]. 1 INDICATIONS AND USAGE 1.1 Adult Patients With Newly Diagnosed Ph+ CML-CP DANZITEN is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.2 Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP DANZITEN is indicated for the treatment of adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) resistant or intolerant to prior therapy that included imatinib. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2 DOSAGE AND ADMINISTRATION 2.1 Important Use and Administration Instructions • Nilotinib is available in different formulations, dosage forms, and strengths that are approved with different indications and recommended dosages. • DANZITEN may not be substitutable with other nilotinib products on a milligram per milligram basis; to avoid medication errors, including overdosage or underdosage, when using DANZITEN ensure that the recommended dosage of DANZITEN (not the recommended dosage of other nilotinib products) is prescribed [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. • When switching between DANZITEN (nilotinib) tablets and Tasigna (nilotinib) capsules, use the dosage conversion table [see Dosage and Administration (2.2)]. 2.2 Recommended Dosage and Administration Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of DANZITEN is 142 mg orally twice daily at approximately 12-hour intervals Reference ID: 5475972 with or without food [see Clinical Pharmacology (12.3)]. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of DANZITEN is 190 mg orally twice daily at approximately 12-hour intervals with or without food [see Clinical Pharmacology (12.3)]. Additional Administration Instructions Advise patients to swallow the tablets whole with water and not to cut, crush, or chew the tablets [see Boxed Warning]. If a dose of DANZITEN is missed, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. Switching Instructions Use Table 1 when switching between DANZITEN and Tasigna based on dosage equivalence. Table 1 Recommendations for Switching between DANZITEN and Tasigna Approved Indications DANZITEN dosage Tasigna dosage Newly diagnosed Ph+ CML-CP 142 mg orally twice daily 300 mg orally twice daily Resistant or intolerant Ph+ CML-CP and CML-AP 190 mg orally twice daily 400 mg orally twice daily Optional Concomitant Therapy DANZITEN may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. DANZITEN may be given with hydroxyurea or anagrelide if clinically indicated. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on DANZITEN Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking DANZITEN for a minimum of 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 0.0032% IS), may be eligible for treatment discontinuation [see Clinical Studies (14.3, 14.4)]. Information on FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at http://www.fda.gov/CompanionDiagnostics. Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of DANZITEN. Patients must continue to be monitored for possible loss of molecular remission after treatment discontinuation. Use the same FDA-authorized test to consistently monitor molecular response levels while on and off treatment. Consider discontinuation in patients with newly diagnosed Ph+ CML-CP who have:  been treated with DANZITEN for at least 3 years Reference ID: 5475972  maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) for one year prior to discontinuation of therapy  achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy  been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)  no history of accelerated phase or blast crisis  no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Consider discontinuation in patients with Ph+ CML-CP that are resistant or intolerant to imatinib who have achieved a sustained molecular response (MR4.5) on DANZITEN who have:  been treated with DANZITEN for a minimum of 3 years  been treated with imatinib only prior to treatment with DANZITEN  achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL ≤ 0.0032% IS)  sustained an MR4.5 for a minimum of one year immediately prior to discontinuation of therapy  been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)  no history of accelerated phase or blast crisis  no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Monitor BCR-ABL transcript levels and complete blood count (CBC) with differential in patients who have discontinued DANZITEN therapy monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter [see Warnings and Precautions (5.16)]. Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) during the treatment-free phase, monitor BCR-ABL transcript levels every 2 weeks until BCR-ABL levels remain lower than major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS] for 4 consecutive measurements. The patient can then proceed to the original monitoring schedule. 2.4 Reinitiation of Treatment in Patients Who Lose Molecular Response After Discontinuation of Therapy With DANZITEN  Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [see Warnings and Precautions (5.16)]. Patients who reinitiate DANZITEN therapy should have their BCR-ABL transcript levels monitored monthly until major molecular response is re-established and every 12 weeks thereafter.  Patients resistant or intolerant to prior treatment that included imatinib with confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [see Warnings and Precautions (5.16)]. Patients who reinitiate DANZITEN therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4.0 is re-established and every 12 weeks thereafter. 2.5 Dosage Modification for QT Interval Prolongation See Table 2 for dose adjustments for QT interval prolongation [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)]. Reference ID: 5475972 Table 2. Dosage Adjustments for Adult Patients with QT Prolongation Degree of QTc Prolongation Dosage Adjustment ECGs with a QTc greater than 480 msec 1. Withhold DANZITEN, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed. 2. Resume within 2 weeks at prior dose if QTcF returns to less than 450 msec and to within 20 msec of baseline. 3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 190 mg once daily in adults. 4. Discontinue DANZITEN if, following dose-reduction to 190 mg once daily in adults, QTcF returns to greater than 480 msec. 5. An ECG should be repeated approximately 7 days after any dose adjustment. Abbreviation: ECG, electrocardiogram. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.6 Dosage Modifications for Myelosuppression Withhold or reduce DANZITEN dosage for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 3) [see Warnings and Precautions (5.2)]. Table 3. Dosage Adjustments for Neutropenia and Thrombocytopenia Diagnosis Degree of Myelosuppression Dosage Adjustment Adult patients with:  Newly diagnosed Ph+ CML in chronic phase at 142 mg twice daily  Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 190 mg twice daily ANC less than 1 x 109/L and/or platelet counts less than 50 x 109/L 1. Stop DANZITEN and monitor blood counts. 2. Resume within 2 weeks at prior dose if ANC greater than 1 x 109/L and platelets greater than 50 x 109/L. 3. If blood counts remain low for greater than 2 weeks, reduce the dose to 190 mg once daily. Abbreviations: ANC, absolute neutrophil count; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.7 Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities See Table 4 for dosage adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases. Reference ID: 5475972 [see Warnings and Precautions (5.6, 5.7) and Adverse Reactions (6.1)]. Table 4. Dosage Adjustments for Selected Non-Hematologic Laboratory Abnormalities Degree of Non- Hematologic Laboratory Abnormality Dosage Adjustment Elevated serum Adult patients: lipase or amylase 1. Withhold DANZITEN and monitor serum lipase or amylase. greater than or 2. Resume treatment at 190 mg once daily if serum lipase or amylase returns to less equal to Grade 3 than or equal to Grade 1. Elevated Adult patients: bilirubin greater 1. Withhold DANZITEN and monitor bilirubin. than or equal to 2. Resume treatment at 190 mg once daily if bilirubin returns to less than or equal to Grade 3 in adult Grade 1. patients Elevated hepatic Adult patients: transaminases 1. Withhold DANZITEN and monitor hepatic transaminases. greater than or 2. Resume treatment at 190 mg once daily if hepatic transaminases return to less equal to Grade 3 than or equal to Grade 1. If clinically significant moderate or severe non-hematologic toxicity develops (including medically severe fluid retention), see Table 5 for dosage adjustments [see Adverse Reactions (6.1)]. Table 5. Dosage Adjustments for Other Non-Hematologic Toxicities Degree of “Other Non- Hematologic Toxicity” Dosage Adjustment Other clinically moderate or severe non- hematologic toxicity Adult patients: 1. Withhold DANZITEN until toxicity has resolved. 2. Resume treatment at 190 mg once daily if previous dose was 142 mg twice daily in adult patients newly diagnosed with CML-CP or 190 mg twice daily in adult patients with resistant or intolerant CML-CP and CML-AP. 3. Discontinue treatment if the prior dose was 190 mg once daily in adult patients 4. If clinically appropriate, consider re-escalation of the dose to 142 mg (newly diagnosed Ph+ CML-CP) or 190 mg (resistant or intolerant Ph+ CML-CP and CML- AP) twice daily. Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia- chronic phase; Ph+, Philadelphia chromosome positive. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.8 Recommended DANZITEN Dosage in Patients with Hepatic Impairment If possible, consider alternative therapies. If DANZITEN must be administered to patients with hepatic impairment, the recommended DANZITEN dosage is provided in Table 6. [see Use in Specific Populations (8.7)] Reference ID: 5475972 Table 6. Recommended DANZITEN Dosage in Patients with Hepatic Impairment Diagnosis Degree of Hepatic Impairment DANZITEN Dosage Newly diagnosed Ph+ CML in chronic phase Mild (Child-Pugh A), Moderate (Child-Pugh B), or Severe (Child- Pugh C) Reduce DANZITEN dosage to 95 mg twice daily. Increase DANZITEN dosage to 142 mg twice daily based on tolerability. Resistant or intolerant Ph+ CML in chronic phase or accelerated phase Mild or Moderate Reduce DANZITEN dosage to 142 mg twice daily. Increase DANZITEN dosage to 190 mg twice daily based on tolerability. Severe Reduce DANZITEN dosage to 95 mg twice daily. Increase DANZITEN dosage to 142 mg twice daily and then to 190 mg twice daily based on tolerability. 2.9 Dosage Modification for Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors. Should treatment with any of these agents be required, interrupt therapy with DANZITEN. If concomitant use is required, reduce DANZITEN dosage to 142 mg once daily in patients with resistant or intolerant Ph+ CML or to 95 mg once daily in patients with newly diagnosed Ph+ CML-CP. If the strong inhibitor is discontinued, allow a washout period of 5 half-lives before adjusting DANZITEN dose upward to the indicated dose. For patients who cannot avoid use of strong CYP3A4 inhibitors, monitor closely for prolongation of the QT interval [see Boxed Warning, Warnings and Precautions (5.3), Drug Interactions (7.1, 7.2), Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Tablets:  71 mg: pink coated oblong tablets, debossed with “N5” on one side and plain on other side. Each tablet contains 71 mg of nilotinib.  95 mg: yellow coated oblong tablets, debossed with “N2” on one side and plain on other side. Each tablet contains 95 mg of nilotinib. 4 CONTRAINDICATIONS DANZITEN is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning and Warnings and Precautions (5.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Substitution with Other Nilotinib Products and Risk of Medication Errors Nilotinib is available in different formulations, recommended dosages, and tablet strengths, and for different indications. DANZITEN (nilotinib) tablets may not be substitutable with other nilotinib products, including other nilotinib tablets, on a milligram per milligram basis. When switching patients between other nilotinib products and DANZITEN (nilotinib) tablets, a dose conversion may be required [see Dosage and Administration (2.1 and 2.2)]. Substitution of DANZITEN (nilotinib) tablets for another nilotinib product to Reference ID: 5475972 achieve the same daily nilotinib dosage on a milligram per milligram basis may result in a clinically significant: • Increase in nilotinib exposure which may increase the risk of nilotinib-associated adverse reactions. • Decrease in nilotinib exposure which may reduce DANZITEN effectiveness. Confirm that the intended nilotinib product is being prescribed and dispensed. 5.2 Myelosuppression Treatment with DANZITEN can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform CBCs every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding DANZITEN temporarily or dose reduction [see Dosage and Administration (2.6)]. 5.3 QT Prolongation Nilotinib has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface electrocardiogram (ECG) in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. Electrocardiograms should be performed at baseline, 7 days after initiation of DANZITEN, and periodically as clinically indicated and following dose adjustments [see Dosage and Administration (2.5) and Warnings and Precautions (5.12)]. DANZITEN should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating DANZITEN and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating DANZITEN and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when DANZITEN is inappropriately taken with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, avoid concomitant DANZITEN use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT [see Dosage and Administration (2.9), Drug Interactions (7.1, 7.2)]. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval [see Warnings and Precautions (5.8, 5.12)]. 5.4 Sudden Deaths Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 5661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.5 Cardiac and Arterial Vascular Occlusive Events Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the postmarketing reports of patients receiving nilotinib therapy [see Adverse Reactions (6.1)]. With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, occurred in 9% and 15% of patients receiving nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events, including ischemic heart disease- related cardiac events (5% and 9% in the nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 2.9% in the nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively and 0% in the imatinib arm), and ischemic cerebrovascular events (1.4% and 3.2% in the nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated, and cardiovascular risk factors should be monitored and actively managed during DANZITEN therapy according to standard guidelines [see Dosage and Reference ID: 5475972 Administration (2.5)]. 5.6 Pancreatitis and Elevated Serum Lipase Nilotinib can cause increases in serum lipase [see Adverse Reactions (6.1)]. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis [see Dosage and Administration (2.7)]. Test serum lipase levels monthly or as clinically indicated. 5.7 Hepatotoxicity Nilotinib may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Grade 3-4 elevations of bilirubin, AST, and ALT were reported in adult patients. Grade 3-4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated [see Warnings and Precautions (5.12)] and following dose adjustments. [see Dosage and Administration (2.8)]. 5.8 Electrolyte Abnormalities The use of nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating DANZITEN and during therapy. Monitor these electrolytes periodically during therapy [see Warnings and Precautions (5.12)]. 5.9 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in nilotinib treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases. Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with DANZITEN. 5.10 Hemorrhage Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with nilotinib. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing nilotinib and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the nilotinib dosage equivalent to DANZITEN 142 mg twice daily arm, in 1.8% of patients in the nilotinib dosage equivalent to DANZITEN 190 mg twice daily arm, and 0.4% of patients in the imatinib arm. GI hemorrhage occurred in 2.9% and 5% of patients in the nilotinib dosage equivalent DANZITEN 142 mg and 190 mg twice daily arms and in 1.4% of patients in the imatinib arm, respectively. Grade 3 or 4 events occurred in 0.7% and 1.4% of patients in the nilotinib dosage equivalent to DANZITEN 142 mg and 190 mg twice daily arms, respectively, and in no patients in the imatinib arm. Monitor for signs and symptoms of bleeding and medically manage as needed. 5.11 Total Gastrectomy Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy [see Clinical Pharmacology (12.3)]. 5.12 Monitoring Laboratory Tests Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose prior to therapy and periodically. Electrocardiograms should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.3)]. Monitor lipid profiles and glucose periodically during the first year of DANZITEN therapy and at least yearly during chronic therapy. Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to treat lipid elevations, evaluate the potential for a drug-drug interaction before Reference ID: 5475972 initiating therapy as certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway [see Drug Interactions (7.1)]. Assess glucose levels before initiating treatment with DANZITEN and monitor during treatment as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines. 5.13 Fluid Retention In the randomized trial in patients with newly diagnosed Ph+ CML in chronic phase, severe (Grade 3 or 4) fluid retention occurred in 3.9% and 2.9% of patients receiving the nilotinib dosage equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively, and in 2.5% of patients receiving imatinib. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema, were observed in 2.2% and 1.1% of patients receiving the nilotinib dosage equivalent to the recommended dosage of DANZITEN 142 mg twice daily and 190 mg twice daily, respectively, and in 2.1% of patients receiving imatinib. Effusions were severe (Grade 3 or 4) in 0.7% and 0.4% of patients receiving the nilotinib dosage equivalent to the recommended dosage of DANZITEN 142 mg and 190 mg twice daily, respectively, and in no patients receiving imatinib. Similar events were also observed in postmarketing reports. Monitor patients for signs of severe fluid retention (e.g., unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during DANZITEN treatment; evaluate etiology and treat patients accordingly. 5.14 Effects on Growth and Development Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with nilotinib. Growth deceleration was more pronounced in children who were less than age 12 at baseline. Monitor growth and development in pediatric patients receiving nilotinib treatment. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 5.15 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, DANZITEN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal lethality/fetal effects (small renal papilla, fetal edema, and skeletal variations) in rats and increased resorptions of fetuses and fetal skeletal variations in rabbits at maternal area under the curve (AUCs) approximately 2 and 0.5 times, respectively, the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)]. 5.16 Monitoring of BCR-ABL Transcript Levels Monitoring of BCR-ABL Transcript Levels in Patients Who Discontinued Nilotinib Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA authorized test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR ABL/ABL ≤ 0.0032% IS). In patients who discontinue DANZITEN therapy, assess BCR-ABL transcript levels monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation [see Clinical Studies (14.3,14.4), Dosage and Administration (2.3)]. Newly diagnosed patients must reinitiate DANZITEN therapy within 4 weeks of a loss of major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS]. Patients resistant or intolerant to prior treatment which included imatinib must reinitiate DANZITEN therapy Reference ID: 5475972 within 4 weeks of a loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0, corresponding to = BCR-ABL/ABL ≤ 0.01% IS). For patients who fail to achieve MMR after three months of treatment reinitiation, BCR-ABL kinase domain mutation testing should be performed. Monitoring of BCR-ABL Transcript Levels in Patients Who Have Reinitiated Therapy After Loss of Molecular Response Monitor CBC and BCR-ABL transcripts in patients who reinitiate treatment with DANZITEN due to loss of molecular response quantitation every 4 weeks until a major molecular response is re-established, then every 12 weeks [see Dosage and Administration (2.4)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with DANZITEN and are discussed in greater detail in other sections of labeling:  Myelosuppression [see Warnings and Precautions (5.2)]  QT Prolongation [see Boxed Warning, Warnings and Precautions (5.3)]  Sudden Deaths [see Boxed Warning, Warnings and Precautions (5.4)]  Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions (5.5)]  Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions (5.6)]  Hepatotoxicity [see Warnings and Precautions (5.7)]  Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions (5.8)]  Hemorrhage [see Warnings and Precautions (5.10)]  Fluid Retention [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of DANZITEN (nilotinib) tablets has been established from adequate and well-controlled studies of Tasigna® (nilotinib) capsules, which has different recommended dosages than DANZITEN, in adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) and adult patients with CP and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib [see Clinical Studies (14)]. Below is a display of the adverse reactions of Tasigna® (nilotinib) capsules in these adequate and well-controlled studies. In Adult Patients With Newly Diagnosed Ph+ CML-CP The data below reflect exposure to nilotinib from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the equivalent recommended dosage of DANZITEN 142 mg twice daily (n = 279). The median time on treatment at the equivalent recommended dosage of DANZITEN 142 mg twice daily group was 61 months (range, 0.1 to 71 months). The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or equal to 10% and greater than 5%). Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) at the equivalent recommended dosage of DANZITEN 142 mg twice daily treatment group. No patient had an absolute QTcF Reference ID: 5475972 of greater than 500 msec while on study drug. The most common hematologic adverse drug reactions (all Grades) were myelosuppression, including: thrombocytopenia (18%), neutropenia (15%), and anemia (8%). See Table 10 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients. In Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP In the single-arm, open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML AP resistant to or intolerant to at least one prior therapy, including imatinib were treated (CML-CP = 321; CML-AP = 137) at the equivalent recommended dosage of DANZITEN 190 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range, 1 to 1096) and 264 (range, 2 to 1160), respectively. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range, 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range, 1 to 234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. The common serious drug-related adverse reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady- state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients and QTcF of greater than 500 msec was observed in 4 patients (less than 1%) [see Boxed Warning, Warnings and Precautions (5.3, 5.4), Clinical Pharmacology (12.2)]. Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 7 and 8 show the percentage of adult patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of adult patients who received at least 1 dose of Nilotinib are listed. Reference ID: 5475972 Reference ID: 5475972 Table 7. Most Frequently Reported Non-Hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Adult Patients With Newly Diagnosed Ph+ CML-CP (≥10% in nilotinib 300 mg twice daily or imatinib 400 mg once daily groups) 60-Month Analysisa Patients With Newly Diagnosed Ph+ CML-CP nilotinib 300 mg Twice Daily* imatinib 400 mg Once Daily nilotinib 300 mg Twice Daily* imatinib 400 mg Once Daily N = 279 N = 280 N = 279 N = 280 Body System and Adverse Reaction All Grades (%) CTC Gradesb 3/4 (%) Skin and subcutaneous tissue disorders Rash 38 19 < 1 2 Pruritus 21 7 < 1 0 Alopecia 13 7 0 0 Dr y skin 12 6 0 0 Gastrointestinal disorders Nausea 22 41 2 2 Constipation 20 8 < 1 0 Diarrhea 19 46 1 4 Vomiting 15 27 < 1 < 1 Abdominal pain upper 18 14 1 < 1 Abdominal pain 15 12 2 0 D yspepsia 10 12 0 0 Nervous system disorders Headache 32 23 3 < 1 Dizziness 12 11 < 1 < 1 General disorders and administration-site conditions Fatigue 23 20 1 1 P yrexia 14 13 < 1 0 Asthenia 14 12 < 1 0 Peripheral edema 9 20 < 1 0 Face edema < 1 14 0 < 1 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 22 17 < 1 < 1 Muscle spasms 12 34 0 1 Pain in extremity 15 16 < 1 < 1 Back pain 19 17 1 1 Respiratory, thoracic, and mediastinal disorders Cough 17 13 0 0 Oropharyngeal pain 12 6 0 0 yspnea 11 6 2 < 1 Infections and infestations Nasopharyngitis 27 21 0 0 Upper respiratory tract infection 17 14 < 1 0 13 9 0 0 Gastroenteritis 7 10 0 < 1 Eye disorders Eyelid edema 1 19 0 < 1 Reference ID: 5475972 Periorbital edema < 1 15 0 0 Psychiatric disorders Insomnia 11 9 0 0 Vascular disorder H ypertension 10 4 1 < 1 Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. aExcluding laboratory abnormalities. bNCI Common Terminology Criteria (CTC) for Adverse Events, version 3.0. Equivalent to the recommended dosage of DANZITEN 142 mg twice daily. I Reference ID: 5475972 Table 8. Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients with Resistant or Intolerant Ph+ CML Receiving Nilotinib 400 mg Twice Daily (regardless of relationship to study drug) (≥10% in any group) 24-Month Analysisa Body System and Adverse Reaction CML-CP CML-AP N = 321 N = 137 All Grades (%) CTC Gradesb 3/4 (%) All Grades (%) CTC Gradesb 3/4 (%) Skin and subcutaneous tissue disorders Rash 36 2 29 0 Pruritus 32 < 1 20 0 Night sweat 12 < 1 27 0 Alopecia 11 0 12 0 Gastrointestinal disorders Nausea 37 1 22 < 1 Constipation 26 < 1 19 0 Diarrhea 28 3 24 2 Vomiting 29 < 1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 < 1 12 < 1 Dyspepsia 10 < 1 4 0 Nervous system disorders Headache 35 2 20 1 General disorders and administration-site conditions Fatigue 32 3 23 < 1 Pyrexia 22 < 1 28 2 Asthenia 16 0 14 1 Peripheral edema 15 < 1 12 0 Musculoskeletal and connective tissue disorders Myalgia 19 2 16 < 1 Arthralgia 26 2 16 0 Muscle spasms 13 < 1 15 0 Bone pain 14 < 1 15 2 Pain in extremity 20 2 18 1 Back pain 17 2 15 < 1 Musculoskeletal pain 11 < 1 12 1 Respiratory, thoracic, and mediastinal disorders Cough 27 < 1 18 0 15 2 9 2 Oropharyngeal pain 11 0 7 0 Infections and infestations Nasopharyngitis 24 < 1 15 0 Upper respiratory tract infection 12 0 10 0 Reference ID: 5475972 Metabolism and nutrition disorders Decreased appetitec 15 < 1 17 < 1 Psychiatric disorders Insomnia 12 1 7 0 Vascular disorders Hypertension 10 2 11 < 1 Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. aExcluding laboratory abnormalities. bNCI Common Terminology Criteria for Adverse Events, version 3.0. cAlso includes preferred term anorexia. Equivalent to the recommended dosage of DANZITEN 190 mg twice daily. Laboratory Abnormalities Table 9 shows the percentage of adult patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of nilotinib. Table 9. Percent Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities Patient Population Newly Diagnosed Adult Ph+ CML-CP Resistant or Intolerant Adult Ph+ CML-CP CML-AP nilotinib 300 mga imatinib 400 mg nilotinib 400 mgb nilotinib 400 mgb Twice Daily Once Daily Twice Daily Twice Daily N = 279 N = 280 N = 321 N = 137 (%) (%) (%) (%) Hematologic Parameters Thrombocytopenia 10 9 301 423 Neutropenia 12 22 312 424 Anemia 4 6 11 27 Biochemistry Parameters Elevated lipase 9 4 18 18 Hyperglycemia 7 < 1 12 6 Hypophosphatemia 8 10 17 15 Elevated bilirubin (total) 4 < 1 7 9 Elevated SGPT (ALT) 4 3 4 4 Hyperkalemia 2 1 6 4 Hyponatremia 1 < 1 7 7 Hypokalemia < 1 2 2 9 Elevated SGOT (AST) 1 1 3 2 Decreased albumin 0 < 1 4 3 Hypocalcemia < 1 < 1 2 5 Elevated alkaline phosphatase 0 < 1 < 1 1 Elevated creatinine 0 < 1 < 1 < 1 Abbreviations: ALT alanine aminotransferase; AST, aspartate aminotransferase; CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. NCI Common Terminology Criteria for Adverse Events, version 3.0. 1CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4. 2CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4. 3CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4. 4CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4. a Equivalent to the recommended dosage of DANZITEN 142 mg twice daily. b Equivalent to the recommended dosage of DANZITEN 190 mg twice daily. Elevated total cholesterol (all Grades) occurred in 28% (equivalent recommended dosage of DANZITEN 142 mg twice daily) and 4% (imatinib). Elevated triglycerides (all Grades) occurred in 12% and 8% of patients in the nilotinib and imatinib arms, respectively. Hyperglycemia (all Grades) occurred in 50% and 31% of patients in the nilotinib and imatinib arms, respectively. Most common biochemistry laboratory abnormalities (all Grades) were alanine aminotransferase increased (72%), blood bilirubin increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood cholesterol increased (28%), and blood triglyceride increased (12%). Reference ID: 5475972 Treatment Discontinuation in Patients With Ph+ CML-CP Who Have Achieved a Sustained Molecular Response (MR4.5) In eligible patients who discontinued nilotinib therapy after attaining a sustained molecular response (MR4.5), musculoskeletal symptoms (e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as noted in Table 9. The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation. In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time during the TFR phase, 23/53 (43%) had not resolved by the TFR end date or data cut-off date. In the population previously treated with imatinib in whom musculoskeletal events occurred at any time during the TFR phase, 32/57 (56%) had not resolved by the data cut-off date. The rate of musculoskeletal symptoms decreased in patients who entered the nilotinib treatment reinitiation (NTRI) phase, at 11/88 (13%) in the newly diagnosed population and 14/56 (25%) in the population previously treated with imatinib. Other adverse reactions observed in the nilotinib re-treatment phase were similar to those observed during nilotinib use in patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP. Table 10. Musculoskeletal Symptoms Occurring Upon Treatment Discontinuation in the Context of Treatment-Free Remission (TFR) Entire TFR Period in all TFR Patients By Time Interval, in Subset of Patients in TFR Greater than 48 Weeks Ph+ CML- CP patients N Median follow- up in Patients with musculoskeletal symptoms N Year prior to nilotinib discontinuation 1st year after nilotinib discontinuation 2nd year after nilotinib discontinuation TFR All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Newly Diagnosed 190 76 weeks 28% 1% 100 17% 0% 34% 2% 9% 0% Previously treated with imatinib 126 99 weeks 45% 2% 73 14% 0% 48% 3% 15% 1% Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive ;TFR, treatment-free remission. Additional Data from Clinical Trials The following adverse drug reactions were reported in adult patients in the nilotinib clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (greater than or equal to 1% and less than 10%), uncommon (greater than or equal to 0.1% and less than 1%), and unknown frequency (single events). For laboratory abnormalities, very common events (greater than or equal to 10%), which were not included in Tables 7 and 8, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies: 1. Adult patients with newly diagnosed Ph+ CML-CP 60 month analysis and, 2. Adult patients with resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis. Infections and Infestations: Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis). Unknown frequency: hepatitis B reactivation, sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant, and Unspecified: Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia. Reference ID: 5475972 Blood and Lymphatic System Disorders: Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia. Psychiatric Disorders: Common: depression, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia, facial paralysis. Unknown frequency: basilar artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Eye Disorders: Common: eye hemorrhage, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilledema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery stenosis, myocardial ischemia, pericardial effusion, cyanosis. Unknown frequency: ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis, peripheral artery stenosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea exertional, epistaxis, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing. Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Hepatobiliary Disorders: Very common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform). Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis. Reference ID: 5475972 Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness. Uncommon: musculoskeletal stiffness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema. Investigations: Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including very low density and high density) increased, total cholesterol increased, blood triglycerides increased. Common: hemoglobin decreased, blood amylase increased, gamma- glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, globulins decreased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased. In Pediatric Patients With Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse reactions were hyperbilirubinemia, headache, alanine aminotransferase increased, rash, pyrexia, nausea, aspartate aminotransferase increased, pain in extremity, upper respiratory tract infection, vomiting, diarrhea, and nasopharyngitis. The most common (greater than 5%) Grade 3/4 non-hematologic adverse reactions were hyperbilirubinemia, rash, alanine aminotransferase increased, and neutropenia. Laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), were reported at a higher frequency than in adult patients. The most common hematological laboratory abnormalities (greater than or equal to 30% of patients, of all Grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (44%), hemoglobin (38%), and absolute lymphocytes (36%). Discontinuation of study treatment due to adverse reactions occurred in 15 patients (22%). The most frequent adverse reactions leading to discontinuation were hyperbilirubinemia (9%) and rash (6%). Increase in QTcF greater than 30 msec from baseline was observed in 19 patients (28%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline. Growth Retardation in Pediatric Population Close monitoring of growth in pediatric patients under nilotinib treatment is recommended [see Warnings and Precautions (5.14)]. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of nilotinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 5475972 Blood and Lymphatic System Disorders: thrombotic microangiopathy Nervous System Disorders: facial paralysis Musculoskeletal and Connective Tissue Disorders: osteonecrosis 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on DANZITEN Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors with DANZITEN. If concomitant use cannot be avoided, reduce DANZITEN dose [see Dosage and Administration (2.9)]. Nilotinib is a CYP3A substrate [see Clinical Pharmacology (12.3)]. Concomitant use with a strong CYP3A inhibitor increases nilotinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of DANZITEN adverse reactions. Strong CYP3A Inducers Avoid concomitant use of strong CYP3A inducers with DANZITEN. Nilotinib is a CYP3A substrate [see Clinical Pharmacology (12.3)]. Concomitant use with a strong CYP3A inducer decreases nilotinib exposure [see Clinical Pharmacology (12.3)], which may reduce DANZITEN efficacy. Proton Pump Inhibitors Avoid concomitant use of PPI with DANZITEN. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of DANZITEN, or use antacids approximately 2 hours before or approximately 2 hours after the dose of DANZITEN. Nilotinib displays pH-dependent aqueous solubility [see Description (11)]. Concomitant use with a proton pump inhibitor (PPI) decreases nilotinib concentrations [see Clinical Pharmacology (12.3)], which may reduce DANZITEN efficacy. 7.2 Drugs That Prolong the QT Interval Avoid coadministration of DANZITEN with agents that may prolong the QT interval, such as anti-arrhythmic drugs [see Boxed Warning, Dosage and Administration (2.5), Warnings and Precautions (5.3), Drug Interactions (7.1), Clinical Pharmacology (12.2)]. Nilotinib is associated with a clinically significant concentration-dependent QT prolongation [see Clinical Pharmacology (12.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, DANZITEN can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo- fetal lethality, fetal effects, and fetal variations in rats and rabbits at maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus. Reference ID: 5475972 The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2%-4% and 15%-20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis. In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses ≥ 30 mg/kg/day. At ≥ 30 mg/kg/day, skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 mg/kg/day. Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day. In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity. Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at this dose. At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72700 nghr/mL and 17100 nghr/mL respectively, representing approximately 2 and 0.5 times the exposure in humans at the highest recommended dose 400 mg twice daily. When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 60 mg/kg (i.e., 360 mg/m2, approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 20 mg/kg (i.e., 120 mg/m2, approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups. 8.2 Lactation Risk Summary There are no data on the presence of nilotinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, nilotinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with DANZITEN and for 14 days after the last dose. Animal Data After a single 20 mg/kg of [14C] nilotinib dose to lactating rats, the transfer of parent drug and its metabolites into milk was observed. The overall milk-to-plasma exposure ratio of total radioactivity was approximately 2, based on the AUC0-24h or AUC0-INF values. No rat metabolites of nilotinib were detected that were unique to milk. 8.3 Females and Males of Reproductive Potential Reference ID: 5475972 Based on animal studies, DANZITEN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Females of reproductive potential should have a pregnancy test prior to starting treatment with DANZITEN. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with DANZITEN and for 14 days after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In studies in rats and rabbits, the fertility in males and females was not affected [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), which were reported at a higher frequency in pediatric patients than in adults [see Adverse Reactions (6.1)]. For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with nilotinib [see Warnings and Precautions (5.14 and 5.12), Adverse Reactions (6.1)]. The safety and effectiveness of nilotinib in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase and accelerated phase, have not been established. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric Use In the clinical trials of nilotinib (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over respectively.  Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged less than 65 years and those greater than or equal to 65 years.  Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged less than 65 years and those greater than or equal to 65 years.  Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients less than 65 years of age and 29% in patients greater than or equal to 65 years. No major differences for safety were observed in patients greater than or equal to 65 years of age as compared to patients less than 65 years. 8.6 Cardiac Disorders In the clinical trials, patients with a history of uncontrolled or significant cardiovascular disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, were excluded. Caution should be exercised in patients with relevant cardiac disorders [see Boxed Warning, Warnings and Precautions (5.3)]. 8.7 Hepatic Impairment Reference ID: 5475972 F F F ?" H O I ~ I N I b l:::-N ..-:: Reduce the DANZITEN dosage in patients with hepatic impairment and monitor the QT interval closely [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of nilotinib were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, observe the patient and provide appropriate supportive treatment. 11 DESCRIPTION DANZITEN (nilotinib) tablets contain nilotinib, a kinase inhibitor. Nilotinib is present as nilotinib tartrate, with the molecular formula of C28H22F3N7O . C4H6O6 and a weight of 679.61 g/mol. Nilotinib tartrate is a white to slightly yellowish powder. The solubility of nilotinib tartrate in aqueous solutions decreases with increasing pH. The pKa1 was determined to be 3.53; pKa2 was estimated to be 1.55. The chemical name of nilotinib tartrate is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5 (trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,(2R,3R)-2,3 dihydroxybutanedionate. Its structure is shown below: DANZITEN (nilotinib) tablets contain 71 mg or 95 mg nilotinib, equivalent to 91.14 mg, and 121.95 mg nilotinib tartrate, respectively. The inactive ingredients are: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, iron oxide red (in 71 mg strength tablets), iron oxide yellow (in 95 mg strength tablets), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Reference ID: 5475972 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM). 12.2 Pharmacodynamics A relationship between nilotinib exposure and a greater likelihood of response and safety events, including a higher occurrence of total bilirubin elevations, was observed in clinical studies. Nilotinib time course of pharmacodynamic response is unknown. Cardiac Electrophysiology Nilotinib is associated with concentration-dependent QT prolongation. At the equivalent recommended dosage of DANZITEN 190 mg twice daily given without food in healthy subjects, the maximum mean placebo-adjusted QTcF changes were 10.4 msec (90% CI: 2.85, 18.0). After a single equivalent recommended dose of DANZITEN 380 mg (two times the maximum approved recommended dose) given with a high fat meal to healthy subjects, the maximum mean placebo-adjusted QTcF changes were) 18.0 msec (90% CI: 9.65, 25.8). Peak plasma concentrations in the QT study were 26% lower than or comparable with those observed in patients enrolled in the single-arm study [see Boxed Warning, Warnings and Precautions (5.3), Adverse Reactions (6.1)]. No new significant QT findings were observed in healthy subject studies with single doses of DANZITEN given with or without food. Throughout the 14 PK studies there were no QT prolongation events associated with DANZITEN. 12.3 Pharmacokinetics Nilotinib single-dose maximum concentration (Cmax), area under the time concentration curve (AUC), predicted steady-state maximum concentration (Cmax,ss) and area under the time concentration curve (AUCss) in fasted subjects receiving the DANZITEN approved recommended dosages are presented in Tables 11 and 12. Table 11: Nilotinib mean ±SD single-dose exposure in fasted patients receiving the DANZITEN approved recommended dosages DANZITEN Dosage Cmax AUC 142 mg 849 ± 366 ng/mL 17637 ± 7744 nghr/mL 190 mg 811 ± 300 ng/mL 15339 ± 6935 nghr/mL Abbreviations: Cmax= maximum concentration; AUC = area under the time concentration curve Table 12: Nilotinib predicted mean ±SD steady-state exposure in fasted patients receiving the DANZITEN approved recommended dosages DANZITEN Dosage Cmax,ss AUCss 142 mg twice daily 2071 ± 761 ng/mL 14525 ± 5690 nghr/mL 190 mg twice daily 2229 ± 790 ng/mL 15662 ± 5738 nghr/mL Abbreviations: Cmax,ss= maximum concentration; AUCss = area under the time concentration curve at steady state Reference ID: 5475972 Absorption The median time (range) to reach peak plasma nilotinib concentrations (Tmax) is 2.7 (1.0 to 4.7 hours) following single dose administration of DANZITEN 190 mg in fasted healthy subjects. Effect of Food No clinically significant differences in nilotinib exposure were observed following administration of DANZITEN 142 mg or 190 mg with a high-fat meal (800 to 1000 calories, 50% fat) or a low-fat meal (400 500 kcal, 25% fat content) compared to fasted healthy subjects. Distribution Serum protein binding is approximately 98% with a blood-to-serum ratio of 0.68. Elimination The mean elimination half-life of nilotinib is approximately 14 hours. Metabolism Nilotinib is primarily metabolized via CYP3A4-mediated oxidation and to a minor extent by CYP2C8. Excretion After a single dose of radiolabeled nilotinib, more than 90% of the administered dose was eliminated within 7 days: 93% of the dose in feces. Parent drug accounted for 69% of the dose. Specific Populations No clinically significant differences in the pharmacokinetic of nilotinib were observed based on age, sex, race/ethnicity, or body weight. The effect of renal impairment on nilotinib pharmacokinetics is unknown. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Patients with Hepatic Impairment Nilotinib mean AUC increased 1.4-fold in mild (Child-Pugh class A), 1.4-fold in moderate (Child-Pugh class B), and 1.6-fold in severe (Child-Pugh class C) hepatic impairment subjects following a single equivalent recommended dose of DANZITEN 95 mg (66% of the lowest approved recommended dosage). Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors: Nilotinib AUC increased by approximately 3-fold following concomitant administration of ketoconazole (strong CYP3A inhibitor) 400 mg once daily for 6 days. Nilotinib AUC increased by 1.3-fold with concomitant use with double-strength grapefruit juice. Strong CYP3A Inducers: Nilotinib AUC decreased by approximately 80% following concomitant use with rifampicin (strong CYP3A inducer) 600 mg daily. Proton Pump Inhibitors (PPIs): Nilotinib displays pH-dependent aqueous solubility [see Description (11)]. Nilotinib AUC decreased by 34% following concomitant use of multiple doses of esomeprazole (PPI) 40 mg daily. Other Drugs: No clinically significant differences in nilotinib pharmacokinetics were observed when used concomitantly with imatinib (moderate CYP3A inhibitor), famotidine (an H2 blocker), or an antacid. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with nilotinib; oral midazolam (CYP3A substrate), imatinib, or warfarin (CYP2C9 substrate). In Vitro Studies Where Drug Interaction Potential was not Further Evaluated Clinically Reference ID: 5475972 CYP Enzymes: Nilotinib is a competitive inhibitor of CYP2C8, CYP2D6, and is an inducer of CYP2B6 and CYP2C8. Transporter Systems: Nilotinib is an inhibitor of UGT1A1 and P-gp. 12.5 Pharmacogenomics Nilotinib can increase bilirubin levels. The (TA)7/(TA)7 genotype of UGT1A1 was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A128) patients [see Warnings and Precautions (5.7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted orally in rats at nilotinib doses of 5, 15, and 40 mg/kg/day. Exposures in animals at the highest dose tested were approximately 2- to 3-fold the human exposure (based on AUC) at the nilotinib dose of 400 mg twice daily. The study was negative for carcinogenic findings. A 26 week carcinogenicity study was conducted orally in Tg.rasH2 mice, a model genetically modified to enhance susceptibility to neoplastic transformation, at nilotinib doses of 30, 100, and 300 mg/kg/day. Nilotinib induced in the skin and subcutis statistically significant increases in the incidence of papillomas in females and of papillomas and combined papillomas and carcinomas in males at 300 mg/kg/day. The no-observed-adverse- effect-level (NOAEL) for skin neoplastic lesions was 100 mg/kg/day. Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral treatments at doses up to 2000 mg/kg/dose. There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in rats (approximately 4- to 7-fold for males and females, respectively, the AUC in patients at the dose of 400 mg twice daily) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the dose of 400 mg twice daily). The effect of nilotinib on human fertility is unknown. In a study where male and female rats were treated with nilotinib at oral doses of 20 to 180 mg/kg/day (approximately 1- to 6.6-fold the AUC in patients at the dose of 400 mg twice daily) during the pre-mating and mating periods and then mated, and dosing of pregnant rats continued through gestation Day 6, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested. Reference ID: 5475972 14 CLINICAL STUDIES 14.1 Adult Newly Diagnosed Ph+ CML-CP The effectiveness of 142 mg twice daily of DANZITEN (nilotinib) tablets for the treatment of adult patients with newly diagnosed Ph+ CML-CP has been established from an adequate and well-controlled study of Tasigna® (nilotinib) capsules, which has a different recommended dosage than DANZITEN. Below is a display of the results of Tasigna® (nilotinib) capsules in this adequate and well-controlled study. The ENESTnd (Evaluating Nilotinib Efficacy and Safety in clinical Trials-Newly Diagnosed patients) study (NCT00471497) was an open-label, multicenter, randomized trial conducted to determine the efficacy of nilotinib versus imatinib in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib dosage equivalent to DANZITEN 142 mg twice daily group, 281 patients in the nilotinib dosage equivalent to DANZITEN 190 mg twice daily group (an unapproved dosage regimen for this indication). Median age was 46 years in the imatinib group and 47 years in the nilotinib group, with 12% and 13% of patients greater than or equal to 65 years of age in imatinib 400 mg once daily and nilotinib dosage equivalent to DANZITEN 142 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56% and 56%, in imatinib 400 mg once daily and nilotinib dosage equivalent to DANZITEN 142 mg twice daily treatment groups). Approximately 60% of all patients were White, and 25% were Asian. The primary data analysis was performed when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment (or discontinued earlier). The median time on treatment was approximately 61 months in all three treatment groups. The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 13. Two patients in the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment) while 12 patients on the imatinib arm progressed to either accelerated phase or blast crisis (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months). Table 13 Efficacy (MMR and CCyR) of Nilotinib Compared to imatinib in Adult Newly Diagnosed Ph+ CML-CP (ENESTnd) Nilotinib 300 mg Twice Daily* Imatinib 400 mg Once Daily N = 282 N = 283 MMR at 12 months (95% CI) 44% (38.4, 50.3) 22% (17.6, 27.6) P-Valuea < 0.0001 CCyRb by 12 months (95% CI) 80% (75.0, 84.6) 65% (59.2, 70.6) MMR at 24 months (95% CI) 62% (55.8, 67.4) 38% (31.8, 43.4) CCyRb by 24 months (95% CI) 87% (82.4, 90.6) 77% (71.7, 81.8) Abbreviation: CI, confidence interval. * Equivalent to DANZITEN 142 mg twice daily. aCMH test stratified by Sokal risk group. bCCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the percentage of Ph+ metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample. By 60 months, MMR was achieved by 77% of patients on nilotinib and 60% of patients on imatinib; MR4.5 Reference ID: 5475972 was achieved by 53.5% of patients on nilotinib and 31.4% on imatinib. Median overall survival was not reached in either arm. At the time of the 60-month final analysis, the estimated survival rate was 93.7% for patients on nilotinib and 91.7% for patients on imatinib. Reference ID: 5475972 14.2 Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP The effectiveness of 190 mg twice daily of DANZITEN (nilotinib) tablets for the treatment of adult patients with Ph+ CML- CP and Ph+ CML-AP resistant or intolerant to prior therapy that included imatinib has been established from an adequate and well-controlled study of Tasigna® (nilotinib) capsules, which has a different recommended dosage than DANZITEN. Below is a display of the results of Tasigna® (nilotinib) capsules in this adequate and well-controlled study. Study CAMN107A2101 (referred to as Study A2101) (NCT00109707) was a single-arm, open-label, multicenter study conducted to evaluate the efficacy and safety of nilotinib (dosage equivalent to DANZITEN 190 mg twice daily) in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut- off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 80% (CML-AP) were White, and approximately 30% were age 65 years or older. Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant. The median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior therapy included hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%. The median highest prior imatinib dose was 600 mg per day for patients with CML-CP and CML-AP, and the highest prior imatinib dose was greater than or equal to 600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses greater than or equal to 800 mg/day. Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients with CML-AP. The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses. The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML AP patients are reported in Table 14. Median durations of response had not been reached at the time of data analysis. Table 14 Efficacy of Nilotinib in Adult Resistant or Intolerant Ph+ CML-CP and CML-AP (Study A2101) Cytogenetic Response Rate (Unconfirmed) (%)a Chronic Phase (n = 321) Major (95% CI) 51% (46%–57%) Complete (95% CI) 37% (32%–42%) Partial (95% CI) 15% (11%–19%) Accelerated Phase (n = 137) Hematologic Response Rate (Confirmed) (95% CI)b 39% (31%–48%) Complete Hematologic Response Rate (95% CI) 30% (22%–38%) No Evidence of Leukemia (95% CI) 9% (5%–16%) aCytogenetic response criteria: Complete (0% Ph+ metaphases) or partial (1% to 35%). Cytogenetic responses were based on the percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample. bHematologic response = CHR + NEL (all responses confirmed after 4 weeks). CHR (CML-CP): WBC less than 10 x 109/L, platelets less than 450,000/mm3, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. CHR (CML-AP): neutrophils greater than or equal to 1.5 x 109/L, platelets greater than or equal to 100 x 109/L, no Reference ID: 5475972 myeloblasts in peripheral blood, myeloblasts less than 5% in bone marrow, and no extramedullary involvement. NEL: same criteria as for CHR but neutrophils greater than or equal to 1.0 x 109/L and platelets greater than or equal to 20 x 109/L without transfusions or bleeding. Reference ID: 5475972 Adult Patients With Chronic Phase The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 months (range, 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of exposure on this single arm-trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of them had MCyR lasting more than 18 months. The CCyR rate was 37%. Adult Patients With Accelerated Phase The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to first hematologic response among responders was 1 month (range, 1 to 14 months). Among the CML-AP patients who achieved HR, 44% of them had a response lasting for more than 18 months. After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of accelerated phase CML patients who were evaluated for mutations. 14.3 Treatment Discontinuation in Newly Diagnosed Ph+ CML-CP Patients Who Have Achieved a Sustained Molecular Response (MR4.5) The efficacy of DANZITEN (nilotinib) tablets treatment discontinuation in adult patients with newly diagnosed Ph+ CML-CP has been established from an adequate and well-controlled study of Tasigna® (nilotinib) capsules, which has a different recommended dosage than DANZITEN. Below is a display of the results of Tasigna® (nilotinib) capsules in this adequate and well-controlled study. The ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in clinical Trials-freedom) study (NCT01784068) is an open-label, multicenter, single-arm study, where 215 adult patients with Ph+ CML-CP treated with nilotinib in first-line for ≥ 2 years who achieved MR4.5 as measured with the MolecularMD MRDx® BCR-ABL Test were enrolled to continue nilotinib treatment for an additional 52 weeks (nilotinib consolidation phase). Of the 215 patients, 190 patients (88.4%) entered the “Treatment-Free Remission” (TFR) phase after achieving a sustained molecular response (MR4.5) during the consolidation phase, defined by the following criteria:  The 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR-ABL/ABL ≤ 0.01% IS), and maintained for 1 year  The last assessment being MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS)  No more than two assessments falling between MR4 and MR4.5 (0.0032% IS < BCR-ABL/ABL ≤ 0.01% IS). The median age of patients who entered the TFR phase was 55 years, 49.5% were females, and 21.1% of the patients were ≥ 65 years of age. BCR-ABL levels were monitored every 4 weeks during the first 48 weeks of the TFR phase. Monitoring frequency was intensified to every 2 weeks upon the loss of MR4.0. Biweekly monitoring ended at one of the following time points:  Loss of MMR requiring patient to reinitiate nilotinib treatment  When the BCR-ABL levels returned to a range between MR4.0 and MR4.5  When the BCR-ABL levels remained lower than MMR for 4 consecutive measurements (8 weeks from initial loss of MR4.0). Any patient with loss of MMR during the TFR phase reinitiated nilotinib at a dosage equivalent to DANZITEN 142 mg twice daily or at a reduced dose level equivalent to DANZITEN 190 mg once daily if required from the perspective of tolerance, within 5 weeks after the collection date of the blood sample demonstrating loss of MMR. Patients who required reinitiation of nilotinib treatment were monitored for BCR-ABL levels every 4 weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR. Efficacy was based on the 96-week analysis data cut-off date, by which time, 91 patients (47.9%) discontinued from the TFR phase due to loss of MMR, and 1 (0.5%), 1 (0.5%), 1 (0.5%) and 3 patients (1.6%) due to death Reference ID: 5475972 100• 90 80· ...... l 70· ni > -~ 60 :, 1/1 QI so QI i 40· QI E io 30· QI ... I- 20· 10· \ \ '. . ' ' ' ' . '' . ' \ ' . ' I \ •, ' . - - , -- -------~--~----------------~ ----~--~-----~- --------- Pat Evt (en 190 98 92 ime when ther was discontinued I I Censored observations 0· 0 12 At-risk : Events 190 : 0 24 36 120 : 70 48 60 72 84 96 Time since TFR (weeks) 99 : 91 95 : 95 75 : 97 108 120 132 144 8: 97 0: 98 from unknown cause, physician decision, lost to follow-up and subject decision, respectively. Among the 91 patients who discontinued the TFR phase due to loss of MMR, 88 patients restarted nilotinib treatment and 3 patients permanently discontinued from the study. By the 96-week data cut-off of the 88 patients who restarted treatment due to loss of MMR in the TFR phase, 87 patients (98.9%) patients regained MMR (one patient discontinued study permanently due to subject decision after 7.1 weeks of retreatment without regaining MMR) and 81 patients (92.0%) regained MR4.5 by the time of the cut-off date. The cumulative rate of MMR and MR4.5 regained at 24 weeks since treatment reinitiation was 97.7% (86/88 patients) and 86.4% (76/88 patients), respectively. Table 15 Efficacy Results for ENESTfreedom Patients Who Entered the Treatment Free Remission (TFR) Phase (Full Analysis Set, N = 190) Patients in TFR phase1 at the specified time point Loss of MMR2 by the specified time point % 95% CI % 24 weeks 62.1 (54.8, 69.0) 35.8 48 weeks 51.6 (44.2, 58.9) 45.8 96 weeks 48.9 (41.6, 56.3) 47.9 Abbreviation: CI, confidence interval. 1Patients in MMR at the specified time point in the TFR phase. 2Based on the time to event (loss of MMR) data during the TFR phase. Among the 190 patients in the TFR phase, 98 patients had a treatment-free survival (TFS) event (defined as discontinuation from TFR phase due to any reason, loss of MMR, death due to any cause, progression to AP/BC up to the end of TFR phase, or reinitiation of treatment due to any cause in the study) by the 96-week cut-off date. Figure 1. Kaplan-Meier Estimate of Treatment-Free Survival After Start of TFR (Full Analysis Set ENESTfreedom) 1. For a given time point, the points on the dashed curves represent the 95% confidence limits for the associated KM estimate on the solid curve. 2. By the time of the 96-week data cut-off date, one single patient lost MMR at Week 120, at the time when only 8 patients were considered at risk. This explains the artificial drop at the end of the curve. Reference ID: 5475972 14.4 Treatment Discontinuation in Ph+ CML-CP Patients Who Have Achieved a Sustained Molecular Response (MR4.5) on DANZITEN Following Prior Imatinib Therapy The efficacy of DANZITEN (nilotinib) tablets treatment discontinuation in adult patients with Ph+ CML-CP following prior imatinib has been established from an adequate and well-controlled study of Tasigna® (nilotinib) capsules. Below is a display of the results of Tasigna® (nilotinib) capsules in this adequate and well-controlled study. The ENESTop (Evaluating Nilotinib Efficacy and Safety in clinical Trials-STop) study (NCT01698905) is an open-label, multicenter, single-arm study, where 163 adult patients with Ph+ CML-CP taking tyrosine kinase inhibitors (TKIs) for ≥ 3 years (imatinib as initial TKI therapy for more than 4 weeks without documented MR4.5 on imatinib at the time of switch to nilotinib, then switched to nilotinib for at least 2 years), and who achieved MR4.5 on nilotinib treatment as measured with the MolecularMD MRDx® BCR-ABL Test were enrolled to continue nilotinib treatment for an additional 52 weeks (nilotinib consolidation phase). Of the 163 patients, 126 patients (77.3%) entered the TFR phase after achieving a sustained molecular response (MR4.5) during the consolidation phase, defined by the following criterion: • The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 (BCR ABL/ABL ≤ 0.0032% IS) during 1 year. The median age of patients who entered the TFR phase was 56 years, 55.6% were females, and 27.8% of the patients were ≥ 65 years of age. The median actual dose intensity during the 52-week nilotinib consolidation phase was 771.8 mg/day with 52.4%, 29.4%, 0.8%, 16.7%, and 0.8% of patients receiving a daily nilotinib dosage equivalent to DANZITEN 380 mg, 284 mg, 213 mg, 190 mg and 142 mg just before entry into the TFR phase, respectively. Patients who entered the TFR phase but experienced two consecutive measurements of BCR-ABL/ABL > 0.01% IS were considered having a confirmed loss of MR4.0, triggering reinitiation of Nilotinib treatment. Patients with loss of MMR in the TFR phase immediately restarted nilotinib treatment without confirmation. All patients who restarted nilotinib therapy had BCR-ABL transcript levels monitored every 4 weeks for the first 24 weeks, then once every 12 weeks. Efficacy was based on the 96-week analysis data cut-off date, by which time, 61 patients (48.4%) had discontinued from the TFR phase: 58 patients (46.0%) due to loss of MMR or confirmed loss of MR4.0, 2 patients (1.6%) due to subject/guardian decision and one patient (0.8%) due to pregnancy. Among the 58 patients who discontinued from the TFR phase due to confirmed loss of MR4.0 or loss of MMR, 56 patients restarted Nilotinib therapy and 2 patients permanently discontinued from the study. By the 96-week data cut-off, of the 56 patients who restarted nilotinib treatment due to confirmed loss of MR4.0 or loss of MMR in the TFR phase, 52 patients (92.9%) regained MR4.0 and MR4.5; 4 patients (7.1%) did not regain MR4.0 by the time of the cut-off date. The cumulative rate of MR4 and MR4.5 regained by 48 weeks since treatment reinitiation, was 92.9% (52/56 patients) and 91.1% (51/56 patients), respectively. Table 16 Efficacy Results for ENESTop Patients Who Entered the Treatment Free Remission (TFR) Phase (Full Analysis Set, N = 126) Patients in TFR phase1 at the specified time point Loss of MMR or confirmed loss of MR42 by the specified time point % 95% CI % 24 weeks 60.3 (51.2, 68.9) 38.9 48 weeks 57.9 (48.8, 66.7) 41.3 96 weeks 53.2 (44.1, 62.1) 43.7 Abbreviation: CI, confidence interval. 1Patients without loss of MMR or confirmed loss of MR4 by specified time point of TFR phase. 2Based on the time to event (loss of MMR or confirmed loss of MR4) data during the TFR phase. Reference ID: 5475972 100 90 80 ~ l 70 "iii "----~-------- > ·~ - - - - - ' - - - - .. _ - - - , 60 :::, 1/) ·- <LI 50 <LI ~ - - - - - - - I, -- - - - - c 40 <LI E iii 30 ~ I- 20 10 i me when the rap was discontinued 0 0 12 24 36 48 At - risk : Events 126 : 0 107 : 19 76 : 50 74 : 52 73 : 53 ----- ... 60 72 84 Time since TFR (weeks) 72 : 54 71 : 55 70 : 56 -- .. __ _ Pat Evt Cen 126 61 65 I I I Censored observations 96 108 120 132 144 55 : 58 32 : 60 13 : 61 1 : 61 0: 61 Among the 126 patients in the TFR phase, 61 patients (48.4%) had a treatment-free survival (TFS) event (defined as discontinuation from TFR phase due to any reason, loss of MMR, confirmed loss of MR4, death due to any cause, progression to AP/BC up to the end of TFR phase, or reinitiation of treatment due to any cause in the study) on or before the 96-month cut-off date. Figure 2: Kaplan-Meier Estimate of Treatment-Free Survival after Start of TFR (Full Analysis Set ENESTop) 1. For a given time point, the points on the dashed curves represent the 95% confidence limits for the associated KM estimate on the solid curve. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 16 HOW SUPPLIED/STORAGE AND HANDLING DANZITEN (nilotinib) 71 mg tablets are pink, coated, oblong tablets, debossed with “N5” on one side and plain on other side. DANZITEN (nilotinib) 95 mg tablets are yellow, coated, oblong tablets, debossed with “N2” on one side and plain on other side. DANZITEN (nilotinib) 71 mg and 95 mg tablets are supplied in blister packs. 71 mg Outer Carton containing 4 inner carton packs (4x28) .................................................. NDC 24338-154-01 Inner carton containing 2 blister packs (2x14) ................................................................ NDC 24338-154-02 Blisters of 14 tablets (1x14) ......................................................................................... NDC 24338-154-03 95 mg Outer Carton containing 4 inner carton packs (4x28) .................................................. .NDC 24338-155-01 Inner carton containing 2 blister packs (2x14)………………………………………. NDC 24338-155-02 Blisters of 14 tablets (1x14) ......................................................................................... NDC 24338-155-03 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Reference ID: 5475972 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Taking DANZITEN Advise patients that DANZITEN may not be substitutable, on a milligram per milligram basis, with other nilotinib products. Advise patients to take DANZITEN exactly as prescribed [see Warnings and Precautions (5.1)]. Advise patients to take DANZITEN doses twice daily approximately 12 hours apart. Advise patients to swallow the tablets whole with water and not to cut, crush, or chew the tablets. Advise patients to take DANZITEN with or without food. Patients should not consume grapefruit products and other foods that are known to inhibit CYP3A4 at any time during DANZITEN treatment [see Dosage and Administration (2.2), Drug Interactions (7.1)]. If the patient misses a dose of DANZITEN, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. Compliance Advise patients of the following:  Continue taking DANZITEN every day for as long as their doctor tells them.  This is a long-term treatment.  Do not change dose or stop taking DANZITEN without first consulting their doctor. Myelosuppression Advise patients that treatment with nilotinib can cause serious thrombocytopenia, neutropenia, and anemia. Advise patients to seek immediate medical attention if symptoms suggestive of low blood counts occur, such as fever, chills or other signs of infection, unexplained bleeding or bruising, or unexplained weakness or shortness of breath [see Warnings and Precautions (5.2)]. QT Prolongation Advise patients that nilotinib can cause possibly life-threatening, abnormal heartbeat. Advise patients to seek immediate medical attention if symptoms of abnormal heartbeat occur, such as feeling light-headed, faint or experiencing an irregular heartbeat [see Warnings and Precautions (5.3)]. Cardiac and Arterial Vascular Occlusive Events Advise patients that cardiovascular events (including ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular events) have been reported. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur, such as chest or leg pain, numbness or weakness, or problems walking or speaking occur suddenly [see Warnings and Precautions (5.5)]. Pancreatitis and Elevated Serum Lipase Advise patients that nilotinib can increase the risk of pancreatitis and that patients with a previous history of pancreatitis may be at greater risk. Advise patients to seek immediate medical attention if symptoms suggestive of pancreatitis occur, such as sudden stomach area pain with accompanying nausea and vomiting [see Warnings and Precautions (5.6)]. Hepatotoxicity Advise patients that nilotinib can increase the risk of hepatotoxicity and that patients with previous history of liver diseases may be at risk. Advise patients to seek immediate medical attention if any symptoms suggestive of hepatotoxicity occur, such as stomach pain, yellow skin and eyes, and dark-colored urine [see Warnings and Precautions (5.7)]. Reference ID: 5475972 Tumor Lysis Syndrome Advise patients that nilotinib can cause TLS and to seek immediate medical attention if any symptoms suggestive of TLS occur, such as an abnormal heartbeat or less urine production [see Warnings and Precautions (5.9)]. Hemorrhage Advise patients that serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with nilotinib. Advise patients to seek immediate medical attention if symptoms suggestive of hemorrhage occur, such as uncontrolled bleeding, changes in eyesight, unconsciousness, or sudden headache or sudden confusion in surroundings [see Warnings and Precautions (5.10)]. Fluid Retention Advise patients that nilotinib can cause fluid retention and to seek immediate medical attention if any symptoms suggestive of fluid retention, such as shortness of breath, rapid weight gain, or swelling occur [see Warnings and Precautions (5.13)]. Effects on Growth and Development in Pediatric Patients Inform pediatric patients and their caregivers of the possibility of developing growth abnormalities. Growth retardation has been reported in pediatric patients treated with nilotinib. Therefore, monitor growth and development in pediatric patients [see Warnings and Precautions (5.14)]. Treatment-Free Remission (TFR) Advise patients that frequent monitoring is required to detect possible loss of remission if TFR is attempted. Advise patients that musculoskeletal symptoms, such as muscle pain, pain in extremity, joint pain, bone pain, or spinal pain, may occur more frequently than before treatment discontinuation [see Warnings and Precautions (5.16)]. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after receiving the last dose of DANZITEN [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with DANZITEN and for 14 days after the last dose [see Use in Specific Populations (8.2)]. Drug Interactions Advise patients that DANZITEN and certain other medicines, including over the counter medications or herbal supplements (such as St. John’s Wort), can interact with each other [see Drug Interactions (7)]. Manufactured for: Azurity Pharmaceuticals, Inc. Woburn, MA 01801 Reference ID: 5475972 Medication Guide DANZITEN (dan-zi-ten) (nilotinib) tablets What is the most important information I should know about DANZITEN? DANZITEN can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an irregular heartbeat, which may lead to sudden death. Your healthcare provider should check the electrical activity of your heart with a test called an electrocardiogram (ECG):  before starting DANZITEN  with any dose changes  7 days after starting DANZITEN  regularly during DANZITEN treatment You may lower your chances for having QTc prolongation with Nilotinib if you:  Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract during treatment with DANZITEN. Grapefruit products increase the amount of Nilotinib in your body.  Avoid taking other medicines or supplements with Nilotinib that can also cause QTc prolongation.  Nilotinib can interact with many medicines and supplements and increase your chance for serious and life- threatening side effects.  Do not take any other medicine during treatment with DANZITEN unless your healthcare provider tells you it is okay to do so.  For more information, see “How should I take DANZITEN?” Call your healthcare provider right away if you feel lightheaded, faint, or have an irregular heartbeat during treatment with DANZITEN. These can be symptoms of QTc prolongation. See “What are the possible side effects of DANZITEN? for more information about side effects. What is DANZITEN? DANZITEN is a prescription medicine used to treat:  adults who have been newly diagnosed with a certain type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.  adults with chronic phase Ph+ CML or accelerated phase Ph+ CML who: o are no longer benefiting from other treatments, including imatinib (Gleevec), or o have taken other treatments, including imatinib (Gleevec), and cannot tolerate them. It is not known if nilotinib is safe and effective in children younger than 1 year of age with newly diagnosed, resistant, or intolerant Ph+ CML in chronic phase. The long-term effects of treating children with nilotinib for a long period of time are not known. Who should not take DANZITEN? Do not take if you have:  low levels of potassium or magnesium in your blood  long QTc syndrome Before taking DANZITEN, tell your healthcare provider about all of your medical conditions, including if you:  have heart problems  have had a stroke or other problems due to decreased blood flow to the brain  have problems with decreased blood flow to your legs  have irregular heartbeat  have QTc prolongation or a family history of it  have liver problems  have had pancreatitis  have low blood levels of potassium or magnesium in your blood  have bleeding problems  had a surgical procedure involving the removal of the entire stomach (total gastrectomy)  are pregnant or plan to become pregnant. Nilotinib can harm your unborn baby. Tell your healthcare provider right away if you are pregnant, or if you become pregnant during treatment with DANZITEN. In females who are able to become pregnant: Reference ID: 5475972  Your healthcare provider should do a pregnancy test before you start treatment with DANZITEN.  Use effective birth control (contraception) during treatment with DANZITEN and for 14 days after the last dose.  are breastfeeding or plan to breastfeed. It is not known if Nilotinib passes into your breast milk. Do not breastfeed during treatment and for 14 days after your last dose of DANZITEN. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. If you need to take antacids (medicines to treat heartburn) do not take them at the same time that you take DANZITEN. If you take:  a medicine to block the amount of acid produced in the stomach (H2 blocker): Take these medicines about 10 hours before you take DANZITEN, or about 2 hours after you take DANZITEN.  an antacid that contains aluminum hydroxide, magnesium hydroxide, and simethicone to reduce the amount of acid in the stomach: Take these medicines about 2 hours before or about 2 hours after you take DANZITEN. Nilotinib can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects. See “What is the most important information I should know about DANZITEN?” How should I take DANZITEN?  Do not switch from DANZITEN to other medicines that contain nilotinib without talking to your healthcare provider. The amount of nilotinib in a dose of DANZITEN may not be the same as the amount in other medicines that contain nilotinib.  Take DANZITEN exactly as your healthcare provider tells you to take it.  Do not change your dose or stop taking DANZITEN unless your healthcare provider tells you.  DANZITEN is a long-term treatment.  Take your prescribed dose of DANZITEN 2 times a day, about 12 hours apart.  Swallow DANZITEN tablets whole with water. Do not cut, crush, or chew the tablets. If you cannot swallow DANZITEN whole, tell your healthcare provider.  Take DANZITEN with or without food.  Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract at any time during treatment. See “What is the most important information I should know about DANZITEN?”  If you miss a dose, just take your next dose at your regular time. Do not take 2 doses at the same time to make up for a missed dose.  If you take too much DANZITEN, call your healthcare provider or go to the nearest hospital emergency room right away. Symptoms may include vomiting and drowsiness.  During treatment with DANZITEN your healthcare provider will do tests to check for side effects and to see how well DANZITEN is working for you. The tests will check your: o heart o blood cells (white blood cells, red blood cells, and platelets). Your blood cells should be checked every 2 weeks for the first 2 months and then monthly. o electrolytes (potassium, magnesium) o pancreas and liver function o bone marrow samples Your healthcare provider may change your dose. Your healthcare provider may have you stop DANZITEN for some time or lower your dose if you have side effects with it.  Your healthcare provider will monitor your CML during treatment with DANZITEN to see if you are in a remission. After at least 3 years of treatment with DANZITEN, your healthcare provider may do certain tests to determine if you continue to be in remission. Based on your test results, your healthcare provider may decide if you may be eligible to try stopping treatment with DANZITEN. This is called Treatment Free Remission (TFR).  Your healthcare provider will carefully monitor your CML during and after you stop taking DANZITEN. Based on your test results, your healthcare provider may need to re-start your DANZITEN if your CML is no longer in remission.  It is important that you are followed by your healthcare provider and undergo frequent monitoring to find out if you need to re-start your DANZITEN treatment because you are no longer in TFR. Follow your healthcare provider’s instructions about re-starting DANZITEN if you are no longer in TFR. What are the possible side effects of DANZITEN? DANZITEN may cause serious side effects, including:  See “What is the most important information I should know about DANZITEN?”  Low blood cell counts. Low blood cell counts (red blood cells, white blood cells, and platelets) are common with DANZITEN, but can also be severe. Your healthcare provider will check your blood counts regularly during treatment Reference ID: 5475972 with DANZITEN. Call your healthcare provider or get medical help right away if you develop any signs or symptoms of low blood counts, including: o fever o unexplained bleeding or bruising o shortness of breath o chills or other signs of o unexplained weakness infection  Decreased blood flow to the leg, heart, or brain. People who have recently been diagnosed with Ph+ CML and take DANZITEN may develop decreased blood flow to the leg, the heart, or brain. Get medical help right away if you suddenly develop any of the following symptoms: o chest pain or discomfort o problems walking or speaking o your leg feels cold o numbness or weakness o leg pain o change in the skin color of your leg  Pancreas inflammation (pancreatitis). Tell your healthcare provider right away if you develop any symptoms of pancreatitis, including sudden stomach area pain with nausea and vomiting.  Liver problems. DANZITEN can increase your risk of liver problems. People who have had liver problems in the past may be at risk for getting liver problems with DANZITEN. Call your healthcare provider or get medical help right away if you develop any symptoms of liver problems, including: o stomach area (abdominal) pain o yellow skin and eyes o dark-colored urine  Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. Your healthcare provider may do blood tests to check you for TLS. TLS can cause you to have: ○ kidney failure and the need for dialysis treatment ○ an abnormal heartbeat  Bleeding problems. Serious bleeding problems and death have happened during treatment with DANZITEN. Tell your healthcare provider right away if you develop any signs and symptoms of bleeding during treatment with DANZITEN.  Fluid retention. Your body may hold too much fluid (fluid retention). Symptoms of fluid retention include shortness of breath, rapid weight gain, and swelling.  Abnormal growth or development in children. Effects on growth and development have happened in children with chronic phase Ph+ CML during treatment with nilotinib. Some children and adolescents may have slower than normal growth during treatment with nilotinib. The most common side effects of DANZITEN in adults include:  nausea  cough  rash  constipation  headache  muscle and joint pain  tiredness  runny or stuffy nose, sneezing, sore throat  itching  fever  vomiting  night sweats  diarrhea Side effects in adults attempting treatment free remission: If you and your healthcare provider decide that you can stop taking DANZITEN and try treatment free remission (TFR), you may have more muscle and bone (musculoskeletal) symptoms than before you stopped treatment. Symptoms may include:  muscle pain  bone pain  spine pain  arm and leg pain  joint pain Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the possible side effects of DANZITEN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DANZITEN?  Store DANZITEN at room temperature between 68°F to 77°F (20°C to 25°C).  Safely throw away medicine that is out of date or no longer needed. Keep DANZITEN and all medicines out of the reach of children. General information about the safe and effective use of DANZITEN. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DANZITEN for a condition for which it was not prescribed. Do not give DANZITEN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DANZITEN that is written for health professionals. Reference ID: 5475972 What are the ingredients in DANZITEN? Active ingredient: nilotinib tartrate Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, iron oxide red (in 71 mg strength tablets), iron oxide yellow (in 95 mg strength tablets), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Manufactured for: Azurity Pharmaceuticals, Inc. Woburn, MA 0180 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5475972	custom-source	2025-02-12T15:46:35.302061	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219293s000lbl.pdf', 'application_number': 219293, 'submission_type': 'ORIG ', 'submission_number': 1}
80,200	Proposed Draft Labeling NDA 22-032 Omeprazole Delayed Release Tablets, 20 mg 14 Tablets (Blister Foil) Location for lot number and expiration date 91574 00 X9 Mfd. by: Dexcel Pharma Technologies Ltd., 10 Hakidma St., Yokneam Illit, 2069200, Israel READ WARNINGS AND DIRECTIONS ON CARTON BEFORE USE. KEEP OUTER CARTON FOR COMPLETE WARNINGS AND PRODUCT INFORMATION. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. Omeprazole DR Tablets 20 mg / Acid Reducer Push tablet through foil. Swallow whole. Do not chew or crush tablets. Take 1 tablet a day for 14 days. THIS SINGLE 14-TABLETS BLISTER PACKAGE CONTAINS ONE 14-DAY COURSE OF TREATMENT. DO NOT TAKE FOR MORE THAN 14 DAYS OR MORE OFTEN THAN EVERY 4 MONTHS UNLESS DIRECTED BY A DOCTOR. Reference ID: 5476284 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ NUSHIN F TODD 11/08/2024 10:02:48 AM Signature Page 1 of 1 Reference ID: 5476284 ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:35.581665	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022032Orig1s065lbl.pdf', 'application_number': 22032, 'submission_type': 'SUPPL ', 'submission_number': 65}
80,190	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LINEZOLID injection safely and effectively. See full prescribing information for LINEZOLID injection. LINEZOLID injection, for intravenous use Initial U.S. Approval: 2000 -------------------------- RECENT MAJOR CHANGES ------------------------- Warnings and Precautions, Myelosuppression (5.1) 11/2024 --------------------------- INDICATIONS AND USAGE --------------------------- Linezolid is an oxazolidinone-class antibacterial indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia (1.1); Community-acquired pneumonia (1.2); Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis (1.3); Vancomycin-resistant Enterococcus faecium infections. (1.4) Limitations of Use: (1.5)  Linezolid is not indicated for the treatment of Gram-negative infections.  The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials. To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid formulations and other antibacterial drugs, linezolid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.6) ----------------------- DOSAGE AND ADMINISTRATION --------------------- Dosage, Route, and Frequency of Administration Infection Pediatric Patients (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Duration (days) Nosocomial pneumonia (1.1) Community-acquired pneumonia, including concurrent bacteremia (1.2) Complicated skin and skin structure infections (1.3) 10 mg/kg intravenously every 8 hours 600 mg intravenously every 12 hours 10 to 14 Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia (1.4) 10 mg/kg intravenously every 8 hours 600 mg intravenously every 12 hours 14 to 28  Pediatric Patients-The recommended dose is 10 mg per kg intravenously every 8 hours. Linezolid Injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof. (2.1) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Injection: 600 mg/300 mL (2 mg/mL) linezolid. (3) ------------------------------ CONTRAINDICATIONS ----------------------------  Known hypersensitivity to linezolid or any of the other product components. (4.1)  Patients taking any monoamine oxidase inhibitors (MAOI) or within two weeks of taking an MAOI. (4.2) ----------------------- WARNINGS AND PRECAUTIONS ----------------------  Myelosuppression: Monitor complete blood counts weekly. Thrombocytopenia has been reported more often in patients with severe renal and in patients with moderate to severe hepatic impairment. Consider discontinuation in patients who develop or have worsening myelosuppression. (5.1)  Peripheral and Optic Neuropathy: Reported primarily in patients treated for longer than 28 days. If patients experience symptoms of visual impairment, prompt ophthalmic evaluation is recommended. (5.2)  Serotonin Syndrome: Monitor patients taking serotonergic agents, including antidepressants and opioids, for signs of serotonin syndrome. Patients taking serotonergic antidepressants should receive linezolid only if no other therapies are available. Discontinue serotonergic antidepressants and monitor patients for signs and symptoms of both serotonin syndrome and antidepressant discontinuation. (5.3)  A mortality imbalance was seen in an investigational study in linezolid-treated patients with catheter-related bloodstream infections. (5.4)  Clostridioides difficile-Associated Diarrhea: Evaluate if diarrhea occurs. (5.5)  Potential interactions producing elevation of blood pressure: monitor blood pressure. (5.6)  Hypoglycemia: Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents. (5.9)  Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Monitor serum sodium levels regularly in patients at risk of hyponatremia and/or SIADH. (5.10) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (>5% of adult and pediatric patients treated with linezolid) include: diarrhea, vomiting, headache, nausea, and anemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS -----------------------------  Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic agents. (4.2, 5.3, 5.6, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 Reference ID: 5476278 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Nosocomial Pneumonia 1.2 Community-acquired Pneumonia 1.3 Complicated Skin and Skin Structure Infections 1.4 Vancomycin-resistant Enterococcus faecium Infections 1.5 Limitations of Use 1.6 Usage 2 DOSAGE AND ADMINISTRATION 2.1 General Dosage and Administration 2.2 Intravenous Administration 2.3 Compatibilities 2.4 Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Monoamine Oxidase Inhibitors 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression 5.2 Peripheral and Optic Neuropathy 5.3 Serotonin Syndrome 5.4 Mortality Imbalance in an Investigational Study in Patients With Catheter-Related Bloodstream Infections, Including Those With Catheter-Site Infections 5.5 Clostridioides difficile-Associated Diarrhea 5.6 Potential Interactions Producing Elevation of Blood Pressure 5.7 Lactic Acidosis 5.8 Convulsions 5.9 Hypoglycemia 5.10 Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) 5.11 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors 7.2 Adrenergic and Serotonergic Agents 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Adults 14.2 Pediatric Patients 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5476278 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Nosocomial Pneumonia Linezolid is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies (14)]. 1.2 Community-acquired Pneumonia Linezolid is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin susceptible isolates only) [see Clinical Studies (14)]. 1.3 Complicated Skin and Skin Structure Infections Linezolid is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid has not been studied in the treatment of decubitus ulcers [see Clinical Studies (14)]. 1.4 Vancomycin-resistant Enterococcus faecium Infections Linezolid is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [see Clinical Studies (14)]. 1.5 Limitations of Use  Linezolid is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Warnings and Precautions (5.4)].  The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials [see Clinical Studies (14)]. 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid and other antibacterial drugs, linezolid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosage and Administration The recommended dosage for linezolid injection for the treatment of infections is described in Table 1. No dose adjustment is necessary when switching from intravenous to oral administration. Page 3 of 29 Reference ID: 5476278 Table 1. Dosage Guidelines for Linezolid Injection Infection* Dosage, Route, and Frequency of Administration Recommended Duration of Treatment (consecutive days) Pediatric Patients† (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Nosocomial pneumonia Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections 10 mg/kg intravenously every 8 hours 600 mg intravenously every 12 hours 10 to 14 Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 10 mg/kg intravenously every 8 hours 600 mg intravenously every 12 hours 14 to 28 * Due to the designated pathogens [see Indications and Usage (1)] † Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. The maximum dose for pediatric patients should not exceed the recommended adult dose. The recommended dose is 10 mg per kg intravenously every 8 hours. Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof. 2.2 Intravenous Administration Linezolid injection is supplied in single-dose, ready-to-use container [see How Supplied/Storage and Handling (16)]. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the containers in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid injection may exhibit a yellow color that can intensify over time without adversely affecting potency. Linezolid injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous container in series connections. Additives should not be introduced into this solution. If Linezolid injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. Discard unused portion. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Linezolid injection with an infusion solution compatible with Linezolid injection and with any other drug(s) administered via this common line. 2.3 Compatibilities Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer’s Injection, USP. Page 4 of 29 Reference ID: 5476278 2.4 Incompatibilities Physical incompatibilities resulted when Linezolid injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when Linezolid injection was combined with ceftriaxone sodium. 3 DOSAGE FORMS AND STRENGTHS Linezolid injection: 600 mg/300 mL (2 mg/mL) linezolid in single-dose, ready-to-use flexible plastic container in a foil laminate overwrap. 4 CONTRAINDICATIONS 4.1 Hypersensitivity Linezolid injection is contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components. 4.2 Monoamine Oxidase Inhibitors Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Thrombocytopenia has been reported more often in patients with severe renal impairment, whether or not on dialysis, and in patients with moderate to severe hepatic impairment. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those with severe renal impairment or moderate to severe hepatic impairment, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial drug therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression [see Adverse Reactions (6.2)]. 5.2 Peripheral and Optic Neuropathy Peripheral and optic neuropathies have been reported in patients treated with linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid for less than 28 days. Peripheral and optic neuropathy has also been reported in children. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks. 5.3 Serotonin Syndrome Page 5 of 29 Reference ID: 5476278 Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, bupropion, buspirone, serotonin 5-HT1 receptor agonists (triptans), and opioids, including meperidine [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms). 5.4 Mortality Imbalance in an Investigational Study in Patients With Catheter-Related Bloodstream Infections, Including Those With Catheter-Site Infections An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16.0%); odds ratio 1.426, 95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only. Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections. Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Indications and Usage (1)]. 5.5 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, Page 6 of 29 Reference ID: 5476278 antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.6 Potential Interactions Producing Elevation of Blood Pressure Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 5.7 Lactic Acidosis Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid should receive immediate medical evaluation. 5.8 Convulsions Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported. 5.9 Hypoglycemia Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid. If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required. 5.10 Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Postmarketing cases of hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been observed in patients treated with linezolid. In reported cases, the signs and symptoms included confusion, somnolence, generalized weakness, and in severe cases led to respiratory failure and even death. Monitor serum sodium levels regularly in the elderly, in patients taking diuretics, and in other patients at risk of hyponatremia and/or SIADH while taking linezolid. If signs and symptoms of hyponatremia and/or SIADH occur, discontinue linezolid, and institute appropriate supportive measures. 5.11 Development of Drug-Resistant Bacteria Prescribing linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug- resistant bacteria. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Page 7 of 29 Reference ID: 5476278 Adults The safety of linezolid formulations was evaluated in 2,046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. For all indications, 20.4% of linezolid-treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event. Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of linezolid. Table 2. Incidence (%) Treatment-Emergent Adverse Reactions Occurring in greater than 1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials ADVERSE REACTIONS Linezolid 600 mg every 12 hours (n = 1498) All Other Comparators* (n = 1464) Headache 5.7 4.4 Diarrhea 8.3 6.4 Nausea 6.6 4.6 Vomiting 4.3 2.3 Dizziness 1.8 1.5 Rash 2.3 2.6 Anemia 2.1 1.4 Taste alteration 1.0 0.3 Vaginal moniliasis 1.1 0.5 Oral moniliasis 1.7 1.0 Abnormal liver function tests 1.6 0.8 Fungal infection 0.3 0.2 Tongue discoloration 0.3 0 Localized abdominal pain 1.2 0.8 Generalized abdominal pain 1.2 1.0 * Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. Discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting. Pediatric Patients The safety of linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator- controlled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. For all indications, 18.8% of linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event. Page 8 of 29 Reference ID: 5476278 Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials. Table 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in greater than 1% of Pediatric Patients (and greater than 1 Patient) in Either Treatment Group in Comparator- Controlled Clinical Trials* ADVERSE REACTIONS Linezolid (n = 215) Vancomycin (n = 101) Diarrhea 10.8 12.1 Vomiting 9.4 9.1 Headache 0.9 0 Anemia 5.6 7.1 Thrombocytopenia 4.7 2.0 Nausea 1.9 0 Generalized abdominal pain 0.9 2.0 Localized abdominal pain 0.5 1.0 Loose stools 2.3 3.0 Eosinophilia 1.9 1.0 Pruritus at non-application site 1.4 2.0 Vertigo 0 0 * Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously and/or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance. For all indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients. Laboratory Abnormalities Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10.0%) with linezolid and 1.5% (range among studies: 0.4 to 7.0%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with linezolid and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of linezolid appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for linezolid; the role of linezolid in these events cannot be determined [see Warnings and Precautions (5.1)]. Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7. Page 9 of 29 Reference ID: 5476278 Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay Linezolid 600 mg every 12 hours All Other Comparators† Hemoglobin (g/dL) 7.1 6.6 Platelet count (x 103/mm3) 3.0 1.8 WBC (x 103/mm3) 2.2 1.3 Neutrophils (x 103/mm3) 1.1 1.2 * Less than 75% (less than 50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; less than 75% (less than 50% for neutrophils) of LLN and of baseline for values abnormal at baseline. † Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay Linezolid 600 mg every 12 hours All Other Comparators† AST (U/L) 5.0 6.8 ALT (U/L) 9.6 9.3 LDH (U/L) 1.8 1.5 Alkaline phosphatase (U/L) 3.5 3.1 Lipase (U/L) 4.3 4.2 Amylase (U/L) 2.4 2.0 Total bilirubin (mg/dL) 0.9 1.1 BUN (mg/dL) 2.1 1.5 Creatinine (mg/dL) 0.2 0.6 * Greater than 2× Upper Limit of Normal (ULN) for values normal at baseline; greater than 2× ULN and greater than 2× baseline for values abnormal at baseline. † Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid† Laboratory Assay Linezolid Vancomycin Hemoglobin (g/dL) 15.7 12.4 Platelet count (x 103/mm3) 12.9 13.4 WBC (x 103/mm3) 12.4 10.3 Neutrophils (x 103/mm3) 5.9 4.3 * Less than 75% ( less than 50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; less than 75% (less than 50% for neutrophils) of LLN and less than 75% (less than 50% for neutrophils, less than 90% for hemoglobin if baseline less than LLN) of baseline for values abnormal at baseline. † Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously and/or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance. Page 10 of 29 Reference ID: 5476278 Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid† Laboratory Assay Linezolid Vancomycin ALT (U/L) 10.1 12.5 Lipase (U/L) -- -- Amylase (U/L) 0.6 1.3 Total bilirubin (mg/dL) 6.3 5.2 Creatinine (mg/dL) 2.4 1.0 * Greater than 2 x Upper Limit of Normal (ULN) for values normal at baseline; greater than 2× ULN and greater than 2 (greater than 1.5 for total bilirubin) × baseline for values abnormal at baseline. † Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously and/or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of linezolid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:  Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia). Thrombocytopenia has been reported more often in patients with severe renal impairment and in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.1)]; sideroblastic anemia.  Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [see Warnings and Precautions (5.2)].  Lactic acidosis [see Warnings and Precautions (5.7)]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy.  Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, and linezolid [see Warnings and Precautions (5.3)].  Convulsions [see Warnings and Precautions (5.8)].  Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis.  Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome.  Hypoglycemia, including symptomatic episodes [see Warnings and Precautions (5.9)].  Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.10)]. 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors Page 11 of 29 Reference ID: 5476278 Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [see Contraindications (4.2) and Clinical Pharmacology (12.3)]. 7.2 Adrenergic and Serotonergic Agents Linezolid has the potential for interaction with adrenergic and serotonergic agents [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6.5 times (mice), equivalent to (rats), or 0.06 times (rabbits) the clinical therapeutic exposure, based on AUCs. However, embryo-fetal lethality was observed in mice at 6.5 times the estimated human exposure. When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs (see Data). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). An oral dose of 450 mg/kg/day given from Gestation Day (GD) 6-16 (6.5 times the estimated human exposure based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion. Neither maternal nor embryo-fetal toxicities were observed at doses up to 150 mg/kg/day. Fetal malformations were not observed. In rats, fetal toxicity was observed at 15 and 50 mg/kg/day administered orally from GD 6-17 (exposures 0.22 times to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Fetal malformations were not observed. Maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day. In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at an oral dose of 15 mg/kg/day given from GD 6-20 (0.06 times the estimated human exposure based on AUCs). Fetal malformations were not observed. When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation (GD 6 through Lactation Day 20), survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss. Page 12 of 29 Reference ID: 5476278 8.2 Lactation Risk Summary Linezolid is present in breast milk. Based on data from available published case reports, the daily dose of linezolid that the infant would receive from breastmilk would be approximately 6% to 9% of the recommended therapeutic infant dose (10 mg/kg every 8 hours). There is no information on the effects of linezolid on the breastfed infant; however, diarrhea and vomiting were the most common adverse reactions reported in clinical trials in infants receiving linezolid therapeutically [see Adverse Reactions (6.1)] and (see Clinical Considerations). There is no information on the effects of linezolid on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for linezolid and any potential adverse effects on the breastfed child from linezolid or from the underlying maternal condition. Clinical Considerations Advise lactating women to monitor a breastfed infant for diarrhea and vomiting. 8.3 Females and Males of Reproductive Potential Infertility Males Based on findings from studies in rats, linezolid may reversibly impair fertility in male patients [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage (1), Clinical Pharmacology (12.3) and Clinical Studies (14)]:  nosocomial pneumonia  complicated skin and skin structure infections  community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)  vancomycin-resistant Enterococcus faecium infections Linezolid injection in a single-dose container should be used only in pediatric patients who require the entire 600 mg dose and not any fraction thereof. Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended. The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age <34 weeks) neonates <7 days of age, linezolid clearance is often lower than in full-term neonates <7 days of age. Consequently, preterm neonates <7 days of age Page 13 of 29 Reference ID: 5476278 I\ 0 INI \ _ _/ may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [see Clinical Pharmacology (12.3) and Dosage and Administration (2)]. 8.5 Geriatric Use Of the 2,046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 10 OVERDOSAGE In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3,000 mg/kg/day and 2,000 mg/kg/day, respectively. 11 DESCRIPTION Linezolid injection contains linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide. The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below: Linezolid injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each container contains 600 mg of linezolid in 300 mL of a clear, colorless to slightly yellow aqueous solution. Inactive ingredients include: citric acid anhydrous USP 1.92 mg/mL, sodium chloride USP 9 mg/mL, sodium hydroxide NF 0.76 mg/mL, and water for injection USP. Sodium hydroxide NF and/or hydrochloric acid NF are used to adjust the pH. The sodium (Na+) content is 3.98 mg/mL (52 mEq/300 mL container). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Linezolid is an antibacterial drug [see Microbiology (12.4)]. Page 14 of 29 Reference ID: 5476278 12.2 Pharmacodynamics In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single linezolid 600 mg dose via a 1 hour IV infusion, a single linezolid 1,200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1,200 mg linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time. 12.3 Pharmacokinetics The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1. Table 8. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults Dose of Linezolid Cmax mcg/mL Cmin mcg/mL Tmax hrs AUC* mcg•h/mL t1/2 hrs CL mL/min 400 mg tablet single dose† every 12 hours 8.10 (1.83) 11.00 (4.37) -- 3.08 (2.25) 1.52 (1.01) 1.12 (0.47) 55.10 (25.00) 73.40 (33.50) 5.20 (1.50) 4.69 (1.70) 146 (67) 110 (49) 600 mg tablet single dose every 12 hours 12.70 (3.96) 21.20 (5.78) -- 6.15 (2.94) 1.28 (0.66) 1.03 (0.62) 91.40 (39.30) 138.00 (42.10) 4.26 (1.65) 5.40 (2.06) 127 (48) 80 (29) 600 mg IV injection‡ single dose every 12 hours 12.90 (1.60) 15.10 (2.52) -- 3.68 (2.36) 0.50 (0.10) 0.51 (0.03) 80.20 (33.30) 89.70 (31.00) 4.40 (2.40) 4.80 (1.70) 138 (39) 123 (40) 600 mg oral suspension single dose 11.00 (2.76) -- 0.97 (0.88) 80.80 (35.10) 4.60 (1.71) 141 (45) * AUC for single dose = AUC0-∞; for multiple dose = AUC0-τ † Data dose-normalized from 375 mg ‡ Data dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion. Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; Tmax = Time to Cmax; AUC = Area under concentration- time curve; t1/2 = Elimination half-life; CL = Systemic clearance Page 15 of 29 Reference ID: 5476278 28 __J _§_ 24 = =- --- 600 mg oral every 1 2 h u ::z: 20 0 u <t: 16 ~ Cf) <t: __J 12 a... Cl ::::::; 0 B r---.r LU ::z: __J 4 0 0 2 4 6 a 10 12 TIM E AFT E R DOS E, hours Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean  Standard Deviation, n=16) Absorption Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment. Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-∞ is similar under both conditions. Distribution Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well- perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration- independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers. Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of linezolid in sweat relative to plasma was 0.55 to 1. Metabolism Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of linezolid is not fully understood. Excretion Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min which suggests net tubular Page 16 of 29 Reference ID: 5476278 reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A. A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life. Specific Populations Geriatric Patients The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary. Pediatric Patients The pharmacokinetics of linezolid following a single intravenous dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses. The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, plasma clearance of linezolid varies as a function of age. With the exclusion of pre term neonates less than one week of age, weight-based clearance is most rapid in the youngest age groups ranging from <1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults. Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours [see Dosage and Administration (2)]. Page 17 of 29 Reference ID: 5476278 Table 9. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV); [Min, Max Values]) Age Group Cmax mcg/mL Vss L/kg AUC* mcg•h/mL t1/2 Hrs CL mL/min/kg Neonatal Patients Pre-term <1 week (N = 9)† Full-term* <1 week (N = 10) † Full-term*** ≥1 week to ≤28 days (N = 10)† 12.7 (30%) [9.6, 22.2] 11.5 (24%) [8.0, 18.3] 12.9 (28%) [7.7, 21.6] 0.81 (24%) [0.43, 1.05] 0.78 (20%) [0.45, 0.96] 0.66 (29%) [0.35, 1.06] 108 (47%) [41, 191] 55 (47%) [19, 103] 34 (21%) [23, 50] 5.6 (46%) [2.4, 9.8] 3.0 (55%) [1.3, 6.1] 1.5 (17%) [1.2, 1.9] 2.0 (52%) [0.9, 4.0] 3.8 (55%) [1.5, 8.8] 5.1 (22%) [3.3, 7.2] Infant Patients >28 days to <3 Months (N = 12)† 11.0 (27%) [7.2, 18.0] 0.79 (26%) [0.42, 1.08] 33 (26%) [17, 48] 1.8 (28%) [1.2, 2.8] 5.4 (32%) [3.5, 9.9] Pediatric Patients 3 months through 11 years† (N = 59) 15.1 (30%) [6.8, 36.7] 0.69 (28%) [0.31, 1.50] 58 (54%) [19, 153] 2.9 (53%) [0.9, 8.0] 3.8 (53%) [1.0, 8.5] Adolescent Subjects and Patients 12 through 17 years‡ (N = 36) 16.7 (24%) [9.9, 28.9] 0.61 (15%) [0.44, 0.79] 95 (44%) [32, 178] 4.1 (46%) [1.3, 8.1] 2.1 (53%) [0.9, 5.2] Adult Subjects§ (N = 29) 12.5 (21%) [8.2, 19.3] 0.65 (16%) [0.45, 0.84] 91 (33%) [53, 155] 4.9 (35%) [1.8, 8.3] 1.7 (34%) [0.9, 3.3] * AUC = Single dose AUC0-∞ In this data set, “pre-term” is defined as less than 34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days) * In this data set, “full-term” is defined as greater than or equal to 34 weeks gestational age † Dose of 10 mg/kg ‡ Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg § Dose normalized to 600 mg Cmax = Maximum plasma concentration; Vss = Volume of distribution; AUC = Area under concentration-time curve; t1/2 = Apparent elimination half-life; CL = Systemic clearance normalized for body weight Gender Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary. Renal Impairment The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal impairment; however, the two primary metabolites of linezolid accumulate in patients with renal impairment, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 10). The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with linezolid 600 mg every 12 hours for 14.5 days (see Table 11). Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information on the clinical significance of Page 18 of 29 Reference ID: 5476278 accumulation of the primary metabolites, use of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by hemodialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis. Table 10. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Patients with Varying Degrees of Renal Impairment After a Single 600 mg Oral Dose of Linezolid Parameter Healthy Subjects CLCR >80 mL/min Moderate Renal Impairment 30< CLCR <80 mL/min Severe Renal Impairment 10< CLCR <30 mL/min LINEZOLID AUC0-∞, mcg h/mL 110 (22) 128 (53) 127 (66) t1/2, hours 6.4 (2.2) 6.1 (1.7) 7.1 (3.7) METABOLITE A AUC0-48, mcg h/mL 7.6 (1.9) 11.7 (4.3) 56.5 (30.6) t1/2, hours 6.3 (2.1) 6.6 (2.3) 9.0 (4.6) METABOLITE B1 AUC0-48, mcg h/mL 30.5 (6.2) 51.1 (38.5) 203 (92) t1/2, hours 6.6 (2.7) 9.9 (7.4) 11.0 (3.9) 1 Metabolite B is the major metabolite of linezolid. Table 11. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Subjects with End-Stage Renal Disease (ESRD) After the Administration of 600 mg Linezolid Every 12 Hours for 14.5 Days Parameter ESRD Subjects1 LINEZOLID AUC0-12, mcg h/mL (after last dose) t1/2, h (after last dose) METABOLITE A 181 (52.3) 8.3 (2.4) AUC0-12, mcg h/mL (after last dose) t1/2, h (after last dose) METABOLITE B2 153 (40.6) 15.9 (8.5) AUC0-12, mcg h/mL (after last dose) t1/2, h (after last dose) 356 (99.7) 34.8 (23.1) 1 between hemodialysis sessions 2 Metabolite B is the major metabolite of linezolid. Hepatic Impairment The pharmacokinetics of linezolid are not altered in patients (n = 7) with mild-to-moderate hepatic impairment (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic impairment. The pharmacokinetics of linezolid in patients with severe hepatic impairment have not been evaluated. Page 19 of 29 Reference ID: 5476278 Drug Interactions Drugs Metabolized by Cytochrome P450 Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen. Antibacterial Drugs Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together. Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together. Antioxidants The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2-9, subjects were given either Vitamin C (1,000 mg/day) or Vitamin E (800 IU/ day). The AUC0-∞ of linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co-administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E. Strong CYP 3A4 Inducers Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid Cmax [90% CI, 15% - 27%] and a 32% decrease in linezolid AUC0-12 [90% CI, 27% - 37%]. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure. Monoamine Oxidase Inhibition Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents. Adrenergic Agents Some individuals receiving linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response. Tyramine: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content [see Patient Counseling Information (17)]. Pseudoephedrine HCl or phenylpropanolamine HCl: A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is Page 20 of 29 Reference ID: 5476278 administered to healthy normotensive subjects [see Warnings and Precautions (5.6) and Drug Interactions (7)]. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg every 12 hours for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20-52 mm Hg) and 38 mm Hg (range: 18-79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively. Serotonergic Agents Dextromethorphan: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan. 12.4 Microbiology Mechanism of Action Linezolid is a synthetic antibacterial agent of the oxazolidinone class, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of isolates. Resistance In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant Enterococcus faecium becoming resistant to linezolid during its clinical use have been published. There are reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during clinical use. The linezolid resistance in these organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to linezolid. Also linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci. Interaction with Other Antimicrobial Drugs In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin. Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Page 21 of 29 Reference ID: 5476278 Gram-positive bacteria Enterococcus faecium (vancomycin-resistant isolates only) Staphylococcus aureus (including methicillin-resistant isolates) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes The following in vitro data are available, but their clinical significance is unknown. Greater than 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the linezolid-susceptible breakpoint for organisms of similar genus. The safety and effectiveness of linezolid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis (including vancomycin-resistant isolates) Enterococcus faecium (vancomycin-susceptible isolates) Staphylococcus epidermidis (including methicillin-resistant isolates) Staphylococcus haemolyticus Viridans group streptococci Gram-negative bacteria Pasteurella multocida Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay. Linezolid did not affect the fertility or reproductive performance of adult female rats given oral doses of up to 100 mg/kg/day for 14 days prior to mating through Gestation Day 7. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs. Page 22 of 29 Reference ID: 5476278 In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7 times greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35. 13.2 Animal Toxicology and/or Pharmacology Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time- dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects. In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion- fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change. These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period. 14 CLINICAL STUDIES 14.1 Adults Nosocomial Pneumonia Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients were treated for 7 to 21 days. One group received Linezolid injection 600 mg every 12 hours, and the other group received vancomycin 1 g every 12 hours intravenously. Both groups received concomitant aztreonam (1 to 2 g every 8 hours intravenously), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (60%) linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 12. Page 23 of 29 Reference ID: 5476278 Table 12. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Nosocomial Pneumonia Pathogen Cured Linezolid n/N (%) Vancomycin n/N (%) Staphylococcus aureus 23/38 (61) 14/23 (61) Methicillin-resistant S. aureus 13/22 (59) 7/10 (70) Streptococcus pneumoniae 9/9 (100) 9/10 (90) Complicated Skin and Skin Structure Infections Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered intravenously followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received Linezolid injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin treated patients. A modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 13. Table 13. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Complicated Skin and Skin Structure Infections Pathogen Cured Linezolid n/N (%) Oxacillin/Dicloxacillin n/N (%) Staphylococcus aureus 73/83 (88) 72/84 (86) Methicillin-resistant S. aureus 2/3 (67) 0/0 (-) Streptococcus agalactiae 6/6 (100) 3/6 (50) Streptococcus pyogenes 18/26 (69) 21/28 (75) A separate study provided additional experience with the use of linezolid in the treatment of methicillin resistant Staphylococcus aureus (MRSA) infections. This was a randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection. One group of patients received Linezolid injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours. The other group of patients received vancomycin 1 g every 12 hours intravenously. Both groups were treated for 7 to 28 days, and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients. Diabetic Foot Infections Adult diabetic patients with clinically documented complicated skin and skin structure infections (“diabetic foot infections”) were enrolled in a randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered intravenously or orally for a total of 14 to 28 days of Page 24 of 29 Reference ID: 5476278 treatment. One group of patients received linezolid 600 mg every 12 hours intravenously or orally; the other group received ampicillin/sulbactam 1.5 to 3 g intravenously or amoxicillin/clavulanate 500 to 875 mg every 8 to 12 hours orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin 1 g every 12 hours intravenously if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 to 2 g every 8-12 hours intravenously. All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments. There were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (86%) linezolid-treated patients and 105 (85%) comparator- treated patients were clinically evaluable. In the ITT population, the cure rates were 68.5% (165/241) in linezolid-treated patients and 64% (77/120) in comparator-treated patients, where those with indeterminate and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid- and comparator-treated patients, respectively. A critical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had a Gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population, and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the comparator- treated patients. None of the above analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 14. Table 14. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Diabetic Foot Infections Pathogen Cured Linezolid n/N (%) Comparator n/N (%) Staphylococcus aureus 49/63 (78) 20/29 (69) Methicillin-resistant S. aureus 12/17 (71) 2/3 (67) Streptococcus agalactiae 25/29 (86) 9/16 (56) Vancomycin-Resistant Enterococcal Infections Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of linezolid (600 mg) with a low dose of linezolid (200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm. The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 15 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level. Page 25 of 29 Reference ID: 5476278 Table 15. Cure Rates at the Test-of-Cure Visit for ITT Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at Baseline Source of Infection Cured Linezolid 600 mg every 12 hours n/N (%) Linezolid 200 mg every 12 hours n/N (%) Any site 39/58 (67) 24/46 (52) Any site with associated bacteremia 10/17 (59) 4/14 (29) Bacteremia of unknown origin 5/10 (50) 2/7 (29) Skin and skin structure 9/13 (69) 5/5 (100) Urinary tract 12/19 (63) 12/20 (60) Pneumonia 2/3 (67) 0/1 (0) Other* 11/13 (85) 5/13 (39) * Includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection. 14.2 Pediatric Patients Infections due to Gram-positive Bacteria A safety and efficacy study provided experience on the use of linezolid in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections and other infections due to Gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected Gram-positive bacteria were enrolled in a randomized, open-label, comparator-controlled trial. One group of patients received Linezolid injection 10 mg/kg every 8 hours followed by Linezolid for Oral Suspension 10 mg/kg every 8 hours. A second group received vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a third arm of the study and received linezolid 10 mg/kg every 8 hours intravenously and/or orally. All patients were treated for a total of 10 to 28 days and could receive concomitant Gram-negative antibacterial drugs if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients randomized to linezolid and 102 patients randomized to vancomycin. The cure rates for ITT, MITT, and clinically evaluable patients are presented in Table 16. After the study was completed, 13 additional patients ranging from 4 days through 16 years of age were enrolled in an open-label extension of the VRE arm of the study. Table 17 provides clinical cure rates by pathogen for microbiologically evaluable patients including microbiologically evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of this study. Page 26 of 29 Reference ID: 5476278 Table 16. Cure Rates at the Test-of-Cure Visit for Intent-to-Treat, Modified Intent-to-Treat, and Clinically Evaluable Pediatric Patients for the Overall Population and by Select Baseline Diagnosis Population ITT MITT* Clinically Evaluable Linezolid n/N (%) Vancomycin n/N (%) Linezolid n/N (%) Vancomycin n/N (%) Linezolid n/N (%) Vancomycin n/N (%) Any diagnosis 150/186 (81) 69/83 (83) 86/108 (80) 44/49 (90) 106/117 (91) 49/54 (91) Complicated skin and skin structure infections 61/72 (85) 31/34 (91) 37/43 (86) 22/23 (96) 46/49 (94) 26/27 (96) Nosocomial pneumonia 13/18 (72) 11/12 (92) 5/6 (83) 4/4 (100) 7/7 (100) 5/5 (100) * MITT = ITT patients with an isolated Gram-positive pathogen at baseline Table 17. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Pediatric Patients with Infections due to Gram-positive Pathogens Pathogen Microbiologically Evaluable Linezolid n/N (%) Vancomycin n/N (%) Vancomycin-resistant Enterococcus faecium 6/8 (75)* 0/0 (-) Staphylococcus aureus 36/38 (95) 23/24 (96) Methicillin-resistant S. aureus 16/17 (94) 9/9 (100) Streptococcus pyogenes 2/2 (100) 1/2 (50) * Includes data from 7 patients enrolled in the open-label extension of this study. 16 HOW SUPPLIED/STORAGE AND HANDLING Linezolid injection is available in a single-dose, ready-to-use flexible plastic container in a foil laminate overwrap. The container is available in the following package size: Unit of sale Concentration NDC 0409-4883-01 Case of 10 single-dose VisIVTM flexible plastic containers 600 mg/300 mL (2 mg/mL) NDC 0409-4883-10 Case of 10 single-dose freeflex® flexible plastic containers 600 mg/300 mL (2 mg/mL) Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from light. It is recommended that the containers be kept in the overwrap until ready to use. Protect containers from freezing. 17 PATIENT COUNSELING INFORMATION Important Administration Instructions Advise patients that linezolid injection may be taken with or without food. Peripheral and Optic Neuropathy Advise patients to inform their physician if they experience changes in vision while taking linezolid [see Warnings and Precautions (5.2)]. Page 27 of 29 Reference ID: 5476278 Serotonin Syndrome Advise patients to inform their physician if taking serotonergic agents, including serotonin re-uptake inhibitors or other antidepressants and opioids [see Warnings and Precautions (5.3)]. Potential Interactions Producing Elevation of Blood Pressure  Advise patients to inform their physician if they have a history of hypertension.  Advise patients to avoid large quantities of foods or beverages with high tyramine content while taking linezolid. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses, fermented or air-dried meats, sauerkraut, soy sauce, tap beers, and red wines. The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.  Advise patients to inform their physician if taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants [see Warnings and Precautions (5.6)]. Lactic Acidosis Advise patients to inform their physician if they experience repeated episodes of nausea or vomiting while receiving linezolid [see Warnings and Precautions (5.7)]. Convulsions Advise patients to inform their physician if they have a history of seizures or convulsions [see Warnings and Precautions (5.8)]. Hypoglycemia Advise patients to inform their physician if they have diabetes mellitus. Hypoglycemic reactions, such as diaphoresis and tremulousness, along with low blood glucose measurements may occur when treated with linezolid. If such reactions occur, patients should contact a physician or other health professional for proper treatment [see Warnings and Precautions (5.9)]. Hyponatremia and/or SIADH Advise patients at risk for hyponatremia to inform their physician if they experience signs and symptoms of hyponatremia and/or SIADH, including confusion, somnolence, generalized weakness, and respiratory distress [see Warnings and Precautions (5.10)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs including linezolid injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When linezolid injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by linezolid or other antibacterial drugs in the future. Diarrhea Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.5)]. Page 28 of 29 Reference ID: 5476278 ~ Hosp,ra Infertility Advise male patients that linezolid injection may reversibly impair fertility [see Use in Specific Populations (8.3)]. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1031-11.0 Page 29 of 29 Reference ID: 5476278	custom-source	2025-02-12T15:46:35.863733	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206473s010lbl.pdf', 'application_number': 206473, 'submission_type': 'SUPPL ', 'submission_number': 10}
80,191	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AYVAKIT safely and effectively. See full prescribing information for AYVAKIT. AYVAKIT® (avapritinib) tablets, for oral use Initial U.S. Approval: 2020 ---------------------------INDICATIONS AND USAGE-------------------------- AYVAKIT is a kinase inhibitor indicated for: Gastrointestinal Stromal Tumor (GIST) • the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. (1.1, 2.2) Advanced Systemic Mastocytosis (AdvSM) • the treatment of adult patients with AdvSM. AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM AHN), and mast cell leukemia (MCL). (1.2) • Limitations of Use: AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 109/L (1.2) Indolent Systemic Mastocytosis (ISM) • the treatment of adult patients with ISM. (1.3) • Limitations of Use: AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 X 109/L (1.2) -----------------------DOSAGE AND ADMINISTRATION---------------------- • GIST: Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation. (2.2) • GIST: The recommended dosage is 300 mg orally once daily. (2.2) • AdvSM: The recommended dosage is 200 mg orally once daily. (2.3) • ISM: The recommended dosage is 25 mg orally once daily. (2.4) • Patients with severe hepatic impairment (Child-Pugh Class C): reduce dose of AYVAKIT. (2.7) ---------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 25 mg, 50 mg, 100 mg, 200 mg and 300 mg. (3) ------------------------------CONTRAINDICATIONS----------------------------- None. (4) -----------------------WARNINGS AND PRECAUTIONS---------------------- • Intracranial Hemorrhage: Permanently discontinue for any occurrence of any grade. (2.5, 5.1) • Cognitive Effects: A broad spectrum of cognitive adverse reactions can occur in patients receiving AYVAKIT. In patients with GIST, AdvSM, or ISM depending on the severity, continue AYVAKIT at same dose, withhold and then resume at same or reduced dose upon improvement, or permanently discontinue. (2.5, 5.2) • Photosensitivity: May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. (5.3) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3) ------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions are: • GIST (≥20% incidence): edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, increased lacrimation, abdominal pain, constipation, rash, dizziness, and hair color changes. (6.1) • AdvSM (≥20% incidence): edema, diarrhea, nausea, and fatigue/asthenia. (6.1) • ISM (≥10% incidence): eye edema, dizziness, peripheral edema and flushing. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Blueprint Medicines Corporation at 1-888-258-7768 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS----------------------------- • Strong and Moderate CYP3A Inhibitors: Avoid coadministration of AYVAKIT with strong and moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate inhibitor cannot be avoided, reduce dose of AYVAKIT in patients with GIST or AdvSM. (2.6, 7.1) • Strong and Moderate CYP3A Inducers: Avoid coadministration of AYVAKIT with strong and moderate CYP3A inducers. (7.1) • Hormonal contraceptives containing ethinyl estradiol: See full prescribing information for dose-specific recommendations for concomitant use (7.2) -----------------------USE IN SPECIFIC POPULATIONS---------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 PDGFRA Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) 1.2 Advanced Systemic Mastocytosis (AdvSM) 1.3 Indolent Systemic Mastocytosis (ISM) 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Administration 2.2 GIST Harboring PDGFRA Exon 18 Mutations 2.3 Advanced Systemic Mastocytosis 2.4 Indolent Systemic Mastocytosis 2.5 Dosage Modifications for Adverse Reactions 2.6 Concomitant Use of Strong or Moderate CYP3A Inhibitors 2.7 Dose Modifications for Severe Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Intracranial Hemorrhage 5.2 Cognitive Effects 5.3 Photosensitivity 5.4 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 1 7.1 Effects of Other Drugs on AYVAKIT 7.2 Effects of AYVAKIT on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Gastrointestinal Stromal Tumors 14.2 Advanced Systemic Mastocytosis 14.3 Indolent Systemic Mastocytosis 16 HOW SUPPLIED/STORAGE AND HANDLING Reference ID: 5475618 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5475618 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 PDGFRA Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) AYVAKIT® is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations [see Dosage and Administration (2.2)]. 1.2 Advanced Systemic Mastocytosis (AdvSM) AYVAKIT is indicated for the treatment of adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Limitations of Use: AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 109/L [see Warnings and Precautions (5.1)]. 1.3 Indolent Systemic Mastocytosis (ISM) AYVAKIT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM). Limitations of Use: AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 X 109/L [see Warnings and Precautions (5.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Administration Administer AYVAKIT orally on an empty stomach, at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not make up for a missed dose within 8 hours of the next scheduled dose. Do not repeat dose if vomiting occurs after AYVAKIT but continue with the next scheduled dose. 2.2 GIST Harboring PDGFRA Exon 18 Mutations Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation [see Clinical Studies (14.1)]. An FDA-approved test for the detection of exon 18 mutations is not currently available. The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST. Continue treatment until disease progression or unacceptable toxicity. 3 Reference ID: 5475618 2.3 Advanced Systemic Mastocytosis The recommended dosage of AYVAKIT is 200 mg orally once daily in patients with AdvSM. Continue treatment until disease progression or unacceptable toxicity. 2.4 Indolent Systemic Mastocytosis The recommended dosage of AYVAKIT is 25 mg orally once daily in patients with ISM. 2.5 Dosage Modifications for Adverse Reactions The recommended dosage reductions and modifications for adverse reactions are provided in Tables 1 and 2. Table 1: Recommended Dosage Reductions for AYVAKIT for Adverse Reactions Dose Reduction Level Dosage in patients with GIST Dosage in patients with AdvSM† First dose reduction 200 mg once daily 100 mg once daily Second dose reduction 100 mg once daily 50 mg once daily Third dose reduction - 25 mg once daily * Permanently discontinue AYVAKIT in patients with GIST who are unable to tolerate a dose of 100 mg once daily. † Permanently discontinue AYVAKIT in patients with AdvSM who are unable to tolerate a dose of 25 mg once daily. Table 2: Recommended Dosage Modifications for AYVAKIT for Adverse Reactions Adverse Reaction Severity* Dosage Modification Patients with GIST or AdvSM Intracranial Hemorrhage [see Warnings and Precautions (5.1)] Any grade Permanently discontinue AYVAKIT. Cognitive Effects [see Warnings and Precautions (5.2)] Grade 1 Continue AYVAKIT at same dose or reduced dose or withhold until improvement to baseline or resolution. Resume at same dose or reduced dose. Grade 2 or Grade 3 Withhold AYVAKIT until improvement to baseline, Grade 1, or resolution. Resume at same dose or reduced dose. Grade 4 Permanently discontinue AYVAKIT. 4 Reference ID: 5475618 Other [see Adverse Reactions (6.1)] Grade 3 or Grade 4 Withhold AYVAKIT until improvement to less than or equal to Grade 2. Resume at same dose or reduced dose, as clinically appropriate. Patients with AdvSM Thrombocytopenia [see Warnings and Precautions (5.1)] <50 × 109/L Interrupt AYVAKIT until platelet count is ≥ 50 × 109/L, then resume at reduced dose (per Table 1). If platelet counts do not recover above 50 × 109/L, consider platelet support. Severity as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 2.6 Concomitant Use of Strong and Moderate CYP3A Inhibitors Avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dosage of AYVAKIT is as follows [see Drug Interactions (7.1)]: • GIST: 100 mg orally once daily • AdvSM: 50 mg orally once daily For ISM, avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors. 2.7 Dosage Modifications for Severe Hepatic Impairment A modified starting dosage of AYVAKIT is recommended for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7)]: • GIST: 200 mg orally once daily • AdvSM: 100 mg orally once daily • ISM: 25 mg orally every other day 3 DOSAGE FORMS AND STRENGTHS Tablets: • 25 mg, round, white film-coated tablet with debossed text. One side reads “BLU” and the other side reads “25”. • 50 mg, round, white film-coated tablet with debossed text. One side reads “BLU” and the other side reads “50”. • 100 mg, round, white film-coated, printed with blue ink “BLU” on one side and “100” on the other side. • 200 mg, capsule shaped, white film-coated, printed with blue ink “BLU” on one side and “200” on the other side. • 300 mg, capsule shaped, white film-coated, printed with blue ink “BLU” on one side and “300” on the other side. 5 Reference ID: 5475618 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Intracranial Hemorrhage Serious intracranial hemorrhage may occur with AYVAKIT treatment; fatal events occurred in less than 1% of patients. Overall, intracranial hemorrhage (e.g., subdural hematoma, intracranial hemorrhage, and cerebral hemorrhage) occurred in 2.9% of the 749 patients with GIST or AdvSM who received AYVAKIT in clinical trials. No events of intracranial hemorrhage occurred in the 246 patients with ISM who received any dose of AYVAKIT in the PIONEER study. Monitor patients closely for risk factors of intracranial hemorrhage which may include history of vascular aneurysm, intracranial hemorrhage or cerebrovascular accident within the prior year, concomitant use of anticoagulant drugs, or thrombocytopenia. Symptoms of intracranial hemorrhage may include headache, nausea, vomiting, vision changes, or altered mental status. Advise patients to seek immediate medical attention for signs or symptoms of intracranial hemorrhage. Permanently discontinue AYVAKIT if intracranial hemorrhage of any grade occurs [see Dosage and Administration (2.5)]. Gastrointestinal Stromal Tumors Intracranial hemorrhage occurred in 3 of 267 patients (1.1%). Two (0.7%) of the events were Grade ≥ 3 and resulted in discontinuation of study drug. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating AYVAKIT. Advanced Systemic Mastocytosis In patients with AdvSM who received AYVAKIT at 200 mg daily, intracranial hemorrhage occurred in 2 of 75 patients (2.7%) who had platelet counts ≥ 50 X 109/L prior to initiation of therapy and in 3 of 80 patients (3.8%) regardless of platelet counts. In patients with AdvSM, a platelet count must be performed prior to initiating therapy; AYVAKIT is not recommended in patients with AdvSM with platelet counts < 50 X 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count. After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically indicated) if values are less than 75 X 109/L, every 4 weeks if values are between 75 and 100 X 109/L, and as clinically indicated if values are greater than 100 X 109/L. Manage platelet counts of < 50 X 109/L by treatment interruption or dose-reduction of AYVAKIT. Platelet support may be necessary [see Dosage and Administration (2.5)]. Dose-interruptions and dose- reductions for thrombocytopenia occurred in 20% and 22% of AYVAKIT-treated patients, respectively. Thrombocytopenia was generally reversible by reducing or interrupting AYVAKIT. 5.2 Cognitive Effects Cognitive adverse reactions can occur in patients receiving AYVAKIT. These cognitive adverse reactions occurred in 33% of the 995 patients with GIST, AdvSM or ISM who received AYVAKIT in clinical trials. These adverse reactions were managed with dose interruption and/or reduction when needed. 6 Reference ID: 5475618 Overall, 10% led to dose interruptions, 7% led to dose reductions and 2.2% led to permanent discontinuation of AYVAKIT treatment in patients with GIST, AdvSM or ISM. Depending on the severity and indication, withhold AYVAKIT and then resume at the same dose or at a reduced dose upon improvement, or permanently discontinue AYVAKIT [see Dosage and Administration (2.5)]. Indolent Systemic Mastocytosis Cognitive adverse reactions occurred in 7.8% of patients with ISM who received AYVAKIT + best supportive care versus 7% of patients who received placebo + best supportive care in the PIONEER study; <1% were Grade 3. The median time to onset of the first cognitive adverse reaction was 2.3 months (range: 0 to 5.4 months). Median time to improvement to Grade 1 or complete resolution was 2.1 months (range: 0.4 to 2.1 months). Gastrointestinal Stromal Tumors Cognitive adverse reactions occurred in 41% of 601 patients with GIST who received AYVAKIT; 5% were Grade > 3. Memory impairment occurred in 21% of patients; <1% of these events were Grade 3. Cognitive disorder occurred in 12% of patients; 1.2% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Amnesia occurred in 3% of patients; <1% of these events were Grade 3. Somnolence and speech disorder occurred in 2% of patients; none of these events were Grade 3. Other events occurred in less than 2% of patients. The median time to onset of the first cognitive adverse reaction was 8.4 weeks (range: 1 day to 4 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 7.9 weeks. Overall, 2.7% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 13.5% required a dosage interruption, and 8.5% required dose reduction. Advanced Systemic Mastocytosis Cognitive adverse reactions occurred in 28% of 148 patients with AdvSM who received AYVAKIT; 3% were Grade > 3. Memory impairment occurred in 16% of patients; all events were Grade 1 or 2. Cognitive disorder occurred in 10% of patients; <1% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Other events occurred in less than 2% of patients. The median time to onset of the first cognitive adverse reaction was 13.3 weeks (range: 1 day to 1.8 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 8.1 weeks. Overall, 2% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 8.1% required a dosage interruption, and 8.8% required dose reduction. 5. 3 Photosensitivity AYVAKIT may cause photosensitivity reactions. In all patients treated with AYVAKIT in clinical trials (n=1049), photosensitivity reactions occurred in 2.5% of patients. Advise patients to limit direct ultraviolet exposure during treatment with AYVAKIT and for one week after discontinuation of treatment. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, AYVAKIT can cause fetal harm when administered to pregnant women. Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 31.4, 6.3 and 2.7 times 7 Reference ID: 5475618 the human exposure based on area under the curve (AUC) at the 25 mg, 200 mg, and 300 mg dose, respectively. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Intracranial hemorrhage [see Warnings and Precautions (5.1)] • Cognitive effects [see Warnings and Precautions (5.2)] • Photosensitivity [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to AYVAKIT at 25 mg to 600 mg orally once daily in 995 patients enrolled in one of five clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER, PATHFINDER and PIONEER [see Clinical Studies (14.1, 14.2, 14.3)]. These patients included 601 patients with GIST, 148 patients with AdvSM and 246 patients with ISM. Among the 995 patients receiving AYVAKIT, 54% were exposed for 6 months or longer and 26% were exposed for greater than 1 year. Gastrointestinal Stromal Tumors Unresectable or Metastatic GIST The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR [see Clinical Studies (14.1)]. The trial excluded patients with history of cerebrovascular accident or transient ischemic attacks, known risk of intracranial bleeding, and metastases to the brain. Patients received AYVAKIT 300 mg or 400 mg orally once daily (n = 204). Among patients receiving AYVAKIT, 56% were exposed for 6 months or longer and 44% were exposed for greater than one year. The median age of patients who received AYVAKIT was 62 years (range: 29 to 90 years), 60% were <65 years, 62% were male, and 69% were White. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7). Serious adverse reactions occurred in 52% of patients receiving AYVAKIT. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%), and tumor hemorrhage (1%). Fatal adverse reactions occurred in 3.4% of patients. Fatal adverse reactions that occurred in more than one patient were sepsis and tumor hemorrhage (1% each). Permanent discontinuation due to adverse reactions occurred in 16% of patients who received AYVAKIT. Adverse reactions requiring permanent discontinuation in more than one patient were fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy. 8 Reference ID: 5475618 Dosage interruptions due to an adverse reaction occurred in 57% of patients who received AYVAKIT. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain. Dose reduction due to an adverse reaction occurred in 49% of patients who received AYVAKIT. Median time to dose reduction was 9 weeks. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea, and periorbital edema. The most common adverse reactions (≥ 20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, increased lacrimation, abdominal pain, constipation, rash, dizziness, and hair color changes. Table 5 summarizes the adverse reactions observed in NAVIGATOR. Table 5. Adverse Reactions (≥ 10%) in Patients with GIST Receiving AYVAKIT in NAVIGATOR Adverse Reactions AYVAKIT N=204 All Grades % Grade ≥ 3 % General Edemaa 72 2 Fatigue/asthenia 61 9 Pyrexia 14 0.5 Gastrointestinal Nausea 64 2.5 Vomiting 38 2 Diarrhea 37 4.9 Abdominal painb 31 6 Constipation 23 1.5 Dyspepsia 16 0 Nervous System Cognitive impairmentc 48 4.9 Dizziness 22 0.5 9 Reference ID: 5475618 Headache 17 0.5 Sleep disordersd 16 0 Taste effectse 15 0 Mood disordersf 13 1 Metabolism and nutrition Decreased appetite 38 2.9 Eye Increased lacrimation 33 0 Skin and subcutaneous tissue Rashg 23 2.1 Hair color changes 21 0.5 Alopecia 13 0 Respiratory, thoracic and mediastinal Dyspnea 17 2.5 Pleural effusion 12 2 Investigations Weight decreased 13 1 Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 a Edema includes face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema. b Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort. c Cognitive impairment includes memory impairment, cognitive disorder, confusional state, disturbance in attention, amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, mental disorder, and retrograde amnesia. d Sleep disorders includes insomnia, somnolence, and sleep disorder. e Taste effects include dysgeusia and ageusia. f Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered, nervousness, personality change, and suicidal ideation. g Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular. Clinically relevant adverse reactions occurring in <10% of patients were: Vascular: hypertension (8%) Endocrine: thyroid disorders (hyperthyroid, hypothyroid) (3%) Skin and subcutaneous: palmar-plantar erythrodysesthesia (1%) 10 Reference ID: 5475618 Table 6 summarizes the laboratory abnormalities observed in NAVIGATOR. Table 6. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with GIST Receiving AYVAKIT in NAVIGATOR Laboratory Abnormality AYVAKITa N=204 All Grades (%) Grade ≥ 3 (%) Hematology Decreased hemoglobin 81 28 Decreased leukocytes 62 5 Decreased neutrophils 43 6 Decreased platelets 27 0.5 Increased INR 24 0.6 Increased activated partial thromboplastin time 13 0 Chemistry Increased bilirubin 69 9 Increased aspartate aminotransferase 51 1.5 Decreased phosphate 49 13 Decreases potassium 34 6 Decreased albumin 31 2 Decreased magnesium 29 1 Increased creatinine 29 0 Decreased sodium 28 7 Increased alanine aminotransferase 19 0.5 Increased alkaline phosphatase 14 1 11 Reference ID: 5475618 a The denominator used to calculate the rate varied from 154 to 201 based on the number of patients with a baseline value and at least one post-treatment value. Advanced Systemic Mastocytosis The safety of AYVAKIT in patients with AdvSM was evaluated in EXPLORER and PATHFINDER [see Clinical Studies (14.2)]. Patients received a starting dose of AYVAKIT ranging from 30 mg to 400 mg orally once daily (n = 131), including 80 patients who received the recommended starting dose of 200 mg once daily. Among patients receiving AYVAKIT, 70% were treated for 6 months or longer and 37% were exposed for greater than one year. The median age of patients who received AYVAKIT was 68 years (range: 31 to 88 years), 38% were <65 years, 57% were male, and 88% were White. Serious adverse reactions occurred in 34% of patients receiving the recommended starting dose of 200 mg once daily and in 50% of patients receiving AYVAKIT at all doses. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (5%), subdural hematoma (4%), pleural effusion, ascites and pneumonia (3% each), acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each). Fatal adverse reactions occurred in 2.5% of patients receiving the recommended starting dose of 200 mg once daily and in 5.3% of patients receiving AYVAKIT at all doses. No specific adverse reaction leading to death was reported in more than one patient. Permanent discontinuation due to adverse reactions occurred in 10% of patients receiving the recommended starting dose of 200 mg once daily and in 15% of patients who received AYVAKIT at all doses. Of patients receiving 200 mg once daily, subdural hematoma was the only adverse reaction requiring permanent discontinuation in more than one patient. Dosage interruptions due to an adverse reaction occurred in 60% of patients receiving the recommended starting dose of 200 mg once daily and in 67% of patients who received AYVAKIT at all doses. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, neutrophil count decreased, platelet count decreased, anemia, white blood cell decreased, cognitive disorder, blood alkaline phosphatase increased, and edema peripheral. Dose reduction due to an adverse reaction occurred in 68% of patients receiving the recommended starting dose of 200 mg once daily and 70% of patients who received AYVAKIT at all doses. Median time to dose reduction was 1.7 months. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, edema peripheral, neutrophil count decreased, platelet count decreased, periorbital edema, cognitive disorder, anemia, fatigue, arthralgia, blood alkaline phosphatase increased, and white blood cell count decreased. The most common adverse reactions (≥ 20%) at all doses were edema, diarrhea, nausea, and fatigue/asthenia. Table 7 summarizes the adverse reactions observed in EXPLORER and PATHFINDER. 12 Reference ID: 5475618 Table 7. Adverse Reactions (≥ 10%) in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER Adverse Reactions AYVAKIT (200 mg once daily) N=80 All Grades % Grade ≥ 3 % General Edemaa 79 5 Fatigue/asthenia 23 4 Gastrointestinal Diarrhea 28 1 Nausea 24 1 Vomiting 18 3 Abdominal painb 14 1 Constipation 11 0 Nervous system Headache 15 0 Cognitive effectsc 14 1 Taste effectsd 13 0 Dizziness 13 0 Musculoskeletal and connective tissue Arthralgia 10 1 Respiratory, thoracic and mediastinal Epistaxis 11 0 Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 a Edema includes face swelling, eyelid edema, orbital edema, periorbital edema, face edema, peripheral edema, edema, generalized edema, and peripheral swelling. b Abdominal pain includes abdominal pain, upper abdominal pain, and abdominal discomfort. c Cognitive effects include memory impairment, cognitive disorder, confusional state, delirium, and disorientation. d Taste effects include dysgeusia. 13 Reference ID: 5475618 Clinically relevant adverse reactions occurring in <10% of patients were: Cardiac: cardiac failure (2.5%), and cardiac failure congestive (1.3%) Gastrointestinal: ascites (5%), gastrointestinal hemorrhage (1.3%), and large intestine perforation (1.3%) Hepatobiliary: cholelithiasis (1.3%) Infections and infestations: upper respiratory tract infection (6%), urinary tract infection (6%), and herpes zoster (2.5%) Vascular: flushing (3.8%), hypertension (3.8%), hypotension (3.8%), and hot flush (2.5%) Nervous: insomnia (6%) Musculoskeletal and connective tissue: pain in extremity (6%) Respiratory, thoracic and mediastinal: dyspnea (9%), and cough (2.5%) Skin and subcutaneous tissue: rasha (8%), alopecia (9%), pruritus (8%), and hair color changes (6%) Metabolism and nutrition: decreased appetite (8%) Eye: lacrimation increased (9%) Laboratory abnormality: decreased phosphate (9%) aGrouped terms Rash includes rash and rash maculo-papular Table 8 summarizes the laboratory abnormalities observed in EXPLORER and PATHFINDER. Table 8. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER Laboratory Abnormality AYVAKIT (200 mg once daily) N=80 All Grades (%) Grade ≥ 3 (%) Hematology Decreased platelets 64 21 Decreased hemoglobin 55 23 Decreased neutrophils 54 25 Decreased lymphocytes 34 11 Increased activated partial thromboplastin time 14 1 14 Reference ID: 5475618 Increased lymphocytes 10 0 Chemistry Decreased calcium 50 3 Increased bilirubin 41 3 Increased aspartate aminotransferase 38 1 Decreased potassium 26 4 Increased alkaline phosphatase 24 5 Increased creatinine 20 0 Increased alanine aminotransferase 18 1 Decreased sodium 18 1 Decreased albumin 15 1 Decreased magnesium 14 1 Increased potassium 11 0 Other Clinically Relevant Adverse Reactions in <10% of patients In the pooled GIST and AdvSM safety populations, photosensitivity occurred in 2.5% of patients [see Warnings and Precautions (5.3)]. Indolent Systemic Mastocytosis The safety of AYVAKIT in patients with ISM was evaluated in PIONEER [see Clinical Studies (14.3)]. Patients received AYVAKIT 25 mg orally once daily with best supportive care (n = 141) or placebo once daily with best supportive care (n = 71). Serious adverse reactions occurred in 1 patient (0.7%) who received AYVAKIT due to pelvic hematoma. Permanent discontinuation of AYVAKIT due to an adverse reaction occurred in 1 patient (0.7%) due to dyspnea and dizziness. Dosage interruptions of AYVAKIT due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dosage interruption included dizziness, blood alkaline phosphatase increased, dyspnea, face edema, pelvic hematoma, liver transaminase increased and respiratory tract infection (1 patient each). Table 9 summarizes the frequency of adverse reactions in the PIONEER study. The most common adverse reactions (≥ 10%) in the AYVAKIT group were eye edema, dizziness, peripheral edema and flushing. Of all adverse reactions, 55% were Grade 1, 38% were Grade 2 and 7% were Grade 3. Among patients with edema adverse reactions, 95% were Grade 1 and 5% were Grade 2. Among patients with hemorrhage adverse reactions, 86% were Grade 1 and 14% were Grade 2. 15 Reference ID: 5475618 Table 9. Adverse Reactions Occurring in AYVAKIT-Treated Patients with Indolent Systemic Mastocytosis During PIONEER Trial Adverse Reactionsa, b AYVAKIT (25 mg once daily) + BSC N=141 % Placebo + BSC N=71 % Eye edemac 13 7 Dizzinessd 13 10 Peripheral edemad 12 6 Flushingd 11 4 Respiratory tract infectione 8 1 Face edema 7 1 Rashd 6 4 Liver transaminase increasedd 6 3 Insomnia 6 3 Hematomaf 6 1 Blood alkaline phosphatase increased 6 1 Hemorrhageg 5 3 Abbreviations: BSC=best supportive care a Adverse reactions that occurred in ≥5% of AYVAKIT-treated patients and ≥2% more than placebo-treated patients. b Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 c Eye edema includes periorbital edema, eye edema, swelling of eyelid, orbital edema, eye swelling, eyelid edema and eyelid ptosis. d Term includes several similar terms. e Respiratory tract infection includes pneumonia, upper respiratory tract infection, bronchitis and respiratory tract infection. f Hematoma includes contusion, hematoma and pelvic hematoma. g Hemorrhage includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, retinal hemorrhage. Clinically relevant adverse reactions occurring in <5% of patients were: Skin and subcutaneous tissue: photosensitivity (2.8%) 16 Reference ID: 5475618 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on AYVAKIT Strong and Moderate CYP3A Inhibitors Coadministration of AYVAKIT with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate CYP3A inhibitor cannot be avoided, reduce the dose of AYVAKIT [see Dosage and Administration (2.6)]. Strong and Moderate CYP3A Inducers Coadministration of AYVAKIT with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease efficacy of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers. 7.2 Effects of AYVAKIT on Other Drugs Coadministration of AYVAKIT with ethinyl estradiol-containing contraceptives may increase the exposure of ethinyl estradiol, which may lead to increased risk of ethinyl estradiol-associated adverse reactions [see Clinical Pharmacology (12.3)]. If the patient is unable to use or tolerate an effective nonhormonal contraceptive or an effective hormonal contraceptive without estrogen, use a formulation of ethinyl estradiol containing 20 mcg or less unless a higher dose is necessary. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], AYVAKIT can cause fetal harm when administered to a pregnant woman. There are no available data on AYVAKIT use in pregnant women. Oral administration of avapritinib to pregnant rats during the period of organogenesis was teratogenic and embryotoxic at exposure levels approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In a reproductive toxicity study, administration of avapritinib to rats during the period of organogenesis resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses greater than or equal to 10 mg/kg/day (approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively). 17 Reference ID: 5475618 8.2 Lactation Risk Summary There are no data on the presence of avapritinib or its metabolites in human milk or the effects of avapritinib on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating AYVAKIT [see Use in Specific Populations (8.1)]. Contraception AYVAKIT can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Females Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Drug Interactions (7.2)]. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose. Infertility Females Based on findings from animal studies, AYVAKIT may impair female fertility. These findings were not reversible within a two month recovery period [see Nonclinical Toxicology (13.1)]. Males Based on findings from animal studies, AYVAKIT may impair male fertility. These findings were not reversible within a two month recovery period [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of AYVAKIT in pediatric patients have not been established. 8.5 Geriatric Use Of the 204 patients with unresectable or metastatic GIST who received AYVAKIT in NAVIGATOR, 40% were 65 years or older, while 6% were 75 years and older. Of the 131 patients with AdvSM who received AYVAKIT in EXPLORER and in PATHFINDER, 62% were 65 years or older, while 21% were 75 years and older. Of the 141 patients with ISM who received AYVAKIT in PIONEER, 6% were 65 years or older, while <1% were 75 years and older. No overall differences in safety or efficacy were observed between these patients and younger adult patients. 18 Reference ID: 5475618 8.6 Renal Impairment No dose adjustment is recommended for patients with mild or moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated by Cockcroft-Gault]. The recommended dose of AYVAKIT has not been established for patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (CLcr <15 mL/min) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild [total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 times ULN and any AST], or moderate [total bilirubin >1.5 to 3 times ULN and any AST] hepatic impairment. Unbound AUC0-INF was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. A lower starting dose is recommended in patients with severe hepatic impairment [see Dosage and Administration (2.7)]. 11 DESCRIPTION Avapritinib is a kinase inhibitor with the chemical name (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-yl)pyrimidin-5-yl)ethan-1-amine. The molecular formula is C26H27FN10, and the molecular weight is 498.57 g/mol. Avapritinib has the following chemical structure: N N N N N N N N N Me H2N F S The solubility of avapritinib in 0.1N HCl (pH 1.0) and buffer solutions at pH 2.5, 4.0, and 7.0 (at 25°C) is 3.6 mg/mL, 0.14 mg/mL, 0.07 mg/mL and <0.001 mg/mL respectively, indicating a decrease in solubility with increasing pH. AYVAKIT (avapritinib) film-coated tablets for oral use are supplied with five strengths that contain 25 mg, 50 mg, 100 mg, 200 mg or 300 mg of avapritinib. The tablets also contain inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablet coating consists of polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The blue printing ink, used only for avapritinib 100 mg, 200 mg and 300 mg strength tablets, contains ammonium hydroxide, black iron oxide, esterified shellac, FD&C blue 1, isopropyl alcohol, n-butyl alcohol, propylene glycol, and titanium dioxide. 19 Reference ID: 5475618 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V, PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC50s) less than 25 nM in biochemical assays. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors which can contribute to tumor and mast cell proliferation. Other potential targets for avapritinib include wild type KIT, PDGFRB, and CSFR1. In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V with an IC50 of 4 nM, approximately 48-fold lower concentration than wild-type KIT. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with KIT exon 17 mutation. Avapritinib inhibited the autophosphorylation of PDGFRA D842V, a mutation associated with resistance to approved kinase inhibitors, with an IC50 of 30 nM. Avapritinib also had anti-tumor activity in mice implanted with an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/17 mutations. 12.2 Pharmacodynamics Exposure-Response Relationships Gastrointestinal Stromal Tumors or Advanced Systemic Mastocytosis Based on the data from four clinicals trials conducted in patients with advanced malignancies and AdvSM, including NAVIGATOR, EXPLORER, and PATHFINDER, higher exposure was associated with increased risk of Grade ≥ 3 related adverse effects, any Grade pooled cognitive adverse effects, Grade ≥ 2 pooled cognitive adverse effects, and Grade ≥ 2 pooled edema adverse effects over the dose range of 30 mg to 400 mg (0.1 to 1.33 times the recommended dose for GIST and 0.15 to 2 times the recommended dose for AdvSM) once daily. Based on exposure and efficacy data from EXPLORER and PATHFINDER (n=84), higher avapritinib exposure was associated with faster time to response over the dose range of 30 mg to 400 mg (0.15 to 2 times the recommended dose for AdvSM) once daily. Cardiac Electrophysiology The effect of AYVAKIT on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered doses of 300 mg or 400 mg (12 to 16 times the lowest recommended 25 mg dose, 1.33 times the highest recommended 300 mg dose) once daily. No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (Cmax) of 899 ng/mL. 12.3 Pharmacokinetics Avapritinib Cmax and AUC increased approximately proportionally over the dose range of 25 mg to 400 mg once daily. Steady state concentrations of avapritinib were reached prior to day 15 following daily dosing. Steady state pharmacokinetic parameters per recommended dosing regimen are described in Table 10. 20 Reference ID: 5475618 Table 10. Steady State Pharmacokinetic Parameters of AYVAKIT Following Different Dosing Regimen Pharmacokinetic Parameters 25 mg once daily (ISM) 200 mg once daily (AdvSM) 300 mg once daily (GIST) Cmax (ng/mL) Geometric Mean (CV%) 70.2 (47.8 %, n=9) 377 (62%, n=18) 813 (52%, n=110) AUC0-24h (h•ng/mL) Geometric Mean (CV%) 1330 (49.5 %, n = 9) 6600 (54%, n=16) 15400 (48%, n=110) Mean accumulation ratio of AUC 0-24h 4.06 (n=9) 6.41 (n=9) 3.82 (n=34) Abbreviations: CV%=coefficient of variation Absorption The median time to peak concentration (Tmax) ranged from 2 to 4 hours following single doses of avapritinib. Effect of Food The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state. Distribution The mean (CV %) apparent volume of distribution of avapritinib is 1310 L (51.5%) at 300 mg in patients with GIST, 1900 L (43.2%) at 200 mg in patients with AdvSM, and 1400 L (59.1%) at 25 mg in patients with ISM. In vitro protein binding of avapritinib is 98.8% and is independent of concentration. The blood- to-plasma ratio is 0.95. Elimination The mean plasma elimination half-life of avapritinib was 32 to 57 hours in patients with GIST, 20 to 39 hours in patients with AdvSM, and 38 to 45 hours in patients with ISM. The steady state mean (CV%) apparent oral clearance of avapritinib is 21.8 L/h (54.9%) at 300 mg in patients with GIST, 40.3 L/h (86.0%) at 200 mg in patients with AdvSM, and 21.6 L/h (58.1%) at 25 mg in patients with ISM. Metabolism Avapritinib is primarily metabolized by CYP3A4, CYP3A5 and to a lesser extent by CYP2C9 in vitro. Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds. The formation of the glucuronide M690 is catalyzed mainly by UGT1A3. Following oral administration of AYVAKIT 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib. 21 Reference ID: 5475618 Excretion Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. In a dedicated hepatic impairment study following a single oral dose administration of 100 mg avapritinib, the mean unbound AUC was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. The effect of severe renal impairment (CLcr 15 to 29 mL/min) and end- stage renal disease (CLcr < 15 mL/min) on the pharmacokinetics of avapritinib is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong and Moderate CYP3A Inhibitors on Avapritinib: Coadministration of AYVAKIT 300 mg once daily with itraconazole 200 mg once daily (a strong CYP3A inhibitor) is predicted to increase avapritinib AUC by 600% at steady state. Coadministration of AYVAKIT 300 mg once daily with fluconazole 200 mg once daily (a moderate CYP3A inhibitor) is predicted to increase avapritinib AUC by 210% at steady state [see Dosage and Administration (2.6), Drug Interactions (7.1)]. Effect of Strong and Moderate CYP3A Inducers on Avapritinib: Coadministration of AYVAKIT 400 mg as a single dose with rifampin 600 mg once daily (a strong CYP3A inducer) decreased avapritinib Cmax by 74% and AUC0-INF by 92%. Coadministration of AYVAKIT 300 mg once daily with efavirenz 600 mg once daily (a moderate CYP3A inducer) is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady state [see Drug Interactions (7.1)]. Effect of Acid-Reducing Agents on Avapritinib: No clinically significant differences in the pharmacokinetics of avapritinib were identified when coadministered with gastric acid reducing agents. Hormonal Contraceptives: In a drug-drug interaction study of 15 subjects, coadministration of AYVAKIT 25 mg once daily with an oral contraceptive (levonorgestrel 0.15 mg/ethinyl estradiol 0.03 mg) resulted in a mean ethinyl estradiol AUC ratio of 1.15 (90% confidence interval [CI]: 1.04, 1.28) and a mean ethinyl estradiol Cmax ratio of 1.46 (90% CI: 1.17, 1.81) relative to participants administered the oral contraceptive alone. This increase in ethinyl estradiol Cmax may lead to an increased risk of ethinyl estradiol-related adverse events. In Vitro Studies Cytochrome P450 (CYP) Enzymes: In vitro studies indicate that avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A at clinically relevant concentrations. 22 Reference ID: 5475618 Avapritinib is an inhibitor of CYP2C9 at clinically relevant concentrations. Avapritinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6 at clinically relevant concentrations. Avapritinib is not an inducer of CYP1A2 or CYP2B6. Avapritinib is a substrate of CYP3A. M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9 at clinically relevant concentrations. M499 is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, or CYP2D6 at clinically relevant concentrations. Transporter Systems: Avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal BCRP, MATE1, MATE2-K, and BSEP, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2. Avapritinib is not a substrate of P-gp or BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K and BSEP. The effect of M499 on transporter systems is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day. Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Avapritinib was positive in the in vitro chromosome aberration test in human peripheral blood lymphocytes but negative in the in vivo rat bone marrow micronucleus test, and overall non-genotoxic. There were no direct effects on fertility in rats of either sex in a dedicated fertility and early embryonic development study. Avapritinib may impair spermatogenesis and adversely affect early embryogenesis. Reduction in sperm production and testicular weight were observed in rats and hypospermatogenesis in dogs administered avapritinib at exposure of 8.7 times and 0.5 time the 300 mg human dose, respectively. Avapritinib partitioned into seminal fluids up to 0.2 times the concentration found in human plasma at 300 mg. In female rats there was an increase in pre-implantation loss at exposure of 5.4 times the human exposure at 300 mg and in early resorptions at exposure 2.7 times the human exposure at 300 mg with an overall decrease in viable embryos. Cystic degeneration of corpora lutea and vaginal mucification was also observed in female rats administered avapritinib for up to 6 months at exposure 1.3 times the human exposure based on AUC at the 300 mg dose. 13.2 Animal Toxicology and/or Pharmacology In repeat dose toxicology studies, administration of avapritinib to rats for up to 28 days and to dogs for up to 3 months resulted in tremors at doses greater than or equal to 100 mg/kg/day or 30 mg/kg/day (approximately 8 and 1.5 times the human exposure based on AUC at the 300 mg dose). Hemorrhage in the brain and spinal cord occurred in dogs at doses greater than or equal to 15 mg/kg/day (approximately 9.0, 1.8, or 0.8 times the human exposure based on AUC at the 25 mg, 200 mg. or 300 mg dose, respectively) and choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day. An in vitro phototoxicity study in 3T3 mouse fibroblasts and an in vivo phototoxicity study in pigmented rats demonstrated that avapritinib has a slight potential for phototoxicity. 14 CLINICAL STUDIES 14.1 Gastrointestinal Stromal Tumors The efficacy of AYVAKIT was demonstrated in NAVIGATOR (NCT02508532), a multi-center, single- arm, open-label clinical trial. Eligible patients were required to have a confirmed diagnosis of GIST and 23 Reference ID: 5475618 an ECOG performance status (PS) of 0 to 2. Patients received AYVAKIT 300 mg or 400 mg (1.33 times the recommended dose) orally once daily until disease progression or unacceptable toxicity. The trial initially enrolled patients at a starting dose of 400 mg, which was later reduced to the recommended dose of 300 mg due to toxicity. As there was no apparent difference in overall response rate (ORR) between patients who received 300 mg daily compared to those who received 400 mg daily, these patients were pooled for the efficacy evaluation. The major efficacy outcome measure was ORR based on disease assessment by independent radiological review using modified RECIST v1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodules within a pre-existing tumor mass was progression. An additional efficacy outcome measure was duration of response (DOR). Patients with GIST Harboring a PDGFRA Exon 18 Mutation Patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation were identified by local or central assessment using a PCR- or NGS-based assay. The assessment of efficacy was based on a total of 43 patients, including 38 patients with PDGFRA D842V mutations. The median duration of follow up for patients with PDGFRA exon 18 mutations was 10.6 months (range: 0.3 to 24.9 months). The study population characteristics were median age of 64 years (range: 29 to 90 years), 67% were male, 67% were White, 93% had an ECOG PS of 0-1, 98% had metastatic disease, 53% had largest target lesion >5 cm, and 86% had prior surgical resection. The median number of prior kinase inhibitors was 1 (range: 0 to 5). Efficacy results in patients with GIST harboring PDGFRA exon 18 mutations including the subgroup of patients with PDGFRA D842V mutations enrolled in NAVIGATOR are summarized in Table 11. Table 11. Efficacy Results for Patients with GIST Harboring PDGFRA Exon 18 Mutations in NAVIGATOR Efficacy Parameter PDGFRA exon 181 N = 43 PDGFRA D842V N = 38 Overall Response Rate (95% CI) 84% (69%, 93%) 89% (75%, 97%) Complete Response, n (%) 3 (7%) 3 (8%) Partial Response, n (%) 33 (77%) 31 (82%) Duration of Response n=36 n=34 Median in months (range) NR (1.9+, 20.3+) NR (1.9+, 20.3+) Patients with DOR ≥ 6 months, n (%) 22 (61%) 20 (59%) Abbreviations: CI=confidence interval; NR=not reached + Denotes ongoing response 1 Exon 18 mutations other than D842V included in this population are: deletion of D842_H845 (n=3); D842Y (n=1); and deletion of D842_H845 with insertion of V (n=1). * 11 patients with an ongoing response were followed < 6 months from onset of response. 24 Reference ID: 5475618 14.2 Advanced Systemic Mastocytosis The efficacy of AYVAKIT was demonstrated in EXPLORER (NCT02561988) and PATHFINDER (NCT03580655), two multi-center, single-arm, open-label clinical trials. Response-evaluable patients include those with a confirmed diagnosis of AdvSM per World Health Organization (WHO) and deemed evaluable by modified international working group-myeloproliferative neoplasms research and treatment- European competence network on mastocytosis (IWG-MRT-ECNM) criteria at baseline as adjudicated by an independent central committee, who received at least 1 dose of AYVAKIT, had at least 2 post-baseline bone marrow assessments, and had been on study for at least 24 weeks, or had an end of study visit. All enrolled patients had an ECOG performance status (PS) of 0 to 3 and 91% had a platelet count of ≥ 50 X 109/L prior to initiation of therapy. Patients enrolled in EXPLORER received a starting dose of AYVAKIT ranging from 30 mg to 400 mg (0.15 – 2 times the recommended dose) orally once daily. In PATHFINDER, patients were enrolled at a starting dose of 200 mg orally once daily. The efficacy of AYVAKIT in the treatment of AdvSM was based on overall response rate (ORR) in 53 patients with AdvSM dosed at up to 200 mg daily per modified IWG-MRT-ECNM criteria as adjudicated by the central committee. Additional efficacy outcome measures were duration of response (DOR), time to response, and changes in individual measures of mast cell burden. The median duration of follow up for these patients was 11.6 months (95% confidence interval: 9.9, 16.3). The study population characteristics were median age of 67 years (range: 37 to 85 years), 58% were male, 98% were White, 68% had an ECOG PS of 0-1, 32% had an ECOG PS of 2-3, 40% had ongoing corticosteroid therapy use for AdvSM at baseline, 66% had prior antineoplastic therapy, 47% had received prior midostaurin, and 94% had a D816V mutation. The median bone marrow mast cell infiltrate was 50%, the median serum tryptase level was 255.8 ng/mL, and the median KIT D816V mutant allele fraction was 12.2%. Efficacy results in patients with AdvSM enrolled in EXPLORER and PATHFINDER are summarized in Table 12. 25 Reference ID: 5475618 Table 12. Efficacy Results for Patients with AdvSM in EXPLORER and PATHFINDER All evaluable patients ASM SM-AHN MCL Overall Response Rate1, % per modified IWG-MRT-ECNM (95% CI2) N=53 57 (42, 70) N=2 100 (16, 100) N=40 58 (41, 73) N=11 45 (17, 77) Complete Remission with full or partial hematologic recovery, % 28 50 33 9 Partial Remission, % 28 50 25 36 Clinical Improvement, % 15 0 20 0 Stable Disease, % 19 0 13 45 Abbreviations: CI=confidence interval; CR=complete remission; CRh=complete remission with partial recovery of peripheral blood counts; PR=partial remission 1 Overall Response Rate (ORR) per modified IWG-MRT-ECNM is defined as patients who achieved a CR, CRh or PR (CR + CRh + PR) 2 Clopper–Pearson confidence interval For all evaluable patients, the median duration of response was 38.3 months (95% confidence interval: 19, not estimable) and the median time to response was 2.1 months. In the subgroup of patients with MCL, the efficacy of AYVAKIT was based on complete remission (CR). 14.3 Indolent Systemic Mastocytosis The efficacy of AYVAKIT was demonstrated in PIONEER (NCT03731260), a randomized, double-blind, placebo-controlled trial conducted in adult patients with Indolent Systemic Mastocytosis (ISM) based on World Health Organization (WHO) classification. Enrolled patients had moderate to severe symptoms despite receiving at least 2 symptom directed therapies. Patients were randomized to receive 25 mg AYVAKIT orally once daily with best supportive care versus placebo with best supportive care. The treatment duration was over a 24-week period, during the randomized portion of the study. Efficacy was based on the absolute mean change from baseline to Week 24 in the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) total symptom score (TSS). The ISM-SAF is a patient-reported outcome measure assessing ISM signs and symptoms: abdominal pain, nausea, diarrhea, spots, itching, flushing, bone pain, fatigue, dizziness, headache, brain fog. Scores ranged from 0 (“none”) to 10 (“worst imaginable”). The item scores were summed to calculate a daily ISM-SAF TSS (range 0 110), with higher scores indicating greater symptom severity. A biweekly average ISM-SAF TSS was used to evaluate efficacy endpoints. Additional supportive results included the proportion of AYVAKIT-treated patients achieving ≥50% reduction from baseline through Week 24 in TSS compared to placebo. Objective measures of mast cell burden were assessed including the proportion of AYVAKIT-treated patients with a ≥50% reduction from 26 Reference ID: 5475618 baseline through Week 24 in serum tryptase, peripheral blood KIT D816V allele fraction and bone marrow mast cells. The median age of the patients who received AYVAKIT was 50 years (range: 18 to 77 years), 71% were female, 77% were White, <1% were Asian, 3% had other race and 19% had missing race. Ethnicities included 4% Hispanic or Latino. KIT D816V mutations were identified in 93% of patients. At baseline, the mean TSS was 50.17 (standard deviation: 19.15), the median serum tryptase level was 38.40 ng/mL, the median KIT D816V mutant allele fraction was 0.39% by ddPCR and the median bone marrow mast cell infiltrate was 7%. Study population characteristics were similar in the placebo group. The majority of patients who received AYVAKIT (99.3%) or placebo (100%) received concomitant best supportive care at baseline (median of 3 therapies in the AYVAKIT group and 4 in the placebo group). The most common therapies in the AYVAKIT group were H1 antihistamines (97%), H2 antihistamines (66%), leukotriene inhibitors (35%) and cromolyn sodium (30%). Efficacy results are summarized in Tables 13 and 14. Table 13. Efficacy Results for Patients with ISM in PIONEER at Week 24 Efficacy Parameter AYVAKIT (25 mg once daily) + BSC N=141 Placebo + BSC N=71 2-sided p-value Absolute Mean change in the ISM-SAF TSS1 Change from baseline (95% CI) -15.33 (-18.36, -12.31) -9.64 (-13.61, -5.68) 0.012 Difference from placebo (95% CI) -5.69 (-10.16, -1.23) % of patients achieving ≥50% reduction in the ISM-SAF TSS2 (95% CI) 25 (17.9, 32.8) 10 (4.1, 19.3) 0.009 Abbreviations: BSC=best supportive care; CI=confidence interval; ISM-SAF= Indolent Systemic Mastocytosis- Symptom Assessment Form TSS=Total Symptom Score 1Markov chain Monte Carlo simulation was used to impute the missing values at Baseline or C7D1. 2Patients with missing values at Baseline or C7D1 were counted in the denominator but not numerator. 27 Reference ID: 5475618 Table 14. Efficacy Results Related to Mast Cell Burden for Patients with ISM in PIONEER at Week 24 Efficacy Parameter AYVAKIT (25 mg once daily) + BSC Placebo + BSC 2-sided p-value % of patients with a ≥50% reduction in serum tryptase (95% CI) N=141 53.9 (45.3, 62.3) N=71 0 (0.0, 5.1) <0.0001 % of patients with a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable (95% CI) N=118 67.8 (58.6, 76.1) N=63 6.3 (1.8, 15.5) <0.0001 % of patients with a ≥50% reduction in bone marrow mast cells or no aggregates (95% CI) N=106 52.8 (42.9, 62.6) N=57 22.8 (12.7, 35.8) <0.0001 Abbreviations: BSC=best supportive care; CI=confidence interval To aid in the interpretation of the ISM-SAF TSS absolute mean change from baseline results, the proportion of patients reporting less than or equal to any particular level of change in the ISM-SAF TSS from baseline to Week 24 is depicted in a cumulative distribution function plot as shown in Figure 1. 28 Reference ID: 5475618 :i = "' ., "' "" '- 0 "' OJ) ~ iii <.I ... "' "" "' .s ..!i = E = u 100% --- Avapritjnib 25 mg - - - • Placebo 90% 80% 70% 60% Improvement 50% 40% 30% / 20% / / --- / 10% / / / / I I I I I I I Worsening 1_.,=====:::::;====:;==~~-:::-:-:::..=:..::~,-------,------,-------,,-----,-------,c-----,-J 0%--l - - - -80 -70 -60 -50 -40 -30 -20 -10 0 20 Change in ISM-SAF TSS from Baseline to Week 24 Figure 1: Cumulative Proportion of Patients with ISM in PIONEER Reporting Change in ISM SAF TSS From Baseline to Week 24 16 HOW SUPPLIED/STORAGE AND HANDLING AYVAKIT (avapritinib) tablets are supplied as follows: 25 mg, round, white film-coated tablet with debossed text. One side reads “BLU” and the other side reads “25”; available in bottles of 30 tablets (NDC 72064-125-30). 50 mg, round, white film-coated tablet with debossed text. One side reads “BLU” and the other side reads “50”; available in bottles of 30 tablets (NDC 72064-150-30). 100 mg, round, white film-coated tablet, printed with blue ink “BLU” on one side and “100” on the other side; available in bottles of 30 tablets (NDC 72064-110-30). 200 mg, capsule shaped, white film-coated tablet, printed with blue ink “BLU” on one side and “200” on the other side; available in bottles of 30 tablets (NDC 72064-120-30). 300 mg, capsule shaped, white film-coated tablet, printed with blue ink “BLU” on one side and “300” on the other side; available in bottles of 30 tablets (NDC 72064-130-30). Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). 29 Reference ID: 5475618 Intracranial Hemorrhage Advise patients to contact their healthcare provider immediately if experiencing neurological signs and symptoms that may be associated with intracranial hemorrhage (i.e., severe headache, vomiting, drowsiness, dizziness, confusion, slurred speech, or paralysis) [see Warnings and Precautions (5.1)]. Inform patients with AdvSM of the need to monitor platelet counts before and during treatment [see Warnings and Precautions (5.1)]. Cognitive Effects Advise patients and caretakers to notify their healthcare provider if they experience new or worsening cognitive symptoms. Advise patients not to drive or operate hazardous machinery if they are experiencing cognitive adverse reactions [see Warnings and Precautions (5.2)]. Photosensitivity Inform patients that there is a potential risk of photosensitivity reactions with AYVAKIT. Advise patients to limit direct ultraviolet exposure by using sunscreen and protective clothing during treatment with AYVAKIT [see Warnings and Precautions (5.3)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Drug Interactions (7.2), Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Lactation Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose [see Use in Specific Populations (8.2)]. Infertility Advise females of reproductive potential that AYVAKIT may impair fertility at 200 mg or 300 mg [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Advise males of reproductive potential that AYVAKIT may decrease sperm production at 200 mg or 300 mg [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7.1)]. Administration Advise patients to take AYVAKIT on an empty stomach, at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.1)]. 30 Reference ID: 5475618 Manufactured for: Blueprint Medicines Corporation, Cambridge, MA 02139, USA 31 Reference ID: 5475618 PATIENT INFORMATION AYVAKIT® (aye vah kit) (avapritinib) tablets, for oral use What is AYVAKIT? AYVAKIT is a prescription medicine used to treat adults with: • a certain type of stomach, bowel, or esophagus cancer called gastrointestinal stromal tumor (GIST) that cannot be treated with surgery or that has spread to other parts of the body (metastatic), and that is caused by certain abnormal platelet-derived growth factor receptor alpha (PDGFRA) genes. Your healthcare provider will perform a test to make sure that you have this abnormal PDGFRA gene and that AYVAKIT is right for you. • advanced systemic mastocytosis (AdvSM), including aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). AYVAKIT is not recommended for the treatment of AdvSM in people with low platelet counts (less than 50 X 109/L). • indolent systemic mastocytosis (ISM). AYVAKIT is not recommended for the treatment of ISM in people with low platelet counts (less than 50 X 109/L). It is not known if AYVAKIT is safe and effective in children. Before taking AYVAKIT, tell your healthcare provider about all of your medical conditions, including if you: • have a history of bulging or weakening of a blood vessel wall (aneurysm) or bleeding in your brain • history of stroke within the last year • have low platelet counts • have or have had liver problems • are pregnant or plan to become pregnant. AYVAKIT can cause harm to your unborn baby. Females who are able to become pregnant: o Your healthcare provider should do a pregnancy test before you start treatment with AYVAKIT. o You should use effective birth control (contraception) during treatment with AYVAKIT and for 6 weeks after the final dose of AYVAKIT. Talk to your healthcare provider about birth control methods that may be right for you. o Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with AYVAKIT. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for 6 weeks after the final dose of AYVAKIT. • are breastfeeding or plan to breastfeed. It is not known if AYVAKIT passes into your breast milk. Do not breastfeed during treatment with AYVAKIT and for at least 2 weeks after the final dose of AYVAKIT. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. AYVAKIT may affect the way other medicines work, and certain other medicines may affect how AYVAKIT works. Especially tell your healthcare provider if you take: • estrogen-containing hormonal birth control (contraception) • medicines that prevent blood clots 32 Reference ID: 5475618 How should I take AYVAKIT? • Take AYVAKIT exactly as your healthcare provider tells you to take it. • Do not change your dose or stop taking AYVAKIT unless your healthcare provider tells you to. • AYVAKIT is usually taken 1 time each day. • Take AYVAKIT tablet(s) on an empty stomach at least 1 hour before or at least 2 hours after a meal. • If you miss a dose of AYVAKIT, take it as soon as you remember unless your next scheduled dose is due within 8 hours. Take the next dose at your regular time. • If you vomit after taking a dose of AYVAKIT, do not take an extra dose. Take your next dose at your next scheduled time. What should I avoid while taking AYVAKIT? • Do not drive or operate heavy machinery if you have confusion or trouble thinking during treatment with AYVAKIT. • Your skin may be sensitive to the sun or other forms of light (photosensitivity) during treatment with AYVAKIT. Avoid or limit exposure to direct sunlight, sunlamps, and other sources of ultraviolet radiation during treatment and for 1 week after stopping treatment with AYVAKIT. Use sunscreen or wear clothes that cover your skin if you need to be out in the sun. 33 Reference ID: 5475618 What are the possible side effects of AYVAKIT? AYVAKIT may cause serious side effects, including: • Bleeding in your brain. Serious bleeding in the brain may happen during treatment with AYVAKIT and may lead to death. Stop taking AYVAKIT and tell your healthcare provider right away if you develop any symptoms such as severe headache, nausea, vomiting, vision changes, drowsiness, dizziness, confusion, or severe weakness on one or more side of your body. Bleeding in the brain has not been seen in people treated with AYVAKIT for ISM. If you have AdvSM, your healthcare provider will check your platelet counts before and during treatment with AYVAKIT. • Cognitive effects. Cognitive side effects can happen during treatment with AYVAKIT and can be severe. Tell your healthcare provider if you develop any new or worsening cognitive symptoms including: o forgetfulness o trouble staying awake (somnolence) o confusion o word finding problems o getting lost o seeing objects or hearing things that are not there o trouble thinking (hallucinations) o drowsiness o change in mood or behavior • Skin sensitivity to sunlight (photosensitivity). See “What should I avoid while taking AYVAKIT?” The most common side effects of AYVAKIT in people with GIST include: • fluid retention or swelling • increased eye tearing • nausea • stomach area (abdominal) pain • tiredness or weakness • constipation • trouble thinking • rash • vomiting • dizziness • decreased appetite • hair color changes • diarrhea • changes in certain blood tests The most common side effects of AYVAKIT in people with AdvSM include: • fluid retention or swelling • tiredness or weakness • diarrhea • changes in certain blood tests • nausea The most common side effects of AYVAKIT in people with ISM include: • swelling around your eyes • swelling of your arms and legs • dizziness • flushing Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with AYVAKIT if you develop certain side effects. AYVAKIT may cause fertility problems in females and males. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of AYVAKIT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AYVAKIT? • Store AYVAKIT tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep AYVAKIT and all medicines out of the reach of children. 34 Reference ID: 5475618 General information about the safe and effective use of AYVAKIT. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not take AYVAKIT for a condition for which it was not prescribed. Do not give AYVAKIT to other people, even if they have the same condition that you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about AYVAKIT that is written for health professionals. What are the ingredients in AYVAKIT? Active ingredient: avapritinib Inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. Film coat: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Blue printing ink (100 mg, 200 mg and 300 mg tablets only): ammonium hydroxide, black iron oxide, esterified shellac, FD&C blue 1, isopropyl alcohol, n-butyl alcohol, propylene glycol, and titanium dioxide. Manufactured for: Blueprint Medicines Corporation, Cambridge, MA 02139, USA © 2023 Blueprint Medicines Corporation. All rights reserved. For more information, go to www.AYVAKIT.com or call 1-888-258-7768. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: November/2024 35 Reference ID: 5475618	custom-source	2025-02-12T15:46:36.065288	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212608s020lbl.pdf', 'application_number': 212608, 'submission_type': 'SUPPL ', 'submission_number': 20}
80,205	I I HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RYSTIGGO safely and effectively. See full prescribing information for RYSTIGGO. RYSTIGGO® (rozanolixizumab-noli) injection, for subcutaneous use Initial U.S. Approval: 2023 -----------------------------INDICATIONS AND USAGE-------------------------- RYSTIGGO (rozanolixizumab-noli) is a neonatal Fc receptor blocker indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti muscle-specific tyrosine kinase (MuSK) antibody positive. (1) ------------------------DOSAGE AND ADMINISTRATION---------------------- • Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with RYSTIGGO. (2.1) • For subcutaneous infusion only. (2.2) • The recommended dosage is administered as a subcutaneous infusion once weekly for 6 weeks. (2.2) Body Weight of Patient Dose Volume to be Infused Less than 50 kg 420 mg 3 mL 50 kg to less than 100 kg 560 mg 4 mL 100 kg and above 840 mg 6 mL • Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 63 days from the start of the previous treatment cycle has not been established. (2.2) ---------------------DOSAGE FORMS AND STRENGTHS------------------- Injection: • 280 mg/2 mL (140 mg/mL) in a single-dose vial. (3) • 420 mg/3 mL (140 mg/mL) in a single-dose vial. (3) • 560 mg/4 mL (140 mg/mL) in a single-dose vial. (3) • 840 mg/6 mL (140 mg/mL) in a single-dose vial. (3) -------------------------------CONTRAINDICATIONS------------------------------ None. (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Infections: Delay administration of RYSTIGGO to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with RYSTIGGO. If serious infection occurs, administer appropriate treatment and consider withholding RYSTIGGO until the infection has resolved. (5.1) • Aseptic Meningitis: Serious events of aseptic meningitis have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to the standard of care. (5.2) • Hypersensitivity Reactions: Angioedema and rash have occurred. If a hypersensitivity reaction occurs, discontinue the infusion and institute appropriate therapy. (5.3) -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions (≥10%) in patients with gMG are headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------DRUG INTERACTIONS-------------------------------- • Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing RYSTIGGO and using alternate therapies. (7.1) --------------------------USE IN SPECIFIC POPULATIONS-------------------- Pregnancy: Based on animal data, may cause fetal harm. (8.1) See 17 for PATIENT COUNSELING INFORMATION Revised: 6/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Vaccination 2.2 Recommended Dosage 2.3 Preparation and Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Infections 5.2 Aseptic Meningitis 5.3 Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 7 DRUG INTERACTIONS 7.1 Effect of RYSTIGGO on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use . 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE RYSTIGGO is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Vaccination Because RYSTIGGO causes transient reduction in IgG levels, immunization with live- attenuated or live vaccines is not recommended during treatment with RYSTIGGO. Evaluate the need to administer age-appropriate immunizations according to immunization guidelines before initiation of a new treatment cycle with RYSTIGGO [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 2.2 Recommended Dosage The recommended dosage of RYSTIGGO is based on body weight, as shown below in Table 1. Table 1: Recommended Dose Based on Body Weight Body Weight of Patient Dose Volume to be Infused Less than 50 kg 420 mg 3 mL 50 kg to less than 100 kg 560 mg 4 mL 100 kg and above 840 mg 6 mL Administer the recommended dosage as a subcutaneous infusion using an infusion pump at a rate of up to 20 mL/hour once weekly for 6 weeks. For detailed preparation and administration instructions, see Preparation and Administration Instructions (2.3). Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 63 days from the start of the previous treatment cycle has not been established. If a scheduled dose is missed, RYSTIGGO may be administered up to 4 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed. 2.3 Preparation and Administration Instructions RYSTIGGO should only be prepared and infused by a healthcare provider. RYSTIGGO is for subcutaneous administration only using an infusion pump. Refer to the infusion pump manufacturer's instructions for full preparation and administration information. It is recommended to use pumps where the administered volume can be pre-set as each vial contains excess volume for priming of the infusion line. The following criteria are recommended for administration of RYSTIGGO: • Syringe pump occlusion alarm limits should be at the maximum setting • Administration tubing length should be 61 cm or shorter • Infusion set with a needle of 26 gauge or larger should be used. Read the instructions below before preparing and administering RYSTIGGO solution. • Use aseptic technique when preparing and administering RYSTIGGO. • Prior to use, allow vials to reach room temperature for approximately 30 minutes. Do not use heating devices. Keep the vial in the original carton to protect from light until ready to use. Do not shake. o Vials may be stored at room temperature up to 77°F (25°C) for a single period of up to 30 days in the original carton [see How Supplied/Storage and Handling (16.2)]. • Infuse RYSTIGGO within 4 hours of puncturing the vial. RYSTIGGO should be administered immediately after priming the infusion set. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be colorless to pale brownish-yellow, clear to slightly opalescent. Do not use the vial if the liquid looks cloudy, contains foreign particles, or has changed color. • Use transfer needles to fill the syringe. • Remove the needle from the syringe and attach the infusion set to the syringe. • Follow the device manufacturer's instructions to prepare the pump and prime the tubing. • Choose an infusion site in the lower right or lower left part of the abdomen below the navel and clean with an alcohol wipe. Do not infuse where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks. Rotate infusion sites for subsequent administrations. • Insert the infusion set needle into the infusion site and secure the needle to the skin with sterile gauze and tape or a transparent dressing. • Infuse RYSTIGGO at a constant flow rate up to 20 mL/hour. • Monitor patients during administration and for 15 minutes after completion for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs during administration, discontinue administration of RYSTIGGO and institute appropriate supportive measures [see Warnings and Precautions (5.3)]. • When the infusion is complete, do not flush the infusion line as the volume of infusion has been adjusted taking into account the losses in the line. • Each RYSTIGGO vial is for one-time use only. RYSTIGGO does not contain preservatives. Discard any remaining solution. 3 DOSAGE FORMS AND STRENGTHS RYSTIGGO is a clear to slightly opalescent, colorless to pale brownish yellow solution available as: • 280 mg/2 mL (140 mg/mL) in a single-dose vial. • 420 mg/3 mL (140 mg/mL) in a single-dose vial. • 560 mg/4 mL (140 mg/mL) in a single-dose vial. • 840 mg/6 mL (140 mg/mL) in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infections RYSTIGGO may increase the risk of infection [see Adverse Reactions (6.1)]. Delay RYSTIGGO administration in patients with an active infection until the infection is resolved. During treatment with RYSTIGGO, monitor for clinical signs and symptoms of infection. If serious infection occurs, administer appropriate treatment and consider withholding RYSTIGGO until the infection has resolved. Immunization Immunization with vaccines during RYSTIGGO treatment has not been studied. The safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine are unknown. Because RYSTIGGO causes a reduction in IgG levels, vaccination with live-attenuated or live vaccines is not recommended during treatment with RYSTIGGO. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with RYSTIGGO. 5.2 Aseptic Meningitis Serious adverse reactions of aseptic meningitis (also called drug-induced aseptic meningitis) have been reported in patients treated with RYSTIGGO [see Adverse Reactions (6.1)]. If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care. 5.3 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and rash, were observed in patients treated with RYSTIGGO [see Adverse Reactions (6.1)]. Management of hypersensitivity reactions depend on the type and severity of the reaction. Monitor patients during treatment with RYSTIGGO and for 15 minutes after the administration is complete for clinical signs and symptoms of hypersensitivity reactions [see Dosage and Administration (2.3)]. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Infections [see Warnings and Precautions (5.1)] • Aseptic Meningitis [see Warnings and Precautions (5.2)] • Hypersensitivity Reactions [see Warnings and Precautions (5.3)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies, the safety of RYSTIGGO has been evaluated in 196 patients who received at least one dose of RYSTIGGO, including 88 patients exposed to at least 5 treatment cycles and 9 patients exposed to at least 10 treatment cycles. In a placebo-controlled study (Study 1) in patients with gMG, 133 patients received RYSTIGGO [see Clinical Studies (14)]. Of these 133 patients, approximately 56% were female, 68% were White, 12% were Asian, and 6% were of Hispanic or Latino ethnicity. The mean age at study entry was 52.5 years (range 19 to 89 years). Patients treated with RYSTIGGO received 1 treatment cycle in Study 1. In an extension study, the minimum time for initiating subsequent treatment cycles, specified by study protocol, was 63 days from the start of the previous treatment cycle. Patients treated with RYSTIGGO on average initiated 4 cycles in one year (range 1 to 7 cycles). The median time between start of treatment cycles was 98 days for patients treated with RYSTIGGO who initiated 4 cycles. Adverse reactions reported in at least 5% of patients treated with RYSTIGGO and more frequently than placebo are summarized in Table 2. The most common adverse reactions (reported in at least 10% of patients treated with RYSTIGGO) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea. Table 2: Adverse Reactions in at least 5% of Patients Treated with RYSTIGGO and More Frequently than in Patients who Received Placebo in Study 1 (Safety Population) Adverse Reaction RYSTIGGO (N = 133) % Placebo (N = 67) % Headache 44 19 Any infection Upper respiratory tract infection 23 8 19 6 Diarrhea 20 13 Pyrexia 17 2 Hypersensitivity reactions 11 5 Nausea 10 8 Administration site reactions 8 3 Abdominal pain 8 6 Arthralgia 7 3 Infections In Study 1 and the extension studies, out of 196 patients treated with RYSTIGGO, 94 (48%) patients reported infections. Common infections (at least 5% frequency) were upper respiratory tract infections (17%), COVID-19 (14%), urinary tract infections (9%), and herpes simplex (6%). Serious infections were reported in 4% of patients treated with RYSTIGGO. Three fatal cases of pneumonia were identified caused by COVID-19 infection in two patients and an unknown pathogen in one patient. Six cases of infections led to discontinuation of RYSTIGGO [see Warnings and Precautions (5.1)]. Aseptic Meningitis In clinical trials, one patient with gMG and two patients with another neurological disease experienced a serious adverse reaction of drug-induced aseptic meningitis, which led to hospitalization and discontinuation of RYSTIGGO [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions and Administration Site Reactions In clinical trials, hypersensitivity reactions occurred within 1 day to 2 weeks of administration. One patient discontinued RYSTIGGO due to a hypersensitivity reaction [see Warnings and Precautions (5.3)]. Local reactions at the administration site occurred within 1 to 3 days after the most recent RYSTIGGO infusion. Headache In Study 1, seven (5.3%) cases of severe headache were reported in patients treated with RYSTIGGO. None of the patients who received placebo reported severe headache. One patient was hospitalized due to severe headache and one patient discontinued treatment due to severe headache associated with fever, photophobia, phonophobia, nausea, and vertigo. 7 DRUG INTERACTIONS 7.1 Effect of RYSTIGGO on Other Drugs Concomitant use of RYSTIGGO with medications that bind to the human neonatal Fc receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivatives containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing RYSTIGGO and using alternative therapies. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited data on RYSTIGGO use in pregnant women to inform a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Following administration of rozanolixizumab-noli to pregnant monkeys at doses greater than those used clinically, increases in embryonic death, reduced body weight, and impaired immune function were observed in the absence of maternal toxicity (see Data). All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Subcutaneous administration of rozanolixizumab-noli (0, 50, or 150 mg/kg) to pregnant monkeys every 3 days throughout pregnancy (gestation day 20 to parturition) resulted in an increase in embryonic death and reduced body weight and impaired immune function in offspring at both doses. A no-effect dose for adverse developmental effects was not identified; the doses tested in monkeys are 10 and 30 times the maximum recommended human dose of approximately 10 mg/kg, on a mg/kg/week basis. 8.2 Lactation Risk Summary There are no data on the presence of rozanolixizumab-noli in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RYSTIGGO and any potential adverse effects on the breastfed child from RYSTIGGO or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of RYSTIGGO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients. 11 DESCRIPTION Rozanolixizumab-noli, a neonatal Fc receptor blocker, is a recombinant, humanized IgG4P monoclonal antibody, expressed in a genetically engineered Chinese hamster ovary DG44 cell line. Rozanolixizumab-noli has an approximate molecular weight of 148 kDa. RYSTIGGO 140 mg/mL (2 mL, 3 mL, 4 mL, and 6 mL vials) RYSTIGGO (rozanolixizumab-noli) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brownish yellow solution for subcutaneous infusion. Each single-dose vial contains 280 mg, 420 mg, 560 mg, or 840 mg of rozanolixizumab noli at a concentration of 140 mg/mL with a pH of 5.6. Each mL also contains histidine (1.05 mg), L-histidine hydrochloride monohydrate (4.87 mg), polysorbate 80 (0.30 mg), proline (28.78 mg), and water for injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rozanolixizumab-noli is a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG. 12.2 Pharmacodynamics In Study 1 [see Clinical Studies (14)], the pharmacological effect of rozanolixizumab-noli was assessed by measuring the decrease in serum IgG levels and AChR and MuSK autoantibody levels. In patients testing positive for AChR and MuSK autoantibodies who were treated with RYSTIGGO, there was a reduction in total IgG levels relative to baseline. Decreases in AChR autoantibody and MuSK autoantibody levels followed a similar pattern. 12.3 Pharmacokinetics Rozanolixizumab-noli exhibited nonlinear pharmacokinetics. Rozanolixizumab-noli exposure increased in a greater than dose-proportional manner over a dose range from 1 mg/kg to 20 mg/kg (two times the maximum recommended dose) following subcutaneous administration. Absorption Following subcutaneous administration of rozanolixizumab-noli, peak plasma levels were achieved after approximately 2 days in healthy subjects. Distribution The apparent volume of distribution of rozanolixizumab-noli is 6.6 L. Elimination Metabolism Rozanolixizumab-noli is expected to be degraded by proteolytic enzymes into small peptides and amino acids. Excretion The apparent clearance for the rozanolixizumab-noli is 0.89 L/day. Specific Populations Age, Sex, and Race The pharmacokinetics of rozanolixizumab-noli were not affected by age, sex, or race based on a population pharmacokinetics analysis. Patients with Renal Impairment No dedicated pharmacokinetic study has been conducted in patients with renal impairment. Renal impairment is not expected to affect the pharmacokinetics of rozanolixizumab-noli. Based on a population pharmacokinetic analysis, which included participants with mild to moderate renal impairment, renal function (estimated glomerular filtration rate [eGFR] 38–161 mL/min/1.73 m2) had no clinically significant effect on rozanolixizumab-noli apparent clearance. No dose adjustment is required in patients with renal impairment. Patients with Hepatic Impairment No dedicated pharmacokinetic study has been conducted in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of rozanolixizumab-noli. Drug Interaction Studies Clinical drug interaction studies have not been performed with rozanolixizumab-noli. P450 Enzymes Rozanolixizumab-noli is not metabolized by cytochrome P450 enzymes. Interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. Drug Interactions with Other Drugs or Biological Products Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn [see Drug Interactions (7.1)]. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of rozanolixizumab-noli or of other rozanolixizumab products. The anti-drug antibody (ADA) incidence from Study 1 (MG0003) was 37% (49/133) at the end of the observation period after one treatment cycle of 6-week dosing. The incidence of neutralizing antibodies was 21% (28/133). For patients who developed ADA, there was up to 60% decrease in trough concentrations compared with those in ADA negative patients. However, these observations need to be interpreted with caution because of the limitations with PK analytical assay sensitivity. There appears to be no clinically meaningful impact of ADA (including neutralizing antibodies) on efficacy of rozanolixizumab-noli. The safety profile appears to be similar in ADA positive and ADA negative patients. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Studies to assess the carcinogenic potential of rozanolixizumab-noli have not been conducted. Studies to assess the genotoxic potential of rozanolixizumab-noli have not been conducted. Impairment of Fertility Subcutaneous administration of rozanolixizumab-noli (0 or 150 mg/kg) every 3 days for 26 weeks to sexually mature cynomolgus monkeys resulted in no adverse effects on sperm parameters (count, motility, or morphology) or estrus cyclicity. The dose tested in monkeys is 30 times the maximum recommended human dose of approximately 10 mg/kg, on a mg/kg/week basis. 14 CLINICAL STUDIES The efficacy of RYSTIGGO for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-AChR antibody positive or anti-MuSK antibody positive was established in a multicenter, randomized, double-blind, placebo-controlled study (Study 1; NCT03971422). The study included a 4-week screening period and a 6-week treatment period followed by 8 weeks of observation. During the treatment period, RYSTIGGO or placebo were administered subcutaneously once a week for six weeks. Study 1 enrolled patients who met the following criteria: • Presence of autoantibodies against AChR or MuSK • Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa • Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score of at least 3 (with at least 3 points from non-ocular symptoms) • On stable dose of MG therapy prior to screening that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone • Serum IgG levels of at least 5.5 g/L In Study 1, a total of 200 patients were randomized 1:1:1 to receive weight-tiered doses of RYSTIGGO (n=133), equivalent to ≈7 mg/kg (n=66) or ≈10 mg/kg (n=67), or placebo (n=67). Baseline characteristics were similar between treatment groups. Patients had a median age of 52 years at baseline (range: 18 to 89 years) and a median time since diagnosis of 6 years. Sixty-one percent of patients were female, 68% were White, 11% were Asian, 3% were Black or African American, 1% were American Indian or Alaska Native, and 7% were of Hispanic or Latino ethnicity. Median MG-ADL total score was 8, and the median Quantitative Myasthenia Gravis (QMG) total score was 15. The majority of patients, 89.5% (n=179) were positive for AChR antibodies and 10.5% (n=21) were positive for MuSK antibodies. At baseline in each group, over 83% of patients received AChE inhibitors, over 56% of patients received steroids, and approximately 50% received NSISTs, at stable doses. Patients were treated with RYSTIGGO via subcutaneous infusion once per week for a period of 6 weeks [see Dosage and Administration (2.2)], followed by an observation period of up to 8 weeks. The efficacy of RYSTIGGO was measured using the MG-ADL scale, which assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. The primary efficacy endpoint was the comparison of the change from baseline between treatment groups in the MG-ADL total score at day 43. A statistically significant difference favoring RYSTIGGO was observed in the MG-ADL total score change from baseline [-3.4 points in RYSTIGGO-treated group at either dose vs -0.8 points in the placebo-treated group (p<0.001)]. The secondary endpoint was the change between treatment groups from baseline to day 43 in the QMG. The QMG is a 13-item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment. A statistically significant difference favoring RYSTIGGO was observed in the QMG total score change from baseline [-5.4 points and -6.7 points in RYSTIGGO-treated group at ≈7 mg/kg and ≈10 mg/kg dose level, respectively, vs -1.9 points in the placebo-treated group (p<0.001)]. The results are presented in Table 3. 0 Placebo O Rystiggo ~7mg/l<g <> Rystiggo - 10rng/kg Treatment Observation 0.5 0.0 -0.5 _J - 1.0 -0- 0 1 (!) - 1.5 ::; -'= IE -2.0 u C: .. - 2.5 .. ::; - 3.0 - 3.5 -4.0 t t t t t t Baseline 8 15 22 2.ll 36 43 57 71 85 FV Time (days) Placebo n 67 67 66 65 64 61 64 54 49 46 64 Rystiggo -7rnglkg n 66 66 62 62 63 63 64 55 52 43 64 Rysliggo - 1 llmgll<g n 67 66 64 64 61 60 62 63 59 47 64 Table 3. Change from Baseline to Day 43 in MG-ADL and QMG Total Score in Adult Patients who are Anti-AChR or Anti-MuSK Antibody Positive (Study 1) Efficacy Endpoints RYSTIGGO ≈7mg/kg N = 66 RYSTIGGO ≈10mg/kg N = 67 Placebo N = 67 MG-ADL Total Score LS Mean (SE) -3.4 (0.5) -3.4 (0.5) -0.8 (0.5) Difference from placebo (95% CI) -2.6 (-4.1, -1.2) -2.6 (-4.0, -1.2) - p-value <0.001 <0.001 - QMG Total Score LS Mean (SE) -5.4 (0.7) -6.7 (0.7) -1.9 (0.7) Difference from placebo (95% CI) -3.5 (-5.6, -1.6) -4.8 (-6.8, -2.9) - p-value <0.001 <0.001 - Abbreviations: CI = confidence interval; MG-ADL, myasthenia gravis activities of daily living scale; QMG, quantitative myasthenia gravis; LS = least square; SE = standard error. Figure 1 shows the mean change from baseline in MG-ADL score at Day 43 in Study 1. Figure 1: Observed Mean Change from Baseline to Day 43 in MG-ADL Score CfB=Change from Baseline; FV=Final Visit; MG−ADL=Myasthenia Gravis Activities of Daily Living. NOTE: Error bars represent +/− standard error; arrows indicate timepoints at which treatment was given. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RYSTIGGO (rozanolixizumab-noli) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brownish yellow solution supplied as: NDC Description Strength 50474-980-79 2 mL single-dose glass vial in a carton 280 mg/2 mL 50474-981-83 3 mL single-dose glass vial in a carton 420 mg/3 mL 50474-982-84 4 mL single-dose glass vial in a carton 560 mg/4 mL 50474-983-86 6 mL single-dose glass vial in a carton 840 mg/6 mL 16.2 Storage and Handling Store vials refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light until the time of use. Do not freeze. Do not shake. If needed, vials may be stored at room temperature up to 77°F (25°C) for a single period of up to 30 days in the original carton to protect the vial from light. Once a vial has been stored at room temperature, it should not be returned to the refrigerator. The discard date is 30 days after removal of the vial from the refrigerator. Write the discard date in the space provided on the carton. Discard the vial if not used within 30 days or if the expiration date has passed, whichever occurs first. 17 PATIENT COUNSELING INFORMATION Infections Instruct patients to communicate any history of infections to the healthcare provider and to contact their healthcare provider if they develop any symptoms of an infection [see Warnings and Precautions (5.1)]. Vaccinations Advise patients to complete age-appropriate vaccines according to immunization guidelines prior to initiation of a new treatment cycle with RYSTIGGO. Administration of live or live-attenuated vaccines is not recommended during treatment with RYSTIGGO [see Warnings and Precautions (5.1)]. Aseptic Meningitis Inform patients that RYSTIGGO could cause aseptic meningitis. Instruct patients to contact their healthcare provider if symptoms consistent with meningitis develop [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions Inform patients about the signs and symptoms of hypersensitivity reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of hypersensitivity reactions [see Warnings and Precautions (5.3)]. Manufactured by: UCB, Inc. 1950 Lake Park Drive Smyrna, GA 30080 US License Number 1736 RYSTIGGO® is a registered trademark of the UCB Group of Companies. ©2024 UCB, Inc., Smyrna, GA 30080. All rights reserved.	custom-source	2025-02-12T15:46:36.218910	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761286s001lbl.pdf', 'application_number': 761286, 'submission_type': 'SUPPL ', 'submission_number': 1}
80,208	label may not be the latest approved by F ng information, please visit https://www.fd This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ramesh Raghavachari Digitally signed by Ramesh Raghavachari Date: 2/11/2022 05:34:34PM GUID: 502d0913000029f375128b0de8c50020 ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:36.894980	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206910Orig1s019lbl.pdf', 'application_number': 206910, 'submission_type': 'SUPPL ', 'submission_number': 19}
80,207	________________ ______________ ______________ ___________________ ______________ ______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VONJO safely and effectively. See full prescribing information for VONJO. VONJO® (pacritinib) capsules, for oral use Initial U.S. Approval: 2022 __________________RECENT MAJOR CHANGES _________________ Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE_________________ VONJO is a kinase inhibitor indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L (1). This indication is approved under accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). DOSAGE AND ADMINISTRATION_____________ • Recommended dosage is 200 mg orally twice daily (2.1). • May be taken with or without food (2.1). DOSAGE FORMS AND STRENGTHS____________ Capsules: 100 mg (3) CONTRAINDICATIONS_________________ Concomitant use of strong CYP3A4 inhibitors or inducers (4) WARNINGS AND PRECAUTIONS______________ • Hemorrhage: Avoid use in patients with active bleeding and hold VONJO prior to any planned surgical procedures. May require dose interruption, dose reduction or permanent discontinuation depending on severity (5.1). • Diarrhea: Manage significant diarrhea with anti-diarrheals, dose reduction, or dose interruption (5.2). • Thrombocytopenia: Manage by dose reduction or interruption (5.3). • Prolonged QT Interval: Avoid use in patients with baseline QTc >480 msec. Interrupt and reduce VONJO dosage in patients who have a QTcF >500 msec. Correct hypokalemia prior to and during VONJO administration (5.4). • Major Adverse Cardiac Events (MACE): Risk may be increased in current/past smokers and patients with other cardiovascular risk factors. Monitor for signs, evaluate and treat promptly (5.5). • Thrombosis: Including deep venous thrombosis, pulmonary embolism, and arterial thrombosis may occur. Monitor for signs, evaluate and treat promptly (5.6). • Secondary Malignancies: Lymphoma and other malignancies may occur. Past/current smokers may be at increased risk (5.7). • Risk of Infection: Delay starting VONJO until active serious infections have resolved. Observe for signs and symptoms of infection and manage promptly (5.8). __________________ADVERSE REACTIONS__________________ The most common (≥20% of patients) adverse reactions are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema (6.1). To report SUSPECTED ADVERSE REACTIONS, contact CTI BioPharma Corp. at (844) 428-4246 (844-4CTIBIO) and www.VONJO.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. __________________DRUG INTERACTIONS__________________ Co-administration of VONJO with moderate CYP3A4 inhibitors can increase the exposure to pacritinib. Monitor for increased adverse reactions of VONJO when administered with moderate CYP3A4 inhibitors (7.1). VONJO is an inhibitor of P-gp, BCRP, and CYP1A2 and an inducer of CYP3A4 and CYP2C19. Monitor patients concomitantly receiving substrates of these transporters and enzymes, and adjust dose of the substrates as needed (7.2). VONJO may reduce the effectiveness of hormonal contraceptives (7.2) USE IN SPECIFIC POPULATIONS______________ Lactation: Advise not to breastfeed (8.2). Hepatic Impairment: Avoid use in moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) (8.6). Renal Impairment: Avoid use in patients with eGFR <30 mL/min (8.7). See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE....................3 2 DOSAGE AND ADMINISTRATION........3 2.1 Recommended Dosage............................3 2.2 Monitoring for Safety..............................3 2.3 Missed Dose ............................................3 2.4 Dose Interruption for Planned Surgical Procedures or Other Interventions ..........3 2.5 Dose Modification for Adverse Reactions .................................................................3 3 DOSAGE FORMS AND STRENGTHS.....5 4 CONTRAINDICATIONS ...........................5 5 WARNINGS AND PRECAUTIONS..........5 5.1 Hemorrhage .............................................5 5.2 Diarrhea ...................................................6 5.3 Thrombocytopenia...................................6 5.4 Prolonged QT Interval.............................6 5.5 Major Adverse Cardiac Events (MACE) 7 5.6 Thrombosis ..............................................7 5.7 Secondary Malignancies..........................7 5.8 Risk of Infection......................................7 5.9 Interactions With CYP3A4 Inhibitors or Inducers ................................................... 7 6 ADVERSE REACTIONS ...........................8 6.1 Clinical Trials Experience.......................8 7 DRUG INTERACTIONS..........................10 7.1 Effect of Other Drugs on VONJO......... 10 7.2 Effect of VONJO on Other Drugs......... 10 8 USE IN SPECIFIC POPULATIONS........12 8.1 Pregnancy .............................................. 12 8.2 Lactation................................................12 8.3 Females and Males of Reproductive Potential................................................. 13 8.4 Pediatric Use ......................................... 13 8.5 Geriatric Use.......................................... 13 8.6 Hepatic Impairment............................... 13 8.7 Renal Impairment..................................13 1 Reference ID: 5477197 10 OVERDOSAGE.........................................13 16 HOW SUPPLIED/STORAGE AND 11 DESCRIPTION..........................................13 HANDLING .............................................. 20 12 CLINICAL PHARMACOLOGY ..............14 16.1 How Supplied........................................ 20 12.1 Mechanism of Action ............................14 16.2 Storage................................................... 20 12.2 Pharmacodynamics................................14 17 PATIENT COUNSELING 12.3 Pharmacokinetics...................................15 INFORMATION ....................................... 21 13 13.1 NONCLINICAL TOXICOLOGY.............18 Carcinogenesis, Mutagenesis, and Impairment of Fertility ..........................18 *Sections or subsections omitted from the full prescribing information are not listed. 14 CLINICAL STUDIES ...............................18 2 Reference ID: 5477197 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE VONJO is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) with a platelet count below 50 × 109/L. This indication is approved under accelerated approval based on spleen volume reduction [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of VONJO is 200 mg orally twice daily. VONJO may be taken with or without food. Swallow capsules whole. Do not open, break, or chew capsules. Patients who are on treatment with other kinase inhibitors before the initiation of VONJO must taper or discontinue according to the prescribing information for that drug. 2.2 Monitoring for Safety Perform a complete blood count (CBC; including white blood cell count differential and platelet count), coagulation testing (prothrombin time, partial thromboplastin time, thrombin time, and international normalized ratio) and a baseline electrocardiogram (ECG), prior to starting VONJO, and monitor as clinically indicated while the patient is on treatment. 2.3 Missed Dose If a dose of VONJO is missed, the patient should take the next prescribed dose at its scheduled time. Extra capsules should not be taken to make up for the missed dose. 2.4 Dose Interruption for Planned Surgical Procedures or Other Interventions Discontinue VONJO 7 days prior to elective surgery or invasive procedures because of the risk of hemorrhage and restart only after hemostasis is assured. 2.5 Dose Modification for Adverse Reactions Dose modifications for diarrhea, thrombocytopenia, hemorrhage, and prolonged QT interval are described in Table 1, Table 2, Table 3, and Table 4 respectively. See Warning and Precautions (5.1, 5.2, 5.3, and 5.4) for additional risk minimization recommendations. Dose levels for VONJO are as follows: 200 mg twice daily (initial starting dose), 100 mg twice daily (first dose reduction), 100 mg once daily (second dose reduction). Discontinue VONJO in patients unable to tolerate a dose of 100 mg daily. 3 Reference ID: 5477197 Table 1 Dosage Modification for Diarrhea Toxicity Management/Action New onset of diarrhea • Initiate anti-diarrheal medications. • Encourage adequate oral hydration. Grade 3 or 4 a • Hold VONJO until the diarrhea resolves to Grade 1b or lower or baseline. Restart VONJO at the last given dose. • Intensify anti-diarrheal regimen. Provide fluid replacement. • If diarrhea recurs, hold VONJO until the diarrhea resolves to Grade 1b or lower or baseline. Restart VONJO at 50% of the last given dose once the toxicity has resolved. • Concomitant antidiarrheal treatment is required for patients restarting VONJO. a Increase of at least 7 stools per day over baseline, or hospitalization indicated, or severe increase in ostomy output over baseline, or if limiting self-care. b Increase of <4 stools per day over baseline or mild increase in ostomy output compared to baseline. Table 2 Dose Modification for Thrombocytopenia Worsening Thrombocytopenia Action For clinically significant worsening of thrombocytopenia that lasts more than 7 days • Hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved. • If toxicity recurs hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved. 4 Reference ID: 5477197 Table 3 Dose Modification for Hemorrhage Toxicity Action Moderate bleeding; intervention indicated • Hold VONJO until hemorrhage resolves. Restart VONJO at the last given dose. • If hemorrhage recurs, hold VONJO until resolution then restart at 50% of the last given dose. Severe bleeding; transfusion, invasive intervention, or hospitalization indicated • Hold VONJO until hemorrhage resolves. • Restart VONJO at 50% of the last given dose. • If bleeding recurs, discontinue VONJO. Life-threatening bleeding; urgent intervention indicated. • Discontinue VONJO. Table 4 Dose Modification for Prolonged QT Interval Toxicity Action QTc prolongation >500 msec or >60 msec from baseline • Hold VONJO. • If QTc prolongation resolves to ≤480 msec or baseline within 1 week, restart VONJO at the same dose. • If time to resolution is greater than 1 week, restart VONJO at a reduced dose. 3 DOSAGE FORMS AND STRENGTHS Capsule: 100 mg, oblong, size 0 hard gelatin capsule with an opaque scarlet cap printed with “Pacritinib 100 mg” and opaque gray body printed with “C78837”. 4 CONTRAINDICATIONS VONJO is contraindicated in patients concomitantly using strong CYP3A4 inhibitors or inducers as these medications can significantly alter exposure to pacritinib, which may increase the risk of adverse reactions or impair efficacy [see Warnings and Precautions (5.1, 5.2, 5.3,5.4), Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 x 109/L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 x 109/L. Grade ≥3 bleeding events (defined as requiring transfusion or invasive intervention) occurred in 15% of patients treated with VONJO 5 Reference ID: 5477197 compared to 7% of patients treated on the control arm. Due to hemorrhage, VONJO dose- reductions, dose interruptions, or permanent discontinuations occurred in 3%, 3%, and 5% of patients, respectively. Avoid use of VONJO in patients with active bleeding and hold VONJO 7 days prior to any planned surgical or invasive procedures. Assess platelet counts periodically, as clinically indicated [see Warnings and Precautions (5.3)]. Manage hemorrhage using treatment interruption and medical intervention [see Dosage and Administration (2.5)]. 5.2 Diarrhea VONJO causes diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm. The median time to resolution in VONJO-treated patients was 2 weeks. The incidence of reported diarrhea decreased over time with 41% of patients reporting diarrhea in the first 8 weeks of treatment, 15% in Weeks 8 through 16, and 8% in Weeks 16 through 24. Diarrhea resulted in treatment interruption in 3% of VONJO-treated patients. None of the VONJO-treated patients reported diarrhea that resulted in treatment discontinuation. Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to no such adverse reactions in patients in the control arm. Control pre-existing diarrhea before starting VONJO treatment. Manage diarrhea with antidiarrheal medications, fluid replacement, and dose-modification. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Interrupt or reduce VONJO dose in patients with significant diarrhea despite optimal supportive care [see Dosage and Administration (2.5)]. 5.3 Thrombocytopenia VONJO can cause worsening thrombocytopenia. VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing moderate to severe thrombocytopenia (platelet count <100 x 109/L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing severe thrombocytopenia (platelet count <50 x 109/L). Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment [see Dosage and Administration (2.2)]. Interrupt VONJO in patients with clinically significant worsening of thrombocytopenia that lasts for more than 7 days. Restart VONJO at 50% of the last given dose once the toxicity has resolved. If toxicity recurs hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved [see Dosage and Administration (2.5)]. 5.4 Prolonged QT Interval VONJO can cause prolongation of the QTc interval. QTc prolongation of >500 msec was higher in VONJO-treated patients than in patients in the control arm (1.4% vs 1%). QTc increase from baseline by 60 msec or higher was greater in VONJO-treated patients than in control arm patients (1.9% vs 1%). Adverse reactions of QTc prolongation were reported for 3.8% of VONJO-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported. 6 Reference ID: 5477197 Avoid use of VONJO in patients with a baseline QTc of >480 msec. Avoid use of drugs with significant potential for QTc prolongation in combination with VONJO. Correct hypokalemia prior to and during VONJO treatment. Manage QTc prolongation using VONJO interruption and electrolyte management [see Dosage and Administration (2.5)]. 5.5 Major Adverse Cardiac Events (MACE) Another Janus associated kinase (JAK)-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. 5.6 Thrombosis Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately. 5.7 Secondary Malignancies Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers. 5.8 Risk of Infection Another JAK-inhibitor increased the risk of serious infections (compared to best available therapy) in patients with myeloproliferative neoplasms. Serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Delay starting therapy with VONJO until active serious infections have resolved. Observe patients receiving VONJO for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines. 5.9 Interactions With CYP3A4 Inhibitors or Inducers Co-administration of VONJO with strong CYP3A4 inhibitors or inducers is contraindicated. Monitor for increased adverse reactions of VONJO when administered with moderate CYP3A4 inhibitors [see Contraindications (4), Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. 7 Reference ID: 5477197 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions (5.1)] • Diarrhea [see Warnings and Precautions (5.2)] • Thrombocytopenia [see Warnings and Precautions (5.3)] • Prolonged QT Interval [see Warnings and Precautions (5.4)] • Major Adverse Cardiac Events [see Warnings and Precautions (5.5)] • Thrombosis [see Warnings and Precautions (5.6)] • Secondary Malignancies [see Warnings and Precautions (5.7)] • Risk of Infection [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. PERSIST-2 Trial The safety of VONJO was evaluated in the randomized, controlled PERSIST-2 trial [see Clinical Studies (14)]. In PERSIST-2, key eligibility criteria included adults with intermediate or high- risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF with splenomegaly and a platelet count ≤100 × 109/L. Prior Janus associated kinase (JAK) inhibitor therapy was permitted. Patients received VONJO at 200 mg twice daily (n=106), 400 mg once daily (n=104), or best available therapy (BAT) (n=98). Forty-seven (44%) of the 106 patients treated with VONJO 200 mg twice daily had a baseline platelet count of <50 × 109/L. The 400 mg once daily dose could not be established to be safe, so further information on this arm is not provided. In PERSIST-2, among the 106 patients treated with VONJO 200 mg twice daily, the median baseline hemoglobin was 9.7 g/dL and the median drug exposure was 25 weeks. Fifty-four percent of patients were exposed for 6 months, and 18% were exposed for approximately 12 months. Accounting for dose reductions, the average daily dose (mean relative dose intensity) and median daily dose (median relative dose intensity) were 380 mg (95%) and 400 mg (100%), respectively, for patients receiving VONJO twice daily. The median age of patients who received VONJO 200 mg twice daily was 67 years (range: 39 to 85 years), 59% were male, 86% were White, 3% were Asian, 2% were Native Hawaiian or Other Pacific Islander, 0% were Black, 9% did not report race, and 87% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Serious adverse reactions occurred in 47% of patients treated with VONJO 200 mg twice daily and in 31% of patients treated with BAT. The most frequent serious adverse reactions occurring in ≥3% patients receiving VONJO 200 mg twice daily were anemia (8%), thrombocytopenia (6%), pneumonia (6%), cardiac failure (4%), disease progression (3%), pyrexia (3%), and squamous cell carcinoma of skin (3%). Fatal adverse reactions occurred in 8% of patients 8 Reference ID: 5477197 receiving VONJO 200 mg twice daily and in 9% of patients treated with BAT. The fatal adverse reactions among patients treated with VONJO 200 mg twice daily included events of disease progression (3%), and multiorgan failure, cerebral hemorrhage, meningorrhagia, and acute myeloid leukemia in <1% of patients each, respectively. Permanent discontinuation due to an adverse reaction occurred in 15% of patients receiving VONJO 200 mg twice daily compared to 12% of patients treated with BAT. The most frequent reasons for permanent discontinuation in ≥2% of patients receiving VONJO 200 mg twice daily included anemia (3%) and thrombocytopenia (2%). Drug interruptions due to an adverse reaction occurred in 27% of patients who received VONJO 200 mg twice daily compared to 10% of patients treated with BAT. The most frequent reasons for drug interruption in ≥2% of patients receiving VONJO 200 mg twice daily were anemia (5%), thrombocytopenia (4%), diarrhea (3%), nausea (3%), cardiac failure (3%), neutropenia (2%), and pneumonia (2%). Dosage reductions due to an adverse reaction occurred in 12% of patients who received VONJO 200 mg twice daily compared to 7% of patients treated with BAT. Adverse reactions requiring dosage reduction in ≥2% of patients who received VONJO 200 mg twice daily included thrombocytopenia (2%), neutropenia (2%), conjunctival hemorrhage (2%), and epistaxis (2%). The most common adverse reactions in ≥20% of patients (N=106) were diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema. Table 5 summarizes the common adverse reactions in PERSIST-2 during randomized treatment. Table 5 Adverse Reactions Reported in ≥10% Patients Receiving VONJO 200 mg Twice Daily or Best Available Therapy During Randomized Treatment in PERSIST-2 Adverse Reactions VONJO (200 mg Twice Daily) (N=106) Best Available Therapy (N=98) All Gradesa % Grade ≥3 % All Gradesa % Grade ≥3 % Diarrhea 48 4 15 0 Thrombocytopenia 34 32 23 18 Nausea 32 1 11 1 Anemia 24 22 15 14 Peripheral edema 20 1 15 0 Vomiting 19 0 5 1 Dizziness 15 1 5 0 Pyrexia 15 1 3 0 Epistaxis 12 5 13 1 Dyspnea 10 0 9 3 Pruritus 10 2 6 0 Upper respiratory tract infection 10 0 6 0 Cough 8 2 10 0 a Grade by CTCAE Version 4.03 9 Reference ID: 5477197 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on VONJO Strong and Moderate CYP3A4 Inhibitors Pacritinib is predominantly metabolized by CYP3A4. Concomitant use of VONJO with strong and moderate CYP3A4 inhibitors increases pacritinib exposure, which may increase the risk of exposure-related adverse reactions [see Clinical Pharmacology (12.3)]. Co-administration of VONJO with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4), Warnings and Precautions (5.4)]. Monitor patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and consider VONJO dose modifications based on safety [see Dose Modifications for Adverse Reactions (2.5)]. Concomitant use of VONJO with doses of fluconazole greater than 200 mg once daily has not been studied. Strong CYP3A4 Inducers Pacritinib is predominantly metabolized by CYP3A4. Concomitant use of VONJO with strong CYP3A4 inducers decreases pacritinib exposure, which may reduce efficacy of VONJO [see Clinical Pharmacology (12.3)]. Co-administration of VONJO with strong CYP3A4 inducers is contraindicated [see Contraindications (4)]. 7.2 Effect of VONJO on Other Drugs CYP1A2 Substrates Pacritinib is an inhibitor of CYP1A2. VONJO increases the plasma concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions from the CYP1A2 substrate. Monitor for CYP1A2 substrate related adverse reactions more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with CYP1A2 substrates where minimal substrate concentration changes may lead to serious adverse reactions. CYP2C19 Substrates Pacritinib is an inducer of CYP2C19. VONJO decreases the plasma concentrations of CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may decrease the efficacy from the CYP2C19 substrate. Monitor the efficacy of CYP2C19 substrate more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with CYP2C19 substrates where minimal substrate concentration changes may lead to diminished efficacy. Dose adjustment of CYP2C19 substrates may be needed. 10 Reference ID: 5477197 CYP3A4 Substrates Pacritinib is an inducer of CYP3A4. VONJO decreases the plasma concentrations of CYP3A4 substrates [see Clinical Pharmacology (12.3)], which may decrease the efficacy from the CYP3A4 substrate. Monitor the efficacy of CYP3A4 substrate more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with CYP3A4 substrates where minimal substrate concentration changes may lead to diminished efficacy. Dose adjustment of CYP3A4 substrates may be needed. Hormonal Contraceptives Avoid concomitant use of VONJO with hormonal contraceptives except for intrauterine systems containing levonorgestrel. The effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel, may be reduced when used with VONJO. If contraception is needed or desired, an alternate contraceptive that is not affected by CYP3A4 inducers (e.g., an intrauterine system) or additional nonhormonal contraceptive (e.g., condoms) should be used when treated concomitantly with VONJO, and for 30 days after last dose of VONJO. P-gp Substrates Pacritinib is an inhibitor of P-gp. VONJO increases the plasma concentrations of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions from the P-gp substrate. Monitor for P-gp substrate related adverse reactions more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with P-gp substrates where minimal substrate concentration changes may lead to serious adverse reactions. Digoxin: Measure serum digoxin concentrations before initiating concomitant use with VONJO and continue monitoring serum digoxin concentrations as recommended in the Prescribing Information for digoxin [see Clinical Pharmacology (12.3)]. BCRP substrates Pacritinib is an inhibitor of BCRP. VONJO increases the plasma concentrations of BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions from the BCRP substrate. When used concomitantly with VONJO, monitor for BCRP substrate related adverse reactions more frequently and consider dose reduction of the BCRP substrate according to its Prescribing Information. 11 Reference ID: 5477197 Rosuvastatin: The dose of rosuvastatin should not exceed 20 mg once daily when concomitantly used with VONJO [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on VONJO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of pacritinib to pregnant mice or rabbits at exposures that were considerably lower than those observed at the recommended human dose were associated with maternal toxicity and embryonic and fetal loss (see Data). Advise pregnant women of the potential risk to a fetus. Consider the benefits and risks of VONJO for the mother and possible risks to the fetus when prescribing VONJO to a pregnant woman. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Pacritinib was administered orally to pregnant mice at doses of 30, 100, or 250 mg/kg/day from gestation day 6 to gestation day 15. Pacritinib was also administered orally to pregnant rabbits at doses of 15, 30, or 60 mg/kg/day from gestation day 7 until gestation day 20. In both species, pacritinib was associated with maternal toxicity, which resulted in post-implantation loss in mice, abortions in rabbits, and reduced fetal body weights in mice and rabbits at exposures 0.1 times (mice) and 0.3 times (rabbits) the exposure at the recommended human dose (AUC-based). In mice, the high dose was associated with an increased incidence of an external malformation (cleft palate) in the presence of maternal toxicity. In a pre- and post-natal development study in mice, pregnant animals were dosed with pacritinib from implantation through lactation at 30, 100, or 250 mg/kg/day. Maternal toxicity was noted at 250 mg/kg and associated with increased gestation length and dystocia, lowered mean birth weights and neonatal survival, and transiently delayed startle response, learning, and memory development at weaning. 8.2 Lactation Risk Summary There are no data on the presence of pacritinib in either human or animal milk, the effects on the breastfed child, or the effects on milk production. It is not known whether VONJO is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with VONJO, and for 2 weeks after the last dose. 12 Reference ID: 5477197 8.3 Females and Males of Reproductive Potential Infertility Males Pacritinib reduced male mating and fertility indices in BALB/c mice [see Nonclinical Toxicology (13.1)]. Pacritinib may impair male fertility in humans. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of VONJO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment Administration of a single dose of VONJO 400 mg to subjects with hepatic impairment resulted in a decrease in the geometric mean AUC of pacritinib by 8.5%, 36%, and 45% in subjects with mild [Child-Pugh A], moderate [Child-Pugh B], or severe hepatic impairment [Child-Pugh C], respectively, compared to subjects with normal hepatic function. Avoid use of VONJO in patients with moderate [Child-Pugh B] or severe hepatic impairment [Child-Pugh C] [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Administration of a single dose of VONJO 400 mg to subjects with renal impairment resulted in approximately 30% increase in Cmax and AUC of pacritinib in subjects with eGFR 15 to 29 mL/min and eGFR <15 mL/min on hemodialysis compared to subjects with normal renal function (eGFR ≥90 mL/min). Avoid use of VONJO in patients with eGFR <30 mL/min [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Overdosage may lead to gastrointestinal toxicities, myelosuppression, blurred vision, dizziness, worsening performance status, and sepsis. There is no known antidote for overdose with VONJO. Hemodialysis is not expected to enhance the elimination of VONJO. 11 DESCRIPTION VONJO contains pacritinib citrate, a kinase inhibitor with the chemical name (2E,16E)-11-[2 (pyrrolidin-1-yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa 1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate and a molecular weight of 664.7 as citrate salt and 472.59 as a free base. The molecular formula is C28H32N4O3•C6H8O7 and the structural formula is: 13 Reference ID: 5477197 01 1 1: h 7o O OHO -;::::,-- ~ -;::::,-- O~ No • HO~OH ~ ~ ¾,._ I O OH N N H VONJO capsule is for oral administration. Each capsule contains 100 mg of pacritinib equivalent to 140.65 mg of pacritinib citrate and the inactive ingredients are microcrystalline cellulose NF, polyethylene glycol 8000 (PEG 8000) NF, and magnesium stearate NF. The gelatin capsule is bovine derived. The capsule shell contains gelatin, titanium dioxide, black iron oxide, erythrosine, red iron oxide, and printing ink containing shellac, propylene glycol, titanium dioxide, sodium hydroxide, and povidone. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pacritinib is an oral kinase inhibitor with activity against wild type Janus associated kinase 2 (JAK2), mutant JAK2V617F, FMS-like tyrosine kinase 3 (FLT3), and interleukin 1 receptor associated kinase-1 (IRAK1) which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Pacritinib is also an inhibitor of activin A receptor, type 1/activin receptor like-kinase 2 (ACVR1/ALK2). MF is often associated with dysregulated JAK2 signaling. At clinically relevant concentrations, pacritinib does not inhibit JAK1. Pacritinib has higher inhibitory activity for JAK2 compared to JAK3 and tyrosine kinase 2 (TYK2). Pacritinib exhibits inhibitory activity against additional cellular kinases, such as colony stimulating factor 1 receptor (CSF1R), of which the clinical relevance in myelofibrosis is unknown. 12.2 Pharmacodynamics Pacritinib inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) protein in a dose-dependent manner (ex vivo) in expanded erythroid progenitor cells derived from healthy subjects. Administration of single doses of 400 mg pacritinib resulted in modest inhibition of interleukin-6-induced STAT3 phosphorylation in whole blood derived from healthy subjects. Cardiac Electrophysiology In a 24-week study of 54 patients with MF treated with VONJO 200 mg twice daily, the maximum mean (90% confidence interval) change in QTcF from baseline was 11 (90% CI: 5-17) msec. 14 Reference ID: 5477197 12.3 Pharmacokinetics Pacritinib steady-state mean (CV%) Cmax is 8.4 mg/L (32.4%) and AUC0-12 is 95.6 mg×h/L (33.1%) following administration of VONJO 200 mg twice daily in patients with MF. Pharmacokinetics of pacritinib increases in a less than dose-proportional manner. VONJO 200 mg twice daily accumulates 386% and reaches steady-state within a week. Absorption Pacritinib achieves Cmax within approximately 4 to 5 hours post-dose. Effect of Food There was no significant effect of food on the pharmacokinetics of pacritinib following oral administration of VONJO 200 mg with a high-fat meal. Distribution The median (range) apparent volume of distribution of pacritinib at steady state is 229 L (156 to 591 L) in patients with MF taking 200 mg twice daily. Plasma protein binding of pacritinib is approximately 98.8%. Metabolism Pacritinib is predominantly metabolized by the CYP3A4 isozyme. Pacritinib is the major circulating component and the pharmacologic activity is mainly attributed to the parent molecule. Two major metabolites, M1 and M2, in human whole plasma represent 9.6% and 10.5% of parent drug exposure, respectively. Elimination The mean apparent clearance at steady-state (CV%) of pacritinib is 2.09 L/h (33.1%), and mean effective half-life (CV%) is 27.7 hours (17.0%). Excretion Following a single oral administration of radiolabeled pacritinib 400 mg in healthy adult subjects, 87% of the radioactivity was recovered in feces, and 6% was recovered in urine. No unchanged drug was excreted in feces and 0.12% of unchanged drug was excreted in urine. Specific Populations No clinically significant differences in the pharmacokinetics of pacritinib were observed based on age, sex, body weight, or race. Patients With Renal Impairment Pacritinib Cmax and AUC were similar in subjects with eGFR 30 to 89 mL/min, as estimated by the MDRD study equation, compared to subjects with eGFR ≥90 mL/min. The Cmax and AUC increased approximately 30% in subjects with eGFR 15 to 29 mL/min and eGFR <15 mL/min on hemodialysis. Patients With Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of pacritinib was studied in 28 healthy subjects with normal or impaired hepatic function after a single VONJO 400 mg dose. Compared to subjects with normal hepatic function, the geometric mean AUC of pacritinib decreased by 15 Reference ID: 5477197 8.5%, 36%, and 45% in subjects with mild [Child-Pugh A], moderate [Child-Pugh B], or severe hepatic impairment [Child-Pugh C], respectively. The geometric mean Cmax to pacritinib decreased by 22%, 47%, and 57% in subjects with mild [Child-Pugh A], moderate [Child-Pugh B], or severe hepatic impairment [Child-Pugh C], respectively, compared to subjects with normal hepatic function. Drug Interactions Effects of Other Drugs on the Pharmacokinetics of VONJO The effect of co-administered drugs on the exposure of pacritinib is shown in Table 6 and Table 7. Table 6 Change in Pharmacokinetics of Pacritinib Following Administration of a Single 400 mg Dose VONJO in the Presence of Co-administered Drugs Co-administered Drug Regimen of Co-administered Ratio (90% CI) of pacritinib exposure1 Drug Cmax AUC0-t Clarithromycin (strong CYP3A4 inhibitor) 500 mg every 12 hours for 5 days 1.30 (1.22, 1.39) 1.80 (1.67, 1.94) Rifampin (strong CYP3A4 inducer) 600 mg once daily for 10 days 0.49 (0.43, 0.55) 0.13 (0.11, 0.15) Notes: AUC0-t = Area under the curve from zero to the last quantifiable concentration; CI = Confidence interval; CYP = Cytochrome P450 1 Ratios for Cmax and AUC compare co-administration of the medication with VONJO vs. single-dose 400 mg VONJO alone administration of Table 7 Change in Pharmacokinetics of 200 mg VONJO BID at Steady State in the Presence of Co-administered Drugs Co-administered Drug Regimen of Co-administered Ratio (90% CI) of pacritinib exposure1 Drug Cmax AUC0-tau Fluconazole (moderate CYP3A4 inhibitor) 200 mg once daily for 7 days 1.41 (1.35, 1.48) 1.45 (1.39, 1.52) Bosentan (moderate CYP3A4 inducer) 125 mg twice daily for 7 days 0.84 (0.76, 0.92) 0.79 (0.72, 0.87) Notes: AUC0-tau = Area under the curve for a dosing interval; BID = Twice daily; CI = Confidence interval; Cmax = Maximum plasma concentration; CYP = Cytochrome P450. 1 Ratios for Cmax and AUC0-tau compare co-administration of the medication with 200 mg VONJO BID vs. administration of 200 mg VONJO alone at steady state. Effects of VONJO on the Pharmacokinetics of Other Drugs The effect of pacritinib on the exposure of other co-administered drugs is shown in Table 8. Table 8 Change in Pharmacokinetics of Co-administered Drugs with 200 mg VONJO BID at Steady State Co-administered Drug Regimen of Co-administered Drug (single dose) Ratio (90% CI) of exposure of co- administered drug1 Cmax AUC Caffeine (CYP1A2 substrate) 100 mg 0.99 (0.92, 1.07) 1.22 (1.12, 1.32) 16 Reference ID: 5477197 Midazolam (CYP3A4 substrate) 2 mg 0.40 (0.34, 0.46) 0.40 (0.35, 0.46) Omeprazole (CYP2C19 substrate) 20 mg 0.73 (0.46, 1.15) 0.49 (0.27, 0.89) Notes: AUC = Area under the curve from zero to the last quantifiable concentration displayed for caffeine and AUC from zero extrapolated to infinity displayed for midazolam and omeprazole; BID = Twice daily; CI = Confidence interval; Cmax = Maximum plasma concentration; CYP = Cytochrome P450. 1 Ratios for Cmax and AUC compare a single dose of co-administered drug with 200 mg VONJO BID at steady state vs. administration of a single dose of the co-administered drug alone. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Pacritinib is a time-dependent inhibitor of CYP1A2 and CYP3A4, and a reversible inhibitor of CYP3A4 and CYP2C19 (Ki ≤10 µM). Pacritinib shows less direct inhibition towards CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 (Ki >10 µM). Pacritinib is an inducer of CYP1A2 and CYP3A4. Transporter Systems Table 9 Change in Pharmacokinetics of Co-administered Drugs with 200 mg VONJO BID at Steady State Co-administered Drug Regimen of Co-administered Drug (single dose) Ratio (90% CI) of exposure of co- administered drug1 Cmax AUC Metformin (OCT1 substrate) 500 mg 0.96 (0.87, 1.07) 1.05 (0.96, 1.15) Digoxin (P-gp substrate) 0.25 mg 1.29 (1.13, 1.47) 1.15 (1.05, 1.27) Rosuvastatin (BCRP substrate) 5 mg 2.04 (1.79, 2.31) 1.80 (1.63, 1.99) Notes: AUC = Area under the curve from zero to the last quantifiable concentration displayed for digoxin and rosuvastatin and AUC from zero extrapolated to infinity displayed for metformin; BID = Twice daily; CI = Confidence interval; Cmax = Maximum plasma concentration; CYP = Cytochrome P450 1 Ratios for Cmax and AUC compare a single dose of co-administered drug with 200 mg VONJO BID at steady state vs. administration of a single dose of the co-administered drug alone. In Vitro Studies Transporter Systems: Pacritinib is not a substrate of BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or P-gp. Pacritinib is an inhibitor of BCRP, OCT1, OCT2, and P-gp. Pacritinib is not an inhibitor of BSEP, MRP2, OAT1, or OAT3. 17 Reference ID: 5477197 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Pacritinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model. Pacritinib was not carcinogenic in a 2-year carcinogenicity study in rats at 0.004 times and 0.014 times, in males and females, respectively, the recommended human dose (AUC-based). Pacritinib exposures achieved in mice and rats during the carcinogenicity assessments were considerably lower than the exposure observed at the recommended human dose. Pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in vitro in a chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice. In a fertility study in male BALB/c mice, pacritinib was administered for at least 70 days prior to cohabitation with untreated partners. Pacritinib had no effects at any dose level on uterine implantation, macroscopic findings, reproductive organ weights, and sperm evaluations. At 213.4 mg/kg/day (3.0 times, the recommended human dose, based on body surface area), reduced mating and fertility indices were observed in male BALB/c mice. In a fertility and early embryonic development study in CD-1 mice, no effects on male or female reproductive performance, including assessments of mating, fertility, estrous cyclicity, and intrauterine survival, were observed at doses up to 250 mg/kg/day (3.0 times, the recommended human dose, based on body surface area). 14 CLINICAL STUDIES PERSIST-2 The efficacy of VONJO in the treatment of patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF was established in the PERSIST-2 trial. PERSIST-2 enrolled patients with intermediate or high-risk primary or secondary (post polycythemia vera or post-essential thrombocythemia) MF with splenomegaly and a platelet count ≤100 × 109/L. Both JAK2 naïve patients and patients with prior JAK2 inhibitor therapy were included. Patients were randomized 1:1:1 to receive VONJO 400 mg once daily, VONJO 200 mg twice daily, or best available therapy (BAT). BAT agents could be used alone, in combinations, sequentially, and intermittently, as clinically indicated by standards of care. BAT included any physician-selected treatment for MF and may have included ruxolitinib, hydroxyurea, glucocorticoids, erythropoietic agents, immunomodulatory agents, mercaptopurine, danazol, interferons, cytarabine, melphalan. BAT also included no treatment (“watch and wait”) or symptom-directed treatment without MF-specific treatment. In this trial, 311 patients were randomized to receive VONJO 400 mg once daily (n=104), VONJO 200 mg twice daily (n=107), or BAT (n=100). The VONJO dose of 400 mg once daily was not established as safe and is not an approved dosage regimen. The demographic characteristics of the efficacy population were median age of 68 years (range 32 to 91), 55% male, 86% Caucasian, and 14% non-Caucasian. The VONJO and BAT treatment arms were well balanced with respect to age, gender, race, ethnicity, body mass index, and geographic region. Sixty-eight percent of patients had primary MF, 20% had post-polycythemia 18 Reference ID: 5477197 vera MF, and 12% had post-essential thrombocythemia MF. Forty-six percent and 51% of patients in the VONJO and BAT treatment arms, respectively, had received prior ruxolitinib therapy. The median baseline hemoglobin level was 9.5 g/dL and 23% of patients were red blood cell (RBC) transfusion dependent at study entry. The median baseline platelet count was 55 × 109/L; 45% of patients had a platelet count <50 × 109/L. Patients had a baseline median spleen length of 14 cm assessed by magnetic resonance imaging (MRI) or computerized axial tomography (CAT). Efficacy was established in patients who received VONJO 200 mg twice daily and had a platelet count <50 x 109 (N=31). The most common agents used in the BAT treatment arm in patients with baseline platelet counts <50 × 109/L (N=32) were ruxolitinib (39%), watchful waiting (32%), and hydroxyurea (26%). Spleen Volume Reduction The efficacy of VONJO in the treatment of patients with primary or secondary MF was established based upon the proportion of patients in the efficacy population receiving VONJO 200 mg twice daily or BAT achieving ≥35% spleen volume reduction from baseline to Week 24 as measured by magnetic resonance imaging or computed tomography. Efficacy results for spleen volume reduction in patients with a platelet count <50 × 109/L are presented in Table 10 Table 10 Percentage of Patients Achieving ≥35% Reduction in Spleen Volume From Baseline to Week 24 in the Phase 3 Study, PERSIST-2 (Efficacy Population) Patient Population VONJO 200mg Twice Daily N=31 Best Available Therapy N=32 Baseline Platelets <50 × 109/L 9 (29.0%) 1 (3.1%) 95% Confidence Interval (CI) 14.2, 48.0 0.1, 16.2 Difference (VONJO-BAT) 95% CI 25.9 (4.3,44.5) 19 Reference ID: 5477197 a, -~ ai fJl ro cc E ,g a, Cl C: ro .c () 100-;-;:::=======:::;-------------------, 90 ■ VONJO 200 mg BID ■ BAT 80 70 60 50 40 30 20 10 oL- ~~,..............;r.r-........--..---..---..----.ri.--..--.i;;;F'-_JLJl~ li7f"1nrT1i.::::l""""~.L...lL..l'--..l!:-'-'---lJ'-....ll....C1 -10 -20 ~ -30 -40 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 35% Decrease -50 -60 -70 -80 --L _______________ -;:P;--a-;:ti-::-e:::--:nt:::s---------------~ A waterfall plot of the percentage of change in spleen volume from baseline to Week 24 is presented in Figure 1 for the PERSIST-2 patients with baseline platelet counts <50 × 109/L. The median reduction in spleen volume for patients with a platelet count <50 × 109/L was 27.3% for patients in the VONJO 200 mg twice daily group compared to 0.9% in the BAT group. Figure 11 Waterfall Plot of Median Percent Change From Baseline in Spleen Volume at Week 24 in Patients With <50 × 109/L Platelet Counts in PERSIST-2a aDropout rates in VONJO and BAT arms were 26% and 44%, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VONJO is supplied in the following strength and package configuration: Strength NDC Number Description Capsules per Bottle 100 mg 72482-100-12 Hard, oblong, opaque, gelatin capsule with scarlet cap and gray body, printed with “Pacritinib 100 mg” on the cap and “C78837” on the body 120 16.2 Storage Store at room temperature, below 30°C (86°F). Keep the bottle tightly closed and protect from light. Store in original package. Dispense in original package or in a light-resistant container. 20 Reference ID: 5477197 17 PATIENT COUNSELING INFORMATION See FDA approved patient labeling (Patient Information). Discuss the following with the patient prior to and during treatment with VONJO: Current therapy with another kinase inhibitor Advise patients who are currently taking a kinase inhibitor that they must taper or discontinue their current kinase inhibitor therapy according to the package insert for that drug prior to starting VONJO. Hemorrhage Advise patients that VONJO can cause hemorrhage and instruct them to consult their healthcare provider right away if bleeding occurs. Advise patients about how to recognize bleeding and of the urgent need to report any unusual bleeding to their physician. Patients should urgently seek emergency medical attention for any bleeding that cannot be stopped [see Warnings and Precautions (5.1)]. Diarrhea Advise patients that VONJO can cause diarrhea. Advise patients to stay hydrated while taking VONJO and to inform their physician if they experience diarrhea. Instruct patients to initiate anti-diarrheal medications (e.g., loperamide) if diarrhea occurs. Advise patients to urgently seek emergency medical attention if diarrhea becomes severe [see Warnings and Precautions (5.2)]. Thrombocytopenia Advise patients that VONJO can cause thrombocytopenia, and of the need to monitor complete blood counts before and during treatment [see Warnings and Precautions (5.3)]. Prolonged QT Interval Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Advise patients with a history of hypokalemia of the importance of monitoring their electrolytes [see Warnings and Precautions (5.4)]. Major Adverse Cardiac Events (MACE) Advise patients that events of major adverse cardiac events (MACE) including myocardial infarction, stroke, and cardiovascular death, have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which VONJO is not indicated. Advise patients, especially current or past smokers or patients with other cardiovascular risk 21 Reference ID: 5477197 factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.5)]. Thrombosis Advise patients that events of deep vein thrombosis and pulmonary embolism have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which VONJO is not indicated. Advise patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions (5.6)]. Secondary Malignancies Advise patients, especially current or past smokers and patients with a known secondary malignancy (other than a successfully treated NMSC), that lymphoma and other malignancies (excluding NMSC) have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which VONJO is not indicated [see Warnings and Precautions (5.7)]. Infections Advise patients that treatment with another JAK-inhibitor has increased the risk of serious infections in patients with myeloproliferative neoplasms and that serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Inform patients of the signs and symptoms of infection and to report any such signs and symptoms promptly [see Warnings and Precautions (5.8)]. Nausea and Vomiting Advise patients that nausea and vomiting may occur during treatment with VONJO. Instruct them on how to manage nausea and vomiting and to immediately inform their healthcare provider if nausea/vomiting become severe. Drug–Drug Interactions Advise patients to inform their healthcare providers of all medications they are taking, including prescription and over-the-counter medications, vitamins, herbal products, and dietary supplements [see Drug Interactions (7)]. Inform women of the possible reduced effectiveness of hormonal contraceptives when under treatment with VONJO and for 30 days after last dose. Advise women of childbearing potential receiving VONJO and hormonal contraception, to use additional nonhormonal contraception or use an alternative contraceptive that is not affected by CYP3A4 inducers [see Drug Interactions (7.2)]. 22 Reference ID: 5477197 Dosing Advise patients to take VONJO twice a day, with or without food or drink. VONJO should be taken at similar times each day. Instruct patients to swallow the VONJO capsules whole and not to open, break, or chew the capsules [see Dosage and Administration (2.1)]. Instruct patients that if they miss a dose of VONJO, to skip the dose and take the next dose when it is due and return to the normal schedule [see Dosage and Administration (2.1)]. Warn patients not to take 2 doses to make up for the missed dose. Instruct patients to discontinue VONJO 7 days prior to any surgery or invasive procedures (such as cardiac catheterization, coronary stenting or varicose vein ablation) due to the risk of bleeding and to only restart VONJO on the instruction of their healthcare provider. Patients should not change or stop taking VONJO without first consulting their physician. Lactation Advise patients to avoid breastfeeding while taking VONJO and for 2 weeks after the final dose [see Use in Specific Populations (8.2)]. Manufactured and marketed by: CTI BioPharma Corp. 3101 Western Ave #800 Seattle, WA 98121 VONJO® is a registered trademark of CTI BioPharma Corp. All rights reserved. ©2022 All rights reserved. 23 Reference ID: 5477197 PATIENT INFORMATION VONJO (VON-joh) (pacritinib) capsules What is VONJO? VONJO is a prescription medicine used to treat adults with certain types of myelofibrosis who have a platelet count below 50 x 109/L. It is not known if VONJO is safe and effective in children. Before taking VONJO, tell your healthcare provider about all of your medical conditions, including if you: • have active bleeding, have had severe bleeding, or plan to have surgery or invasive procedures. You should stop taking VONJO 7 days before any planned surgery or invasive procedures. See “What are the possible side effects of VONJO?” • have diarrhea or commonly have loose stools • have had a blood clot, heart attack, other heart problems, or stroke • have a history of low blood levels of potassium. It is important that you get blood tests done during treatment with VONJO to monitor your body salts (electrolytes). • smoke or were a smoker in the past • have had any other cancers. See “What are the possible side effects of VONJO?” • have an infection. See “What are the possible side effects of VONJO?” • have nausea or vomiting • have liver or kidney problems • are pregnant or plan to become pregnant. It is not known if VONJO will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if VONJO passes into your breast milk. You should not breastfeed during treatment and for 2 weeks after your last dose of VONJO. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking VONJO with certain other medicines may affect the amount of VONJO or the other medicines in your blood and may increase your risk of side effects or affect how well VONJO works. Especially tell your healthcare provider if you take hormonal contraceptives (birth control). Hormonal birth control methods, except for intrauterine systems containing levonorgestrel may not work during treatment with VONJO and for 30 days after your last dose. Talk to your healthcare provider about birth control methods that may be right for you during treatment with VONJO. Know the medicines you take. Keep a list of the medicines you take to show your healthcare provider and pharmacist when you get a new medicine. How should I take VONJO? • Take VONJO exactly as your healthcare provider tells you to take it. • Do not change your dose or stop taking VONJO without first talking to your healthcare provider. • If you take other kinase inhibitors, carefully follow your healthcare provider’s instructions about how to slowly decrease (taper) your dose or stop the other kinase inhibitor medicines before you begin taking VONJO. • VONJO is usually taken by mouth 2 times each day. • Swallow VONJO capsules whole. Do not open, break, or chew capsules. • You can take VONJO with or without food or drink. • Take your VONJO doses at about the same time every day. • If you notice any change in how often you have bowel movements, if they become softer or you have diarrhea, start taking an antidiarrheal medicine (for example, loperamide) as soon as you notice changes, as directed by your healthcare provider. • If you miss a dose of VONJO, skip the dose and just take your next dose at your regularly scheduled time. Do not take 2 doses at the same time to make up for the missed dose. • If you take too much VONJO, call your healthcare provider or go to the nearest emergency room right away and take your bottle of VONJO with you. Reference ID: 5477197 What are the possible side effects of VONJO? VONJO can cause serious side effects including: • Bleeding. VONJO can cause severe bleeding, which can be serious and, in some cases may lead to death. o Stop taking VONJO and tell your healthcare provider right away if you develop any of these symptoms: unusual bleeding, bruising, and fever. Get medical help right away for any bleeding that you cannot stop. o You will need to stop taking VONJO 7 days before any planned surgery or invasive procedure (such as a heart catheterization, stent placement in a coronary artery in your heart, or a procedure for varicose veins). Your healthcare provider should tell you when you can start taking VONJO again. • Diarrhea. Diarrhea is common with VONJO, but can also be severe, and cause loss of too much body fluid (dehydration). Tell your healthcare provider if you have diarrhea and follow instructions for what to do to help treat diarrhea. Drink plenty of fluids to help prevent dehydration. • Worsening low platelet counts. • Changes in the electrical activity of your heart called QTc prolongation. QTc prolongation can cause irregular heartbeats that can be life-threatening. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint. • Increased risk of major cardiovascular events such as heart attack, stroke, or death in people have happened, especially in those who have cardiovascular risk factors and who are current or past smokers taking another Janus Kinase (JAK)-inhibitor to treat rheumatoid arthritis. Get emergency help right away if you have any symptoms of a heart attack or stroke during treatment with VONJO, including: o discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back o severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw o pain or discomfort in your arms, back, neck, jaw, or stomach o shortness of breath with or without chest discomfort o breaking out in a cold sweat o nausea or vomiting o feeling lightheaded o weakness in one part or on one side of your body o slurred speech • Increased risk of blood clots. Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE) have happened in some people taking another JAK-inhibitor for rheumatoid arthritis and may be life-threatening. Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with VONJO, including: o swelling, pain, or tenderness in one or both legs o sudden, unexplained chest pain o shortness of breath or difficulty breathing • Possible increased risk of new (secondary) cancers. People who take another JAK-inhibitor for rheumatoid arthritis have an increased risk of new (secondary) cancers, including lymphoma and other cancers, except non- melanoma skin cancer. The risk of new cancers is further increased in people who smoke or who smoked in the past. • Risk of infection. People who have certain blood cancers and take another JAK-inhibitor have an increased risk of serious infections. People who take VONJO may also develop serious infections, including bacterial, mycobacterial, fungal, and viral infections. If you have a serious infection, your healthcare provider may not start you on VONJO until your infection is gone. Your healthcare provider will monitor you and treat you for any infections that you get during treatment with VONJO. Tell your healthcare provider right away if you develop any of the following symptoms of infection: o chills o vomiting o aches o weakness o fever o painful skin rash or blisters o nausea The most common side effects of VONJO include: • low platelet counts Reference ID: 5477197 • nausea and vomiting • low red blood cell counts (anemia) • swelling of your ankles, legs, and feet Your healthcare provider will do blood tests and an electrocardiogram (ECG) before you start treatment with VONJO and as needed during treatment to check for side effects. Your healthcare provider may change your dose or how often you take VONJO, temporarily stop or permanently stop treatment with VONJO if you have certain side effects. VONJO may affect fertility in males. You may have problems fathering a child. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects with VONJO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VONJO? • Store VONJO at room temperature, below 86°F (30°C). • Store VONJO in the original package. • Keep the bottle tightly closed to protect VONJO from light. Keep VONJO and all medicines out of the reach of children. General information about the safe and effective use of VONJO. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VONJO for a condition for which it was not prescribed. Do not give VONJO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VONJO that is written for health professionals. What are the ingredients in VONJO? Active ingredient: pacritinib Inactive ingredients: microcrystalline cellulose, polyethylene glycol 8000 (PEG 8000), and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, black iron oxide, erythrosine, red iron oxide, and printing ink containing shellac, propylene glycol, titanium dioxide, sodium hydroxide, and povidone. Manufactured and Marketed by: CTI BioPharma Corp., 3101 Western Ave #800, Seattle WA 98121 VONJO® is a registered trademark of CTI BioPharma Corp. All rights reserved. For more information call 1-844-428-4246 (1-844-4CTIBIO) or go to www.VONJO.com. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5477197	custom-source	2025-02-12T15:46:36.951909	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208712s003lbl.pdf', 'application_number': 208712, 'submission_type': 'SUPPL ', 'submission_number': 3}
80,206	]HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OMNITROPE safely and effectively. See full prescribing information for OMNITROPE. OMNITROPE® (somatropin) injection, for subcutaneous use OMNITROPE® (somatropin) for injection, for subcutaneous use Initial U.S. Approval: 1987 --------------------------- INDICATIONS AND USAGE ------------------------- OMNITROPE is a recombinant human growth hormone indicated for: • Pediatric: Treatment of children with growth failure due to growth hormone deficiency (GHD), Prader-Willi Syndrome, Small for Gestational Age, Turner Syndrome, and Idiopathic Short Stature (1.1) • Adult: Treatment of adults with either adult onset or childhood onset GHD (1.2) ---------------------- DOSAGE AND ADMINISTRATION --------------------- OMNITROPE should be administered subcutaneously (2). • Pediatric GHD: 0.16 to 0.24 mg/kg/week, divided into 6 to 7 daily injections (2.1) • Prader-Willi Syndrome: 0.24 mg/kg/week, divided into 6 to 7 daily injections (2.1) • Small for Gestational Age: Up to 0.48 mg/kg/week, divided into 6 to 7 daily injections (2.1) • Turner Syndrome: 0.33 mg/kg/week, divided into 6 to 7 daily injections (2.1) • Idiopathic Short Stature: Up to 0.47 mg/kg/week, divided into 6 to 7 daily injections (2.1) • Adult GHD: not more than 0.04 mg/kg/week (divided into daily injections) to be increased as tolerated to not more than 0.08 mg/kg/week; to be increased gradually every 1 to 2 months (2.2) • OMNITROPE Cartridges 5 mg/1.5 mL and 10 mg/1.5 mL must be used with the corresponding OMNITROPE Pen 5 and Pen 10 delivery system, respectively (2.3) • Injection sites should always be rotated to avoid lipoatrophy (2.3) --------------------- DOSAGE FORMS AND STRENGTHS ------------------- • Injection: 5 mg/1.5 mL or 10 mg/1.5 mL solution in a single-patient-use prefilled cartridge (3) • For injection: 5.8 mg lyophilized powder in a single-patient-use vial (3) ------------------------------ CONTRAINDICATIONS ---------------------------- • Acute Critical Illness (4) • Children with Prader-Willi Syndrome who are severely obese or have severe respiratory impairment - reports of sudden death (4) • Active Malignancy (4) • Hypersensitivity to somatropin or its excipients (4) • Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy (4) • Children with closed epiphyses (4) ----------------------- WARNINGS AND PRECAUTIONS --------------------- • Acute Critical Illness: Potential benefit of treatment continuation should be weighed against the potential risk (5.1) • Prader-Willi Syndrome in children: Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment. Discontinue treatment if these signs occur (5.2) • Neoplasm: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin - in particular meningiomas in patients treated with radiation to the head for their first neoplasm (5.3) • Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment (5.4) • Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction (5.5) • Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention (5.6) • Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome especially in adults): May occur frequently. Reduce dose as necessary (5.7) • Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism (5.8) • Hypothyroidism: May first become evident or worsen (5.9) • Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the onset of a limp or hip/knee pain (5.10) • Progression of Preexisting Scoliosis: May develop (5.11) • Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.15) ------------------------------ ADVERSE REACTIONS ---------------------------- Other common somatropin-related adverse reactions include injection site reactions/rashes and lipoatrophy (6.1) and headaches (6.2). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------------ DRUG INTERACTIONS ---------------------------- • 11β-Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses (7.1, 7.2) • Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: Should be carefully adjusted (7.2) • Cytochrome P450-Metabolized Drugs: Monitor carefully if used with somatropin (7.3) • Oral Estrogen: Larger doses of somatropin may be required in women (7.4) • Insulin and/or Oral Hypoglycemic Agents: May require adjustment (7.5) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Pediatric Patients 1.2 Adult Patients 2 DOSAGE AND ADMINISTRATION 2.1 Dosing of Pediatric Patients 2.2 Dosing of Adult Patients 2.3 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Acute Critical Illness 5.2 Prader-Willi Syndrome in Children 5.3 Neoplasms 5.4 Impaired Glucose Tolerance and Diabetes Mellitus 5.5 Intracranial Hypertension (IH) 5.6 Hypersensitivity 5.7 Fluid Retention 5.8 Hypoadrenalism 5.9 Hypothyroidism 5.10 Slipped Capital Femoral Epiphysis in Pediatric Patients 5.11 Progression of Preexisting Scoliosis in Pediatric Patients 5.12 Otitis Media and Cardiovascular Disorders in Turner Syndrome 5.13 Lipoatrophy 5.14 Laboratory Tests 5.15 Pancreatitis 5.16 Benzyl Alcohol Reference ID: 5477192 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1) 7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment 7.3 Cytochrome P450-Metabolized Drugs 7.4 Oral Estrogen 7.5 Insulin and/or Oral Hypoglycemic Agents 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Pediatric Growth Hormone Deficiency (GHD) 14.2 Adult Growth Hormone Deficiency (GHD) 14.3 Prader-Willi Syndrome (PWS) 14.4 Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2 14.5 Idiopathic Short Stature (ISS) 14.6 Turner Syndrome 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Pediatric Patients OMNITROPE is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone (GH). OMNITROPE is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi Syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing [see Contraindications (4) and Warnings and Precautions (5.2)]. OMNITROPE is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years. OMNITROPE is indicated for the treatment of growth failure associated with Turner Syndrome. OMNITROPE is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) ≤ -2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means. 1.2 Adult Patients OMNITROPE is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD) who meet either of the following two criteria: • Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or • Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency. Reference ID: 5477192 2 DOSAGE AND ADMINISTRATION The weekly dose should be divided over 6 or 7 days of subcutaneous injections. Therapy with OMNITROPE should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with GHD, Prader-Willi Syndrome (PWS), Turner Syndrome (TS), those who were born small for gestational age (SGA), Idiopathic Short Stature (ISS) and adult patients with either childhood onset or adult onset GHD. 2.1 Dosing of Pediatric Patients General Pediatric Dosing Information The OMNITROPE dosage and administration schedule should be individualized based on the growth response of each patient. Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH). Treatment with OMNITROPE for short stature should be discontinued when the epiphyses are fused. Pediatric Growth Hormone Deficiency (GHD) Generally, a dosage of 0.16 to 0.24 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections. Prader-Willi Syndrome (PWS) Generally, a dosage of 0.24 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections. Small for Gestational Age (SGA) Generally, a dosage of up to 0.48 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections. Turner Syndrome (TS) Generally, a dose of 0.33 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections. Idiopathic Short Stature (ISS) Generally, a dose up to 0.47 mg/kg of body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections. 2.2 Dosing of Adult Patients Adult Growth Hormone Deficiency (GHD) Weight-Based Dosing Based on the weight-based dosing utilized in clinical studies with another somatropin product, the recommended dosage at the start of therapy is not more than 0.04 mg/kg/week given as a daily subcutaneous injection. The dose may be increased at 4- to 8-week intervals according to individual patient requirements to not more than 0.08 mg/kg/week. Reference ID: 5477192 Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-1 levels may be used as guidance in dose titration. Non-Weight Dosing Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-1 levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person. A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women. 2.3 Preparation and Administration OMNITROPE Cartridge 5 mg/1.5 mL and Cartridge 10 mg/1.5 mL Each cartridge of OMNITROPE must be inserted into its corresponding OMNITROPE Pen 5 or OMNITROPE Pen 10 delivery system. Instructions for delivering the dosage are provided in the OMNITROPE INSTRUCTIONS FOR USE booklet enclosed with the OMNITROPE drug and the OMNITROPE Pens. OMNITROPE for injection 5.8 mg/vial Instructions for delivering the dosage are provided in the INSTRUCTIONS FOR USE leaflets enclosed with the OMNITROPE drug. Once the diluent is added to the lyophilized powder, swirl gently; do not shake. Shaking may cause denaturation of the active ingredient. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. OMNITROPE MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. OMNITROPE must be refrigerated at 2° to 8°C (36° to 46°F). Patients and caregivers who will administer OMNITROPE in medically unsupervised situations should receive appropriate training and instruction on the proper use of OMNITROPE from the physician or other suitably qualified health professional. The dosage of OMNITROPE must be adjusted for the individual patient. The dose should be given daily by subcutaneous injections (administered preferably in the evening). OMNITROPE may be given in the thigh, buttocks, or abdomen. Injection sites should always be rotated to avoid lipoatrophy. 3 DOSAGE FORMS AND STRENGTHS Injection: 5 mg/1.5 mL or 10 mg/1.5 mL clear, colorless solution in a single-patient-use prefilled cartridge. For Injection: 5.8 mg white to off-white lyophilized powder in a single-patient-use vial. Reference ID: 5477192 4 CONTRAINDICATIONS OMNITROPE is contraindicated in patients with: • Acute Critical Illness Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure [see Warnings and Precautions (5.1)]. • Prader-Willi Syndrome in Children Somatropin is contraindicated in patients with Prader-Willi Syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions (5.2)]. • Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since GHD may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [see Warnings and Precautions (5.3)]. • Hypersensitivity OMNITROPE is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropins [see Warnings and Precautions (5.6)]. • Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. • Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses. 5 WARNINGS AND PRECAUTIONS 5.1 Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk. Reference ID: 5477192 5.2 Prader-Willi Syndrome in Children There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi Syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi Syndrome should be evaluated for signs of upper airway obstruction (including onset of or increased snoring) and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi Syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)]. 5.3 Neoplasms In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications (4)]. Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor [see Contraindications (4)]. Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi. 5.4 Impaired Glucose Tolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked, and new onset type 2 diabetes mellitus has been reported in patients taking somatropin. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner Syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients [see Drug Interactions (7.5)]. 5.5 Intracranial Hypertension (IH) Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropins. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by fundoscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner Syndrome and Prader-Willi Syndrome may be at increased risk for the development of IH. Reference ID: 5477192 5.6 Hypersensitivity Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)]. 5.7 Fluid Retention Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) are usually transient and dose dependent. 5.8 Hypoadrenalism Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment [see Drug Interactions (7.1)]. 5.9 Hypothyroidism Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner Syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism and should have their thyroid function checked prior to initiation of somatropin therapy. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated. 5.10 Slipped Capital Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner Syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated. 5.11 Progression of Preexisting Scoliosis in Pediatric Patients Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner Syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi Syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy. 5.12 Otitis Media and Cardiovascular Disorders in Turner Syndrome Patients with Turner Syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner Syndrome. In addition, patients with Turner Syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions. 5.13 Lipoatrophy When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration (2.3)]. Reference ID: 5477192 5.14 Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-1 may increase after somatropin therapy. 5.15 Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner Syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin treated patient, especially a child, who develops persistent severe abdominal pain. 5.16 Benzyl Alcohol Benzyl alcohol, a component of OMNITROPE Cartridge 5 mg/1.5 mL and the diluent for OMNITROPE for injection 5.8 mg/vial, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. 6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in labeling: • Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)] • Fatalities in children with Prader-Willi Syndrome [see Warnings and Precautions (5.2)] • Neoplasms [see Warnings and Precautions (5.3)] • Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)] • Intracranial hypertension [see Warnings and Precautions (5.5)] • Severe hypersensitivity [see Warnings and Precautions (5.6)] • Fluid retention [see Warnings and Precautions (5.7)] • Hypoadrenalism [see Warnings and Precautions (5.8)] • Hypothyroidism [see Warnings and Precautions (5.9)] • Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)] • Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)] • Otitis media and cardiovascular disorders in patients with Turner Syndrome [see Warnings and Precautions (5.12)] • Lipoatrophy [see Warnings and Precautions (5.13)] • Pancreatitis [see Warnings and Precautions (5.15)] • Benzyl Alcohol [see Warnings and Precautions (5.16)] 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice. Clinical Trials in Pediatric GHD Patients The following events were observed during clinical studies with OMNITROPE Cartridge conducted in children with GHD: Reference ID: 5477192 Table 1. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE Cartridge (N=86) Adverse Event n (%) Elevated HbA1c 12 (14%) Eosinophilia 10 (12%) Hematoma 8 (9%) N=number of patients receiving treatment n=number of patients who reported the event during study period %=percentage of patients who reported the event during study period The following events were observed during clinical studies with OMNITROPE for injection conducted in children with GHD: Table 2. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE for Injection (N=44) Adverse Event n (%) Hypothyroidism 7 (16%) Eosinophilia 5 (11%) Elevated HbA1c 4 (9%) Hematoma 4 (9%) Headache 3 (7%) Hypertriglyceridemia 2 (5%) Leg Pain 2 (5%) N=number of patients receiving treatment n=number of patients who reported the event during study period %= percentage of patients who reported the event during study period Clinical Trials in PWS In two clinical studies in pediatric patients with Prader-Willi Syndrome carried out with another somatropin product, the following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia. Clinical Trials in Children with SGA In clinical studies of 273 pediatric patients born small for gestational age treated with another somatropin product, the following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Clinical Trials in Children with Idiopathic Short Stature In two open-label clinical studies conducted with another somatropin product in pediatric patients with ISS, the most commonly encountered adverse events were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies during treatment with this other somatropin product, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0.23 and the 0.47 mg/kg/week groups respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD. Reference ID: 5477192 Clinical Trials in Children with Turner Syndrome In two clinical studies with another somatropin product in pediatric patients with Turner Syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain. Clinical Trials in Adults with GHD In clinical trials with another somatropin product in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction. Table 3 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with another somatropin product. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials. Reference ID: 5477192 Table 3. Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of Another Somatropin Product and Placebo, Grouped by Duration of Treatment Adverse Event Double Blind Phase Open Label Phase Another Somatropin Product Placebo 0–6 mo. (n = 572) % Patients Another Somatropin Product 0–6 mo. (n = 573) % Patients 6–12 mo. (n = 504) % Patients 12–18 mo. (n = 63) % Patients 18–24 mo. (n = 60) % Patients Swelling, peripheral 5.1 17.51 5.6 0 1.7 Arthralgia 4.2 17.31 6.9 6.3 3.3 Upper respiratory infection 14.5 15.5 13.1 15.9 13.3 Pain, extremities 5.9 14.71 6.7 1.6 3.3 Edema, peripheral 2.6 10.81 3.0 0 0 Paresthesia 1.9 9.61 2.2 3.2 0 Headache 7.7 9.9 6.2 0 0 Stiffness of extremities 1.6 7.91 2.4 1.6 0 Fatigue 3.8 5.8 4.6 6.3 1.7 Myalgia 1.6 4.91 2.0 4.8 6.7 Back pain 4.4 2.8 3.4 4.8 5.0 n=number of patients receiving treatment during the indicated period %=percentage of patients who reported the event during the indicated period 1. Increased significantly when compared to placebo, P ≤ .025: Fisher’s Exact Test (one-sided) Post-Trial Extension Studies in Adults In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with another somatropin product. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving this other somatropin product. Of the 3,031 patients receiving this other somatropin product, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia. 6.2 Postmarketing Experience Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The adverse events reported during postmarketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins [see Warnings and Precautions (5.6)]. Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see Contraindications (4) and Warnings and Precautions (5.3)]. The following additional adverse reactions have been observed during the use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults) [see Warnings and Precautions (5.16)]. Reference ID: 5477192 New-onset type 2 diabetes mellitus has been reported. 7 DRUG INTERACTIONS 7.1 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1) The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1 [see Warnings and Precautions (5.8)]. 7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. 7.3 Cytochrome P450-Metabolized Drugs Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted. 7.4 Oral Estrogen In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see Dosage and Administration (2.2)]. 7.5 Insulin and/or Oral Hypoglycemic Agents In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary OMNITROPE contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.16)]. Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal studies (rats and rabbits), there was no evidence of embryo-fetal or neonatal Reference ID: 5477192 harm following somatropin administration during organogenesis at doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies with somatropin during the period of organogenesis at doses of 0.3, 1, and 3.3 mg/kg/day administered subcutaneously in pregnant rats and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in pregnant rabbits were not teratogenic (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area). In perinatal and postnatal studies in rats, doses of 0.3, 1, and 3.3 mg/kg/day somatropin produced growth-promoting effects in the dams but not in the fetuses. Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offspring due to somatropin. 8.2 Lactation Risk Summary There is no information regarding the presence of somatropin in human milk. Limited published data indicate that exogenous somatropin does not increase normal breastmilk concentrations of growth hormone. No adverse effects related to somatropin in the breastfed infant have been reported. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OMNITROPE and any potential adverse effects on the breastfed infant from OMNITROPE or from the underlying maternal condition. 8.5 Geriatric Use The safety and effectiveness of OMNITROPE in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration (2.2)]. 10 OVERDOSAGE Short-Term Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention. Long-Term Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [see Dosage and Administration (2)]. Reference ID: 5477192 11 DESCRIPTION Somatropin is a human growth hormone (GH) produced by recombinant DNA technology using Escherichia coli. The protein is comprised of 191 amino acid residues and a molecular weight of approximately 22,125 daltons. The amino acid sequence is identical to that of human GH of pituitary origin. OMNITROPE (somatropin) injection is a clear, colorless, sterile solution for subcutaneous injection supplied in a cartridge for use with OMNITROPE Pen delivery system. Sodium hydroxide and/or phosphoric acid may be added during manufacture to adjust pH. OMNITROPE (somatropin) for injection is a white to off-white lyophilized powder supplied in a vial for subcutaneous injection after reconstitution. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust pH. Vials are co-packaged with accompanying 1.14 mL vials of a diluent containing Bacteriostatic Water for Injection with 1.5% benzyl alcohol as a preservative. After reconstitution, the concentration is 5 mg/mL. Each OMNITROPE cartridge or vial contains the following (see Table 4): Table 4. Contents of OMNITROPE Cartridges and Vial Product Cartridge 5 mg/ 1.5 mL Cartridge 10 mg/ 1.5 mL For Injection 5.8 mg/ vial Component Somatropin 5 mg 10 mg 5.8 mg Dibasic sodium phosphate 0.609 mg 0.71 mg 0.996 mg Monobasic sodium phosphate 1.28 mg 1.2 mg 0.52 mg Poloxamer 3 mg 3 mg - Mannitol 52.5 mg - - Glycine - 27.75 mg 27.6 mg Benzyl alcohol 13.5 mg - - Phenol - 4.5 mg - Water for Injection to make 1.5 mL to make 1.5 mL - Diluent (vials only) Bacteriostatic Water for Injection Water for injection to make 1.14 mL Benzyl alcohol 17 mg 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Somatropin (as well as endogenous GH) binds to a dimeric GH receptor in the cell membrane of target cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by IGF-1 produced in the liver and also locally (e.g., skeletal growth, protein synthesis), while others are primarily a consequence of the direct effects of somatropin (e.g., lipolysis) [see Pharmacodynamics (12.2)]. Reference ID: 5477192 12.2 Pharmacodynamics Tissue Growth The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in children with GHD and children who have PWS, were born SGA, have TS or have ISS. Skeletal Growth The measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGFs). The somatomedins, among them IGF-1, are polypeptide hormones which are synthesized in the liver, kidney, and various other tissues. IGF-1 levels are low in the serum of hypopituitary dwarfs and hypophysectomized humans or animals and increase after treatment with somatropin. Cell Growth It has been shown that the total number of skeletal muscle cells is markedly decreased in children with short stature lacking endogenous GH compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells. Organ Growth Somatropin influences the size of internal organs, and it also increases red cell mass. Protein Metabolism Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy. Carbohydrate Metabolism Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase. Administration of human growth hormone to normal adults and patients with growth hormone deficiency results in increases in mean serum fasting and postprandial insulin levels, although mean values remain in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remain in the normal range. Lipid Metabolism Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat stores, including increased abdominal visceral and subcutaneous adipose tissue. Treatment of growth hormone deficient patients with somatropin results in a general reduction of fat stores, and decreased serum levels of low density lipoprotein (LDL) cholesterol. Mineral Metabolism Administration of somatropin results in an increase in total body potassium and phosphorus and to a lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of phosphate increase in children with GHD after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment. Reference ID: 5477192 Connective Tissue Metabolism Somatropin stimulates the synthesis of chondroitin sulfate and collagen and increases the urinary excretion of hydroxyproline. 12.3 Pharmacokinetics There are no pharmacokinetic studies using OMNITROPE Cartridges in patients with growth hormone deficiency. Absorption Following a subcutaneous injection of single dose of 5 mg OMNITROPE 5 mg/1.5 mL Cartridge or 5 mg OMNITROPE 10 mg/1.5 mL Cartridge in healthy male and female adults, the peak concentration (Cmax) was 72-74 mcg/L. The time to reach Cmax (tmax) for OMNITROPE was 4.0 hours. The aqueous formulations of 5 mg/1.5 mL OMNITROPE cartridge and 10 mg/mL OMNITROPE cartridge are bioequivalent to the lyophilized 5.8 mg/vial OMNITROPE formulation. Metabolism Somatropin is metabolized in both the liver and kidneys by proteolytic degradation. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. Excretion The mean terminal half-life of somatropin after subcutaneous administration of OMNITROPE Cartridge in healthy adults is 2.5-2.8 hours. The mean clearance of subcutaneously administered OMNITROPE Cartridge in healthy adults was about 0.14 L/hr∙kg. Specific Populations Pediatric: No pharmacokinetic studies of OMNITROPE have been conducted in pediatric patients. Gender: The effect of gender on pharmacokinetics of OMNITROPE has not been evaluated in pediatric patients. Race: No studies have been conducted with OMNITROPE to assess pharmacokinetic differences among races. Renal or hepatic impairment: No pharmacokinetic studies have been conducted with OMNITROPE in patients with renal or hepatic impairment. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of OMNITROPE or other somatropins. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted with OMNITROPE. Reference ID: 5477192 In rats receiving subcutaneous somatropin doses during gametogenesis and up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day (approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted. 14 CLINICAL STUDIES 14.1 Pediatric Growth Hormone Deficiency (GHD) The efficacy and safety of OMNITROPE were compared with another somatropin product approved for growth hormone deficiency (GHD) in pediatric patients. In sequential clinical trials involving a total of 89 GHD children, 44 patients received OMNITROPE for Injection (lyophilized powder) 5.8 mg/vial and 45 patients received the comparator somatropin product for 9 months. After 9 months of treatment patients who had received the comparator somatropin product were switched to OMNITROPE Cartridge (liquid) 5 mg/1.5 mL. After 15 months of treatment, all patients were switched to OMNITROPE Cartridge to collect long-term efficacy and safety data. In both groups, somatropin was administered as a daily subcutaneous injection at a dose of 0.03 mg/kg. Similar effects on growth were observed between OMNITROPE for Injection and the comparator somatropin product during the initial 9 months of treatment. The efficacy results after 9 months of treatment (OMNITROPE for Injection vs. the comparator somatropin product) and after 15 months (OMNITROPE Cartridge) are summarized in Table 5. Table 5. Baseline Growth Characteristics and Effect of OMNITROPE after 9 and 15 Months of Treatment Treatment Duration Treatment Group Treatment Group 0 - 9 months OMNITROPE for Injection (n=44) Another Somatropin Product (n=45) 9 - 15 months OMNITROPE for Injection (n=42) OMNITROPE Cartridge (n=44) Treatment Parameter Mean (SD) Mean (SD) Height velocity (cm/yr) Pre-treatment 3.8 (1.2) 4.0 (0.8) Month 9 10.7 (2.6) 10.7 (2.9) Month 15 8.5 (1.8) 8.6 (2.0) Height velocity SDS Pre-treatment -2.4 (1.3) -2.3 (1.1) Month 9 6.1 (3.7) 5.4 (3.2) Month 15 3.4 (2.6) 3.2 (2.9) Height SDS Pre-treatment -3.0 (0.7) -3.1 (0.9) Month 9 -2.3 (0.7) -2.5 (0.7) Month 15 -2.0 (0.7) -2.2 (0.7) IGF-11 Pre-treatment 159 (92) 158 (43) Month 9 291 (174) 302 (183) Month 15 300 (225) 323 (189) IGFBP-31 Pre-treatment 3.5 (1.3) 3.5 (1.0) Month 9 4.6 (3.0) 4.0 (1.5) Reference ID: 5477192 Month 15 4.6 (1.3) 4.9 (1.4) 1. Calculated only for patients with measurements above the level of detection 14.2 Adult Growth Hormone Deficiency (GHD) Another somatropin lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6-month double-blind treatment period, during which 85 patients received this other somatropin and 87 patients received placebo, followed by an open-label treatment period in which participating patients received this other somatropin for up to a total of 24 months. This other somatropin product was administered as a daily SC injection at a dose of 0.04 mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months. Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving this other somatropin product as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment. 14.3 Prader-Willi Syndrome (PWS) The safety and efficacy of another somatropin product in the treatment of pediatric patients with Prader-Willi Syndrome (PWS) were evaluated in two randomized, open-label, controlled clinical trials. Patients received either this other somatropin product or no treatment for the first year of the studies, while all patients received this other somatropin product during the second year. This other somatropin product was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group received this other somatropin product at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received this other somatropin product at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.36 mg/kg/week. Patients who received this other somatropin product showed significant increases in linear growth during the first year of study, compared with patients who received no treatment (see Table 6). Linear growth continued to increase in the second year, when both groups received treatment with this other somatropin product. Table 6. Efficacy of Another Somatropin Product in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD) Linear growth (cm) Baseline height Study 1 Study 2 Another Somatropin Product (0.24 mg/kg/week) (n=15) Untreated Control (n=12) Another Somatropin Product (0.36 mg/kg/week) (n=7) Untreated Control (n=9) 112.7 ± 14.9 109.5 ± 12.0 120.3 ± 17.5 120.5 ± 11.2 Growth from months 0 to 12 11.61 ± 2.3 5.0 ± 1.2 10.71 ± 2.3 4.3 ± 1.5 Baseline SDS -1.6 ± 1.3 -1.8 ± 1.5 -2.6 ± 1.7 -2.1 ± 1.4 SDS at 12 months -0.52 ± 1.3 -1.9 ± 1.4 -1.42 ± 1.5 -2.2 ± 1.4 1. p ≤ 0.001 2. p ≤ 0.002 (when comparing SDS change at 12 months) Reference ID: 5477192 Changes in body composition were also observed in the patients receiving this other somatropin product (see Table 7). These changes included a decrease in the amount of fat mass, and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no treatment. Treatment with this other somatropin product did not accelerate bone age, compared with patients who received no treatment. Reference ID: 5477192 Table 7. Effect of Another Somatropin Product on Body Composition in Pediatric Patients with Prader- Willi Syndrome (Mean ± SD) Another Somatropin Product (n=14) Untreated Control (n=10) Fat mass (kg) Baseline 12.3 ± 6.8 9.4 ± 4.9 Change from months 0 to 12 -0.91 ± 2.2 2.3 ± 2.4 Lean body mass (kg) Baseline 15.6 ± 5.7 14.3 ± 4.0 Change from months 0 to 12 4.71 ± 1.9 0.7 ± 2.4 Lean body mass/Fat mass Baseline 1.4 ± 0.4 1.8 ± 0.8 Change from months 0 to 12 1.01 ± 1.4 -0.1 ± 0.6 Body weight (kg)2 Baseline 27.2 ± 12.0 23.2 ± 7.0 Change from months 0 to 12 3.73 ± 2.0 3.5 ± 1.9 1. p < 0.005 2. n=15 for the group receiving another somatropin product; n=12 for the Control group 3. n.s. 14.4 Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2 The safety and efficacy of another somatropin product in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either this other somatropin product (two doses per study, most often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received this other somatropin product. Patients who received any dose of this other somatropin product showed significant increases in growth during the first 24 months of study, compared with patients who received no treatment (see Table 8). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown). Table 8. Efficacy of Another Somatropin Product in Children Born Small for Gestational Age (Mean ± SD) Another Somatropin Product (0.24 mg/kg/week) (n=76) Another Somatropin Product (0.48 mg/kg/week) (n=93) Untreated Control (n=40) Height Standard Deviation Score (SDS) Baseline SDS -3.2 ± 0.8 -3.4 ± 1.0 -3.1 ± 0.9 SDS at 24 months -2.0 ± 0.8 -1.7 ± 1.0 -2.9 ± 0.9 Change in SDS from baseline to month 24 1.21 ± 0.5 1.71,2 ± 0.6 0.1 ± 0.3 1. p = 0.0001 vs Untreated Control group 2. p = 0.0001 vs group treated with another somatropin product 0.24 mg/kg/week Reference ID: 5477192 14.5 Idiopathic Short Stature (ISS) The long-term efficacy and safety of another somatropin product in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to this other somatropin product or observation only and followed to final height. Two somatropin doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD): chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 9. Therapy with this other somatropin product improved final height in ISS children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to untreated control subjects. A height gain of 1 SDS was observed in 10% of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects receiving 0.47 mg/kg/week. Table 9. Final height SDS results for pre-pubertal patients with ISS1 Untreated (n=30) Another Somatropin Product 0.033 mg/kg/day (n=30) Another Somatropin Product 0.067 mg/kg/day (n=42) Another Somatropin Product 0.033 vs. Untreated (95% CI) Another Somatropin Product 0.067 vs. Untreated (95% CI) Baseline height 0.41 0.95 (0.75) 1.36 (0.64) +0.53 (0.20, +0.94 (0.63, SDS (0.58) 0.87) 1.26) Final height SDS minus Baseline p=0.0022 p<0.0001 Baseline 0.23 (0.66) 0.73 (0.63) 1.05 (0.83) +0.60 (0.09, +0.90 (0.42, predicted ht 1.11) 1.39) Final height SDS minus baseline predicted final height SDS p=0.0217 p=0.0004 Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS) 1. Mean (SD) are observed values. 14.6 Turner Syndrome Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of another somatropin product in Turner Syndrome patients with short stature. Turner Syndrome patients were treated with this other somatropin product alone or this other somatropin product plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38 patients were treated with this other somatropin product alone in the two studies. In Study 1, 22 patients were treated for 12 months, and in Study 2, 16 patients were treated for 12 months. Patients received this other somatropin product at a dose between 0.13 to 0.33 mg/kg/week. SDS for height velocity and height are expressed using either the Tanner (Study 1) or Sempé (Study 2) standards for age- matched normal children as well as the Ranke standard (both studies) for age-matched, untreated Turner Syndrome patients. As seen in Table 10, height velocity SDS and height SDS values were smaller at baseline and after treatment with this other somatropin product when the normative standards were utilized as opposed to the Turner Syndrome standard. Reference ID: 5477192 Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and height SDS) after treatment with this other somatropin product (see Table 10). The linear growth response was greater in Study 1 wherein patients were treated with a larger dose of this other somatropin product. Table 10. Growth Parameters (mean ± SD) after 12 Months of Treatment with Another Somatropin Product in Pediatric Patients with Turner Syndrome in Two Open Label Studies Another somatropin product 0.33 mg/kg/week Study 1 n=22 Another somatropin product 0.13-0.23 mg/kg/week Study 2† n=16 Height Velocity (cm/yr) Baseline 4.1 ± 1.5 3.9 ± 1.0 Month 12 7.8 ± 1.6 6.1 ± 0.9 Change from baseline (95% CI) 3.7 (3.0, 4.3) 2.2 (1.5, 2.9) Height Velocity SDS (Tanner/Sempé† Standards) (n=20) Baseline Month 12 Change from baseline (95% CI) -2.3 ± 1.4 2.2 ± 2.3 4.6 (3.5, 5.6) -1.6 ± 0.6 0.7 ± 1.3 2.2 (1.4, 3.0) Height Velocity SDS (Ranke Standard) Baseline Month 12 Change from baseline (95% CI) -0.1 ± 1.2 4.2 ± 1.2 4.3 (3.5, 5.0) -0.4 ± 0.6 2.3 ± 1.2 2.7 (1.8, 3.5) Height SDS (Tanner/Sempé† Standards) Baseline Month 12 Change from baseline (95% CI) -3.1 ± 1.0 -2.7 ± 1.1 0.4 (0.3, 0.6) -3.2 ± 1.0 -2.9 ± 1.0 0.3 (0.1, 0.4) Height SDS (Ranke Standard) Baseline Month 12 Change from baseline (95% CI) -0.2 ± 0.8 0.6 ± 0.9 0.8 (0.7, 0.9) -0.3 ± 0.8 0.1 ± 0.8 0.5 (0.4, 0.5) SDS = Standard Deviation Score Ranke standard based on age-matched, untreated Turner Syndrome patients Tanner*/Sempé† standards based on age-matched normal children p<0.05, for all changes from baseline 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied OMNITROPE (somatropin) injection is a clear, colorless, sterile solution for subcutaneous injection supplied in a cartridge for use with OMNITROPE Pen delivery system. OMNITROPE (somatropin) for injection is a white to off-white lyophilized powder supplied in a vial for subcutaneous injection after reconstitution with co-packaged diluent. Carton Contents Strength NDC 1 single-patient-use cartridge 5 mg/1.5 mLa NDC 0781-3001-07 Reference ID: 5477192 5 single-patient-use cartridges 5 mg/1.5 mLa NDC 0781-3001-26 1 single-patient-use cartridge 10 mg/1.5 mLb NDC 0781-3004-07 5 single-patient-use cartridges 10 mg/1.5 mLb NDC 0781-3004-26 8 single-patient-use vials 8 single-dose vials of diluent (Bacteriostatic Water for Injection containing 1.5% benzyl alcohol as a preservative) 5.8 mg per vial NDC 0781-4004-36 a For use only with the OMNITROPE Pen 5 delivery system, which is sold separately. b For use only with the OMNITROPE Pen 10 delivery system, which is sold separately. 16.2 Storage and Handling Before use, store OMNITROPE vials and cartridges refrigerated at 2° to 8°C (36° to 46°F) in the original carton to protect from light. Do not freeze. After first use, the OMNITROPE cartridge should remain in the pen and kept the original carton in a refrigerator at 2° to 8°C (36° to 46°F) for a maximum of 28 days (see Table 11). Discard unused portions in the cartridge after 28 days. After reconstitution of the lyophilized powder, the contents of the OMNITROPE vial must be used within 21 days. After the first injection, store the vial in the original carton in a refrigerator at 2° to 8°C (36° to 46°F) (see Table 11). Discard unused portions after 21 days. Table 11. Storage Options OMNITROPE Storage Requirement Product Formulation Before Use In-use (after 1st injection) 5 mg/1.5 mL cartridge Refrigerate at 2° to 8°C (36° to 46°F) Until exp date Refrigerate at 2° to 8°C (36° to 46°F) up to 28 days 10 mg/1.5 mL cartridge Refrigerate at 2° to 8°C (36° to 46°F) up to 28 days 5.8 mg per vial Refrigerate at 2° to 8°C (36° to 46°F) Until exp date Refrigerate at 2° to 8°C (36° to 46°F) up to 21 days 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Instructions For Use: OMNITROPE Pen 5 Instructions For Use, OMNITROPE Pen 10 Instructions For Use, Instructions For OMNITROPE 5.8 mg/Vial). Patients being treated with OMNITROPE (and/or their parents) should be informed about the potential risks and benefits associated with somatropin treatment. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects. Patients and caregivers who will administer OMNITROPE should receive appropriate training and instruction on the proper use of OMNITROPE from the physician or other suitably qualified health care professional. A puncture-resistant container for the disposal of used syringes and needles should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles and syringes. Reference ID: 5477192 Counsel patients and parents that they should never share an OMNITROPE Pen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection. If patients are prescribed OMNITROPE Cartridge 5 mg/1.5 mL or 10 mg/1.5 mL (to be inserted into OMNITROPE Pen 5 or Pen 10 delivery systems), physicians should instruct patients to read the corresponding Instructions For Use provided with the OMNITROPE Pens delivery systems and the OMNITROPE Cartridges. If patients are prescribed OMNITROPE for injection, physicians should instruct patients to read the Instructions For Use leaflets provided with the OMNITROPE for injection 5.8 mg/vial. Manufactured by: Sandoz Inc., Princeton, NJ 08540 US License No. 2003 Product of Austria Reference ID: 5477192 O..,,.,..Pen Inner Pe.n Needle Needf• Cop Sl,;eld Shield - Omn11ropeG-Pcn 5 ~ c=::::::J 4 SANDOJ: Pet1 Needle Cottnde-Holde, Coltriclge -=I] ( c:::===::) II [ :J A------'-+-'' I I AkoholSwob ALCOHOL SWAB c-;;,. - .............. ... Pen Body INSTRUCTIONS FOR USE OMNITROPE® PEN 5 OMNITROPE (om-KNEE-trope) (somatropin) injection, for subcutaneous use 5 mg/1.5 mL Single-Patient-Use cartridges for use with Omnitrope Pen 5 Read this Instructions for Use before you start using Omnitrope Pen 5 and each time you get a refill. There may be new information. This information does not take the place of talking to the healthcare provider about the medical condition or the treatment. Note: • Omnitrope is for use under the skin only (subcutaneous). • Do not share your Omnitrope Pen or needles with anyone else. You may give an infection to them or get an infection from them. • The “Start use by no later than” date, printed in year, month, and day on the outer carton, shows the date after which treatment should not be started with this pen. Omnitrope Pen 5, Single-Patient-Use cartridge containing Omnitrope, needle, alcohol swab and storage case: Figure A Supplies you will need to give an Omnitrope Injection. See Figure A. • Omnitrope Pen 5 • 5 mg/1.5 mL cartridge containing Omnitrope • 1 new BD™ Pen needle (29G x 12.7 mm or 31G x 8 mm or 31G x 5 mm). Needles are not included with the Pen. • 1 alcohol swab • flat surface like a table • a sharps disposal container. See Step 6 for information on how to throw away (dispose of) used needles and cartridges. Steps you should follow to give an Omnitrope injection: Reference ID: 5477192 / Pen Cop Cartridge Holder Step 1. Placing the cartridge in the Omnitrope Pen 5 Step 2. Attaching the needle to the Omnitrope Pen 5 Step 3. Priming a new cartridge Step 4. Selecting the correct dose of Omnitrope Step 5. Selecting the injection site and injecting the dose of Omnitrope Step 6. Removing and throwing away the needle and empty cartridge Step 1. Placing the cartridge in the Omnitrope Pen 5 • Take an Omnitrope cartridge out of the refrigerator and leave at room temperature for about 30 minutes. Wash and dry your hands while you wait. • Assemble all of the supplies needed on a flat surface. Remove the Pen and cartridge from their cartons if you are preparing the injection for the first time. • Hold the body of the Pen with 1 hand and pull off the Pen cap with the other hand. See Figure B. Figure B • Hold the body of the Pen with 1 hand and unscrew the cartridge holder in a clockwise direction until the Pen and cartridge holder are completely separated. See Figure C. Figure C Reference ID: 5477192 Cartridge Cartridge Holder • Hold the cartridge in 1 hand with the metal cap end pointing down. Insert the cartridge into the cartridge holder. See Figure D. Figure D • Lower the Pen body onto the cartridge holder so that the black rod presses against the cartridge plunger. Screw the cartridge holder onto the Pen body in a counterclockwise direction until the cartridge holder will not turn anymore. One of the blue arrows on the cartridge holder must line up with the yellow line mark on the Pen body. Do not over tighten the cartridge holder. See Figure E. Figure E Reference ID: 5477192 New Disposable Pen Needle New Disposable Pen Needle (1 Step 2. Attaching the needle to the Omnitrope Pen 5 • Take a new disposable needle and tear off the paper tab. Do not touch the needle or lay it on a surface. See Figure F. Figure F • Holding the cartridge holder with 1 hand, firmly press the needle onto the cartridge holder end of the Pen. See Figure G. Screw the threaded part of the needle onto the cartridge holder in a counterclockwise direction until the needle will not turn anymore. See Figure H. Figure G Figure H Reference ID: 5477192 Outer Needle Shield • Gently pull off the outer needle shield and put it on a flat surface. You will use the outer needle shield later to remove the needle from the Pen after the injection is finished. See Figure I. Figure I Note: Check that the cartridge holder is attached to the Pen body before each injection. One of the blue arrows on the cartridge should be lined up with the yellow mark on the Pen body. After you attach the needle, you may see a few drops of medicine at the tip of the needle. Step 3. Priming a new cartridge • Priming is not needed for a cartridge you have used before. If the cartridge has already been primed, go to Step 4. • Before you use a new cartridge you must first prepare it for use. Hold the Pen with the needle pointing upwards. Gently tap the cartridge holder with your finger to help air bubbles rise to the top of the cartridge. See Figure J. Figure J Reference ID: 5477192 ,· • Hold the pen with the needle pointing up and the dose window facing you and you will see the numbers in the dose window at the bottom of the Pen body. Using the dose knob on the bottom of the Pen, slowly turn the dose knob in a clockwise direction as shown in Figure K until you hear 1 “click”. The arrow on the Pen body will then be lined up with the small line between “0” and “0.1” (0.05 mg). See Figure K. Figure K • Remove the inner needle shield. See Figure L. • With the needle pointing up, firmly turn the dose knob in a counterclockwise direction and back to the “0” position. Figure L At least 2 drops of medicine must flow out of the needle for the Pen to be properly primed. See Figure M. Figure M Reference ID: 5477192 • If at least 2 drops of medicine do not flow out, set the dose to 0.05 mg and repeat this step until at least 2 drops of medicine appear at the tip of the needle. • When you see 2 drops of medicine flow out of the needle, the Pen is correctly primed and ready to use. Step 4. Selecting the correct dose of Omnitrope • Hold the pen with the needle pointing up and the dose window facing you and turn (dial) the dose knob in a clockwise direction until you see the number of mg for the prescribed dose in the middle of the dose window. The dose should be lined up with the arrow on the Pen body. You will hear 1 click for every single unit you dial. See Figure N. Do not count the clicks to measure the correct dose of medicine. Figure N • If you turn the dose knob past the correct dose, do not dial counterclockwise. Instead, hold the Pen body with the needle pointing up and turn the dose knob in a clockwise direction until you see a bent arrow ( ) in the dose dialing window. See Figure O. Now continue to turn the dose knob in a clockwise direction until you hear a click and the entire Pen body is fully extended. The injection button can now be fully pressed, resetting the dial to “0” without giving medicine. The correct dose can now be redialed. Figure O • Check that the cartridge holder is still attached to the Pen body, with the blue arrow lined up with the yellow mark on the Pen body. Reference ID: 5477192 Step 5. Selecting the injection site and injecting the dose of Omnitrope The best sites for injection are tissues with a layer of fat between skin and muscle such as the upper leg (thigh), buttocks, or stomach area (abdomen) as in the picture shown below. Do not inject near your belly button (navel) or waistline. Change the injection site every day. See Figure P. Figure P • Select the injection site and wipe the skin with an alcohol swab as your healthcare provider showed you. • With 1 hand, pinch a fold of loose skin at the injection site. • With your other hand, insert the needle under the skin (at an angle of 45° to 90°) as your healthcare provider showed you. See Figure Q. Figure Q • After inserting the needle into the skin, push the injection button as far in as it will go and press the button firmly. A clicking sound will be heard while the dose is being injected. Continue to press firmly on the injection button for 5 seconds before you remove the needle from the skin. See Figure R. Reference ID: 5477192 Dose Window Injection Button Figure R • Stop pressing the injection button before you carefully remove the needle from the skin. • If the injection button cannot be pushed in completely or stops during the injection, and the cartridge is empty, then the full dose has not been given. The dose indicator window will show the amount of medicine still needed. Reset the dose knob to “0” as described in Step 4. Remove the needle as described in Step 6. Replace the empty cartridge with a new cartridge as described in Step 1. Prime the new cartridge as described in Step 3. Set the dose, which you noted, and inject. This completes your dose. Step 6. Removing and throwing away the needle and empty cartridge • Carefully replace the outer needle shield. See Figure S. Figure S • Hold the Pen by the cartridge holder and carefully remove the needle from the Pen by turning the needle in a clockwise direction. See Figure T. Recap the pen. Reference ID: 5477192 Figure T • Put your used needles and cartridges in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and cartridges in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and cartridges. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. How should I store Omnitrope Pen 5? • Store Omnitrope cartridges in the refrigerator between 36°F and 46°F (2°C and 8°C). • When the Omnitrope Pen 5 contains a cartridge, do not remove the cartridge from the Pen in between injections. Store the Pen containing the cartridge in the storage case provided and place in the refrigerator. • When the Pen does not contain a cartridge, you may store the Pen at room temperature. • Do not freeze Omnitrope cartridges. • Protect the Omnitrope Pen 5 and cartridge from light by storing in their cartons or the storage case. • The Omnitrope cartridge must be thrown away 28 days after the first injection. The Omnitrope Pen 5 can be reloaded with a new cartridge and can be used multiple times. Important information about possible problems you may have with the Omnitrope Pen 5 Problem Possible cause How to fix Dial unit does not turn easily. Dust or dirt Turn the dial beyond the highest setting on the scale. Wipe all exposed surfaces with a clean, damp cloth. The injection button cannot be pushed or stops during injection. The dose knob does not return to “0”. Cartridge is empty and full dose has not been given. Remove the needle as described in Step 6. Replace the empty cartridge with a new cartridge as described in Step 1. Prime the new cartridge as described in Step 3. Clogged needle. Remove the needle as described in Step 6. Replace with a new needle as described in Step 2. No clicking is heard during the injection and dose knob moves freely. Pen is in dose correction mode. Remove the needle from skin. Press injection button all the way in so the dial returns to zero and repeat Step 2, Step 4 and Step 5 to give the injection. Medicine continues to drip from the needle before injection. Cartridge holder is not properly attached to the Pen body. Line up blue arrow on cartridge holder with yellow mark on Pen body. Reference ID: 5477192 Problem Possible cause How to fix Medicine continues to drip from the needle after injection. Needle was removed from the skin too early. Hold the needle in the skin for 5 seconds to complete the injection, before you carefully remove the needle from the skin. For the next injection, make sure that you hold the needle in the skin for 5 seconds. Cartridge holder is not properly attached to the Pen body. Line up blue arrow on cartridge holder with yellow mark on Pen body. The needle is left on the Pen after injection. Carefully remove the needle from the Pen right after the injection. If the Omnitrope Pen 5 is damaged or does not work, call the pharmacy where you got the Omnitrope Pen 5. If you got your Omnitrope Pen 5 from OmniSource, call 1-877-456-6794. For other questions or additional information, call OmniSource at 1-877-456-6794. Do not try to repair the Pen yourself. Your Omnitrope Pen 5 is covered by a 2 year guarantee. Contact your Omnitrope Pen 5 provider after you have used the pen for 2 years to have it replaced by a new one. This guarantee is invalid if your Omnitrope Pen 5 has not been used in accordance with the manufacturer’s instruction leaflet or if the defect has been caused by neglect, misuse or accident. BD and BD Logo are trademarks of Becton, Dickinson and Company © 2019 BD. All rights reserved. Manufactured for Sandoz GmbH, Kundl, Austria Product of Taiwan Manufactured by: Sandoz Inc., Princeton, NJ 08540 US License No. 2003 This Instructions for Use has been approved by the U.S. Food and Drug Administration. November 2024 NNNNNNNN Reference ID: 5477192 Ovt...Pen Inner Pe.n Needle Needf• Cop S!.eld Shield -- --1 OmMrope G, Pcol O - I ~ c=::::::J Pen lni-<,tot Sto,og41 Cose & SANDO% Pet1 Needle Cottf'idge Holde, Coltric19e -=I] ( c:::=::::::::: II [ :J A-----'-+-'' I I AkoholSwob ALCOHOL SWAB c.,;a,. - .............. ... Pen Body INSTRUCTIONS FOR USE OMNITROPE® PEN 10 OMNITROPE (om-KNEE-trope) (somatropin) injection, for subcutaneous use 10 mg/1.5 mL Single-Patient-Use cartridges for use with Omnitrope Pen 10 Read this Instructions for Use before you start using Omnitrope Pen 10 and each time you get a refill. There may be new information. This information does not take the place of talking to the healthcare provider about the medical condition or the treatment. Note: • Omnitrope is for use under the skin only (subcutaneous). • Do not share your Omnitrope Pen or needles with anyone else. You may give an infection to them or get an infection from them. • The “Start use by no later than” date, printed in year, month, and day on the outer carton, shows the date after which treatment should not be started with this pen. Omnitrope Pen 10, Single-Patient-Use cartridge containing Omnitrope, needle, alcohol swab and storage case: Figure A Supplies you will need to give an Omnitrope Injection. See Figure A. • Omnitrope Pen 10 • 10 mg/1.5 mL cartridge containing Omnitrope • 1 new BD™ Pen needle (29G x 12.7 mm or 31G x 8 mm or 31G x 5 mm). Needles are not included with the Pen. • 1 alcohol swab • flat surface like a table • a sharps disposal container. See Step 6 for information on how to throw away (dispose of) used needles and cartridges. Steps you should follow to give an Omnitrope injection: Reference ID: 5477192 / Pen Cop Cartridge Holder Step 1. Placing the cartridge in the Omnitrope Pen 10 Step 2. Attaching the needle to the Omnitrope Pen 10 Step 3. Priming a new cartridge Step 4. Selecting the correct dose of Omnitrope Step 5. Selecting the injection site and injecting the dose of Omnitrope Step 6. Removing and throwing away the needle and empty cartridge Step 1. Placing the cartridge in the Omnitrope Pen 10 • Take an Omnitrope cartridge out of the refrigerator and leave at room temperature for about 30 minutes. Wash and dry your hands while you wait. • Assemble all of the supplies needed on a flat surface. Remove the Pen and cartridge from their cartons if you are preparing the injection for the first time. • Hold the body of the Pen with 1 hand and pull off the Pen cap with the other hand. See Figure B. Figure B • Hold the body of the Pen with 1 hand and unscrew the cartridge holder in a clockwise direction until the Pen and cartridge holder are completely separated. See Figure C. Figure C Reference ID: 5477192 Cartridge White Line Mark-r-~ • Hold the cartridge in 1 hand with the metal cap end pointing down. Insert the cartridge into the cartridge holder. See Figure D. Figure D • Lower the Pen body onto the cartridge holder so that the black rod presses against the cartridge plunger. Screw the cartridge holder onto the Pen body in a counterclockwise direction until the cartridge holder will not turn anymore. One of the blue arrows on the cartridge holder must line up with the white line mark on the Pen body. Do not over tighten the cartridge holder. See Figure E. Figure E Reference ID: 5477192 New Disposable Pen Needle New Disposable Pen Needle (1 Step 2. Attaching the needle to the Omnitrope Pen 10 • Take a new disposable needle and tear off the paper tab. Do not touch the needle or lay it on a surface. See Figure F. Figure F • Holding the cartridge holder with 1 hand, firmly press the needle onto the cartridge holder end of the Pen. See Figure G. Screw the threaded part of the needle onto the cartridge holder in a counterclockwise direction until the needle will not turn anymore. See Figure H. Figure G Figure H Reference ID: 5477192 Outer Needle Shield • Gently pull off the outer needle shield and put it on a flat surface. You will use the outer needle shield later to remove the needle from the Pen after the injection is finished. See Figure I. Figure I Note: Check that the cartridge holder is attached to the Pen body before each injection. One of the blue arrows on the cartridge should be lined up with the white mark on the Pen body. After you attach the needle, you may see a few drops of medicine at the tip of the needle. Step 3. Priming a new cartridge • Priming is not needed for a cartridge you have used before. If the cartridge has already been primed, go to Step 4. • Before you use a new cartridge you must first prepare it for use. Hold the Pen with the needle pointing upwards. Gently tap the cartridge holder with your finger to help air bubbles rise to the top of the cartridge. See Figure J. Figure J Reference ID: 5477192 ,· • Hold the pen with the needle pointing up and the dose window facing you and you will see the numbers in the dose window at the bottom of the Pen body. Using the dose knob on the bottom of the Pen, slowly turn the dose knob in a clockwise direction as shown in Figure K until you hear 1 “click”. The arrow on the Pen body will then be lined up with the small line between “0” and “0.2” (0.1 mg). See Figure K. Figure K • Remove the inner needle shield. See Figure L. • With the needle pointing up, firmly turn the dose knob in a counterclockwise direction and back to the “0” position. Figure L At least 2 drops of medicine must flow out of the needle for the Pen to be properly primed. See Figure M. Figure M Reference ID: 5477192 • If at least 2 drops of medicine do not flow out, set the dose to 0.1 mg and repeat this step until at least 2 drops of medicine appear at the tip of the needle. • When you see 2 drops of medicine flow out of the needle, the Pen is correctly primed and ready to use. Step 4. Selecting the correct dose of Omnitrope • Hold the pen with the needle pointing up and the dose window facing you and turn (dial) the dose knob in a clockwise direction until you see the number of mg for the prescribed dose in the middle of the dose window. The dose should be lined up with the arrow on the Pen body. You will hear 1 click for every single unit you dial. See Figure N. Do not count the clicks to measure the correct dose of medicine. Figure N • If you turn the dose knob past the correct dose, do not dial counterclockwise. Instead, hold the Pen body with the needle pointing up and turn the dose knob in a clockwise direction until you see a bent arrow ( ) in the dose dialing window. See Figure O. Now continue to turn the dose knob in a clockwise direction until you hear a click and the entire Pen body is fully extended. The injection button can now be fully pressed, resetting the dial to “0” without giving medicine. The correct dose can now be redialed. Figure O • Check that the cartridge holder is still attached to the Pen body, with the blue arrow lined up with the white mark on the Pen body. Step 5. Selecting the injection site and injecting the dose of Omnitrope Reference ID: 5477192 The best sites for injection are tissues with a layer of fat between skin and muscle such as the upper leg (thigh), buttocks, or stomach area (abdomen) as in the picture shown below. Do not inject near your belly button (navel) or waistline. Change the injection site every day. See Figure P. Figure P • Select the injection site and wipe the skin with an alcohol swab as your healthcare provider showed you. • With 1 hand, pinch a fold of loose skin at the injection site. • With your other hand, insert the needle under the skin (at an angle of 45° to 90°) as your healthcare provider showed you. See Figure Q. Figure Q • After inserting the needle into the skin, push the injection button as far in as it will go and press the button firmly. A clicking sound will be heard while the dose is being injected. Continue to press firmly on the injection button for 5 seconds before you remove the needle from the skin. See Figure R. Reference ID: 5477192 Dose Window Injection Button Figure R • Stop pressing the injection button before you carefully remove the needle from the skin. • If the injection button cannot be pushed in completely or stops during the injection, and the cartridge is empty, then the full dose has not been given. The dose indicator window will show the amount of medicine still needed. Reset the dose knob to “0” as described in Step 4. Remove the needle as described in Step 6. Replace the empty cartridge with a new cartridge as described in Step 1. Prime the new cartridge as described in Step 3. Set the dose, which you noted, and inject. This completes your dose. Step 6. Removing and throwing away the needle and empty cartridge • Carefully replace the outer needle shield. See Figure S. Figure S • Hold the Pen by the cartridge holder and carefully remove the needle from the Pen by turning the needle in a clockwise direction. See Figure T. Recap the pen. Reference ID: 5477192 Figure T • Put your used needles and cartridges in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and cartridges in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and cartridges. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. How should I store Omnitrope Pen 10? • Store Omnitrope cartridges in the refrigerator between 36°F and 46°F (2°C and 8°C). • When the Omnitrope Pen 10 contains a cartridge, do not remove the cartridge from the Pen in between injections. Store the Pen containing the cartridge in the storage case provided and place in the refrigerator. • When the Pen does not contain a cartridge, you may store the Pen at room temperature. • Do not freeze Omnitrope cartridges. • Protect the Omnitrope Pen 10 and cartridge from light by storing in their cartons or the storage case. • The Omnitrope cartridge must be thrown away 28 days after the first injection. The Omnitrope Pen 10 can be reloaded with a new cartridge and can be used multiple times. Important information about possible problems you may have with the Omnitrope Pen 10 Problem Possible cause How to fix Dial unit does not turn easily. Dust or dirt Turn the dial beyond the highest setting on the scale. Wipe all exposed surfaces with a clean, damp cloth. The injection button cannot be pushed or stops during injection. The dose knob does not return to “0”. Cartridge is empty and full dose has not been given. Remove the needle as described in Step 6. Replace the empty cartridge with a new cartridge as described in Step 1. Prime the new cartridge as described in Step 3. Clogged needle. Remove the needle as described in Step 6. Replace with a new needle as described in Step 2. No clicking is heard during the injection and dose knob moves freely. Pen is in dose correction mode. Remove the needle from skin. Press injection button all the way in so the dial returns to zero and repeat Step 2, Step 4 and Step 5 to give the injection. Medicine continues to drip from the needle before injection. Cartridge holder is not properly attached to the Pen body. Line up blue arrow on cartridge holder with white mark on Pen body. Reference ID: 5477192 Problem Possible cause How to fix Medicine continues to drip from the needle after injection. Needle was removed from the skin too early. Hold the needle in the skin for 5 seconds to complete the injection, before you carefully remove the needle from the skin. For the next injection, make sure that you hold the needle in the skin for 5 seconds. Cartridge holder is not properly attached to the Pen body. Line up blue arrow on cartridge holder with white mark on Pen body. The needle is left on the Pen after injection. Carefully remove the needle from the Pen right after the injection. If the Omnitrope Pen 10 is damaged or does not work, call the pharmacy where you got the Omnitrope Pen 10. If you got your Omnitrope Pen 10 from OmniSource, call 1-877-456-6794. For other questions or additional information, call OmniSource at 1-877-456-6794. Do not try to repair the Pen yourself. Your Omnitrope Pen 10 is covered by a 2 year guarantee. Contact your Omnitrope Pen 10 provider after you have used the pen for 2 years to have it replaced by a new one. This guarantee is invalid if your Omnitrope Pen 10 has not been used in accordance with the manufacturer’s instruction leaflet or if the defect has been caused by neglect, misuse or accident. BD and BD Logo are trademarks of Becton, Dickinson and Company © 2019 BD. All rights reserved. Manufactured for Sandoz GmbH, Kundl, Austria Product of Taiwan Manufactured by: Sandoz Inc., Princeton, NJ 08540 US License No. 2003 This Instructions for Use has been approved by the U.S. Food and Drug Administration. November 2024 NNNNNNNN Reference ID: 5477192 1. 2. 3. 4. 5. 6. 2 3 4 vial with lyophilized powder alcohol swabs 5 vial with diluent for OMNITROPE 6 sterile, disposable syringe (e.g. a 3ml syringe) needle for withdrawing the diluent from the vial sterile, disposable syringe of appropriate size (e.g a 1 ml syringe) and needle for subcutaneous injection l. 2. 3. 4. 2 3 needle cap needle 4 barrel with dosing scale plunger INSTRUCTIONS FOR USE OMNITROPE (om-KNEE-trope) (somatropin) for injection, for subcutaneous use OMNITROPE® 5.8 mg/vial The following instructions explain how to inject OMNITROPE 5.8 mg. Do not inject OMNITROPE yourself until your healthcare provider has taught you and you understand the instructions. Ask your healthcare provider or pharmacist if you have any questions about injecting OMNITROPE. • OMNITROPE 5.8 mg is for Single-Patient-Use. • The concentration of OMNITROPE after mixing is 5 mg/mL. • After mixing, OMNITROPE 5.8 mg contains a preservative and should not be used in newborns. Preparation Collect the needed items before you begin: • a vial with OMNITROPE 5.8 mg • a vial with diluent (mixing liquid - Bacteriostatic Water for Injection containing benzyl alcohol as preservative) for OMNITROPE 5.8 mg • a sterile, disposable 3 mL syringe and needle for withdrawing the diluent from the vial (not supplied in the pack) • sterile disposable 1 mL syringes and needles for under the skin (subcutaneous) injection (not supplied in the pack) • 2 alcohol swabs (not supplied in the pack) Reference ID: 5477192 Wash your hands before you start with the next steps. Mixing OMNITROPE 5.8 mg • Remove the protective caps from the two vials. With one alcohol swab, clean both the rubber top of the vial that contains the powder and the rubber top of the vial that contains diluent. • Next use the sterile diluent vial, the disposal 3 mL syringe and a needle. Reference ID: 5477192 • Attach the needle to the syringe (if not attached already). Pull back the syringe plunger and fill the syringe with air. Push the needle fitted to the syringe through the rubber top of the diluent vial, push all the air from the syringe into the vial, turn the vial upside down, and withdraw all the diluent from the vial into the syringe. Remove the syringe and needle. • Next take the syringe with the diluent in it and push the needle through the rubber stopper of the vial that contains the white powder. Inject the diluent slowly. Aim the stream of liquid against the glass wall in order to avoid foam. Remove the syringe and needle and throw them away. Reference ID: 5477192 • Gently swirl the vial until the content is completely dissolved. Do not shake. • If the medicine is cloudy or contains particles, it should not be used. The medicine must be clear and colorless after mixing. • After mixing the medicine, the medicine in the vial must be used within 3 weeks. Store the vial in a refrigerator between 36°F to 46°F (2°C to 8°C) after mixing and using it each time. Measuring the Dose of OMNITROPE 5.8 mg to Be Injected • Next use the sterile, disposable 1 mL (or similar) syringe and needle for subcutaneous injection. Push the needle through the rubber top of the vial that contains the medicine that you have just mixed. • Turn the vial and the syringe upside down. • Be sure the tip of the syringe is in the OMNITROPE mixed medicine. • Pull back on the plunger slowly and withdraw the dose prescribed by your healthcare provider into the syringe. • Hold the syringe with the needle in the vial pointing up and remove the syringe from the vial. • Check for air bubbles in the syringe. If you see any bubbles, pull the plunger slightly back; tap the syringe gently, with the needle pointing upwards, until the bubble disappears. Push the plunger slowly back up to the correct dose. If there is not enough medicine in the syringe after removing the air bubbles, draw more medicine into the syringe from the mixed medicine vial and repeat checking for bubbles. • Look at the mixed medicine in the syringe before using. Do not use if discolored or particles are present. You are now ready to inject the dose. Injecting OMNITROPE 5.8 mg • Choose the site of injection on your body. The best sites for injection are tissues with a layer of fat between skin and muscle such as the upper leg (thigh), buttocks, or stomach area (abdomen) as in the picture shown below. Do not inject near your belly button (navel) or waistline. Reference ID: 5477192 • Make sure you rotate the injection sites on your body. Inject at least 1/2 inch from the last injection. Change the places on your body where you inject, as instructed by your healthcare provider. • Before you make an injection, clean your skin well with an alcohol swab. Wait for the area to air dry. Reference ID: 5477192 • With one hand, pinch a fold of loose skin at the injection site. With your other hand, hold the syringe as you would hold a pencil. Insert the needle into the pinched skin straight in or at a slight angle (an angle of 45° to 90°). After the needle is in, remove the hand used to pinch the skin and use it to hold the syringe barrel. Pull back the plunger very slightly with one hand. If blood comes into the syringe, the needle has entered a blood vessel. Do not inject into this site; withdraw the needle and repeat the procedure at a different site. If no blood comes into the syringe, inject the solution by pushing the plunger all the way down gently. • Pull the needle straight out of the skin. After injection, press the injection site with a small bandage or sterile gauze if needed for bleeding, for several seconds. Do not massage or rub the injection site. After Injecting OMNITROPE 5.8 mg • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and cartridges. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. How should I store OMNITROPE 5.8 mg? • Before Use: store the vials in the refrigerator between 36°F to 46°F (2°C to 8°C) until the expiration date. Do not use if the expiration date has passed. • After Mixing: store the vial of mixed medicine in the refrigerator between 36°F to 46°F (2°C to 8°C) and use within 3 weeks. Throw away any unused medicine after 3 weeks. • Protect the vials from light by storing in their cartons. • Do not freeze. • The liquid should be clear after removal from the refrigerator. If the liquid is cloudy or contains particles, throw away the vial. Do not inject the medicine from this vial. Start over with a new vial of OMNITROPE 5.8 mg. Call your pharmacist if you need a replacement. • Before each use clean the rubber top of the mixed medicine vial with an alcohol swab. You must use a new disposable 1 mL syringe and needle for each injection. Reference ID: 5477192 Manufactured by: Sandoz Inc., Princeton, NJ 08540 US License No. 2003 Product of Austria This Instructions for Use has been approved by the U.S. Food and Drug Administration. November 2024 NNNNNNNN Reference ID: 5477192	custom-source	2025-02-12T15:46:37.080059	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021426s043lbl.pdf', 'application_number': 21426, 'submission_type': 'SUPPL ', 'submission_number': 43}
80,210	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OGIVRI safely and effectively. See full prescribing information for OGIVRI. OGIVRI® (trastuzumab-dkst) for injection, for intravenous use Initial U.S. Approval: 2017 OGIVRI® (trastuzumab-dkst) is biosimilar* to HERCEPTIN (trastuzumab). WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete boxed warning Cardiomyopathy: Trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Ogivri for cardiomyopathy. (2.5, 5.1) Infusion Reactions, Pulmonary Toxicity: Discontinue Ogivri for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. (5.2, 5.4) Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patient’s of these risks and the need for effective contraception. (5.3, 8.1, 8.3) -------------------------RECENT MAJOR CHANGES---------------------------- Dosage and Administration, Evaluation and Testing Before Initiating Ogivri (2.1) 11/2024 ------------------------------ INDICATIONS AND USAGE ------------------------ Ogivri is a HER2/neu receptor antagonist indicated in adults for: • The treatment of HER2-overexpressing breast cancer. (1.1, 1.2) • The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. (1.3) Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product (1, 2.2). -------------------------- DOSAGE AND ADMINISTRATION ------------------ For intravenous (IV) infusion only. Do not administer as an IV push or bolus. Ogivri has different dosage and administration instructions than subcutaneous trastuzumab products. (2.3) Do not substitute Ogivri (trastuzumab-dkst) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. (2.3) Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.2) Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.2) Administer at either: • Initial dose of 4 mg/kg over 90 minutes IV infusion, then 2 mg/kg over 30 minutes IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Ogivri, administer 6 mg/kg as an IV infusion over 30 to 90 minutes every three weeks to complete a total of 52 weeks of therapy, or FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY 1 INDICATIONS AND USAGE 1.1 Adjuvant Breast Cancer 1.2 Metastatic Breast Cancer 1.3 Metastatic Gastric Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Evaluation and Testing Before Initiating Ogivri 2.2 Patient Selection 2.3 Recommended Dosage 2.4 Important Dosing Considerations 2.5 Dosage Modifications for Adverse Reactions 2.6 Preparation Instructions 3 DOSAGE FORMS AND STRENGTHS • Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every three weeks for 52 weeks. Metastatic HER2-Overexpressing Breast Cancer (2.3) • Initial dose of 4 mg/kg as a 90 minutes IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minutes IV infusions. Metastatic HER2-Overexpressing Gastric Cancer (2.3) • Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks. ------------------ DOSAGE FORMS AND STRENGTHS ------------------ • For Injection: 150 mg lyophilized powder in a single-dose vial for reconstitution • For Injection: 420 mg lyophilized powder in a multiple-dose vial for reconstitution supplied with a separate vial containing 20 mL of Bacteriostatic Water for Injection, USP, to be used as a diluent. • For Injection: 420 mg lyophilized powder in a multiple-dose vial for reconstitution. No diluent is provided. ------------------------- CONTRAINDICATIONS ---------------------------- • None. (4) -------------------- WARNINGS AND PRECAUTIONS ------------------- • Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1) ------------------------- ADVERSE REACTIONS ----------------------------- Adjuvant Breast Cancer • Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and chills. (6.1) Metastatic Breast Cancer • Most common adverse reactions (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. (6.1) Metastatic Gastric Cancer • Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------- USE IN SPECIFIC POPULATIONS ------------------- Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of Ogivri (8.3). See 17 for PATIENT COUNSELING INFORMATION. Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Ogivri has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 11/2024 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy 5.2 Infusion Reactions 5.3 Embryo-Fetal Toxicity 5.4 Pulmonary Toxicity 5.5 Exacerbation of Chemotherapy-Induced Neutropenia 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use Reference ID: 5478075 1 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adjuvant Breast Cancer 14.2 Metastatic Breast Cancer 14.3 Metastatic Gastric Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5478075 2 FULL PRESCRIBING INFORMATION WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY Cardiomyopathy Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Ogivri. Discontinue Ogivri treatment in patients receiving adjuvant therapy and withhold Ogivri in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. Infusion Reactions; Pulmonary Toxicity Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration of trastuzumab products. Interrupt Ogivri infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Ogivri for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.2, 5.4)]. Embryo-Fetal Toxicity Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. 1 INDICATIONS AND USAGE 1.1 Adjuvant Breast Cancer Ogivri is indicated in adults for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • as part of a treatment regimen with docetaxel and carboplatin • as a single agent following multi-modality anthracycline based therapy. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2)]. 1.2 Metastatic Breast Cancer Ogivri is indicated in adults: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Reference ID: 5478075 3 Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2)]. 1.3 Metastatic Gastric Cancer Ogivri is indicated in adults, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Evaluation and Testing Before Initiating Ogivri Assess left ventricular ejection fraction (LVEF) prior to initiation of Ogivri and at regular intervals during treatment. [see Boxed Warning, Dosage and Administration (2.5), Warnings and Precautions (5.1)]. Verify the pregnancy status of females of reproductive potential prior to the initiation of Ogivri [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)]. 2.2 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.3 Recommended Dosage • Ogivri is for intravenous infusion only. Do not administer as an intravenous push or bolus. • Ogivri has different dosage and administration instructions than subcutaneous trastuzumab products. • Do not mix Ogivri with other drugs. • Do not substitute Ogivri (trastuzumab-dkst) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. Reference ID: 5478075 4 Adjuvant Treatment of Breast Cancer: Administer according to one of the following doses and schedules for a total of 52 weeks of Ogivri therapy: During and following paclitaxel, docetaxel, or docetaxel and carboplatin: • Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin). • One week following the last weekly dose of Ogivri, administer Ogivri at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks. As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens: • Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes • Subsequent doses at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks. • Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)]. Metastatic Breast Cancer: • Administer Ogivri, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression. Metastatic Gastric Cancer: • Administer Ogivri at an initial dose of 8 mg/kg as a 90 minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks until disease progression. 2.4 Important Dosing Considerations Missed Dose If the patient has missed a dose of Ogivri by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; once every three weeks schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent Ogivri maintenance doses should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively. If the patient has missed a dose of Ogivri by more than one week, a re-loading dose of Ogivri should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; once every threeweek schedule: 8 mg/kg) as soon as possible. Subsequent Ogivri maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively. 2.5 Dosage Modifications for Adverse Reactions Infusion Reactions [see Boxed Warning, Warnings and Precautions (5.2)] • Decrease the rate of infusion for mild or moderate infusion reactions Reference ID: 5478075 5 • Interrupt the infusion in patients with dyspnea or clinically significant hypotension • Discontinue Ogivri for severe or life-threatening infusion reactions. Cardiomyopathy [see Boxed Warning, Warnings and Precautions (5.1)] Assess left ventricular ejection fraction (LVEF) prior to initiation of Ogivri and at regular intervals during treatment. Withhold Ogivri dosing for at least 4 weeks for either of the following: • ≥16% absolute decrease in LVEF from pre-treatment values • LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. Ogivri may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤15%. Permanently discontinue Ogivri for a persistent (>8 weeks) LVEF decline or for suspension of Ogivri dosing on more than 3 occasions for cardiomyopathy. 2.6 Preparation Instructions To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Ogivri (trastuzumab-dkst) and not ado-trastuzumab emtansine or fam- trastuzumab deruxtecan. 420 mg Multiple-dose vial supplied with a separate vial containing 20 mL of Bacteriostatic Water for Injection, USP, to be used as diluent. 420 mg Multiple-dose vial drug only carton. No diluent is provided. Reconstitution: Reconstitute each 420 mg vial of Ogivri with 20 mL of Bacteriostatic Water for Injection, USP (BWFI), containing 0.9% to 1.1% benzyl alcohol (not supplied for the 420 mg multiple-dose vial drug only carton) as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab-dkst that delivers 20 mL (420 mg trastuzumab-dkst). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection, USP (SWFI) without preservative to yield a one-time use solution. Use appropriate aseptic technique when performing the following reconstitution steps: • Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized powder of Ogivri, which has a cake-like appearance. The stream of diluent should be directed into the lyophilized cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab-dkst. • Swirl the vial gently to aid reconstitution. DO NOT SHAKE. • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. Reference ID: 5478075 6 • Store reconstituted Ogivri in the refrigerator at 2° to 8°C (36° to 46°F); discard unused Ogivri after 28 days. If Ogivri is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze. Dilution: • Determine the dose (mg) of Ogivri [see Dosage and Administration (2.3)]. Calculate the volume of the 21 mg/mL reconstituted Ogivri solution needed. • Withdraw this amount from the vial using a sterile needle and syringe and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. • Gently invert the bag to mix the solution. • The solution of Ogivri for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2° to 8°C (36° to 46°F) for no more than 24 hours prior to use. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze. 150 mg Single-dose vial Reconstitution: Reconstitute each 150 mg vial of Ogivri with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab dkst that delivers 7.15 mL (150 mg trastuzumab-dkst). Use appropriate aseptic technique when performing the following reconstitution steps: • Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of Ogivri, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution containing 21 mg/mL trastuzumab-dkst. • Swirl the vial gently to aid reconstitution. DO NOT SHAKE. • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. • Use the Ogivri solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for one-time use only. If not used immediately, store the reconstituted Ogivri solution for up to 24 hours at 2° to 8°C (36° to 46°F); discard any unused Ogivri after 24 hours. Do not freeze. Dilution: • Determine the dose (mg) of Ogivri [see Dosage and Administration (2.3)]. • Calculate the volume of the 21 mg/mL reconstituted Ogivri solution needed • Withdraw this amount from the vial using a sterile needle and syringe and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. • Gently invert the bag to mix the solution. Reference ID: 5478075 7 3 • The solution of Ogivri for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2° to 8°C (36° to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze. DOSAGE FORMS AND STRENGTHS • For injection: 150 mg of Ogivri as an off-white to pale yellow lyophilized powder in a single-dose vial. • For injection: 420 mg of Ogivri as an off-white to pale yellow lyophilized powder in a multiple-dose vial supplied with a separate vial containing 20 mL of Bacteriostatic Water for Injection (BWFI), to be used as a diluent. • For injection: 420 mg of Ogivri as an off-white to pale yellow lyophilized powder in a multiple-dose vial. No diluent is provided. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4 to 6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with an anthracycline. Withhold Ogivri for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.5)]. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Patients who receive anthracycline after stopping trastuzumab products may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement immediately prior to initiation of Ogivri Reference ID: 5478075 8 • LVEF measurements every 3 months during and upon completion of Ogivri • Repeat LVEF measurement at 4 week intervals if Ogivri is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.5)] • LVEF measurements every 6 months for at least 2 years following completion of Ogivri as a component of adjuvant therapy. In NSABP B31, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In HERA (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In BCIRG006, a total of 2.9% (31/1056) of patients in the TCH (docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity. Among 64 patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Table 1: Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of Congestive Heart Failure % (n) Study Regimen Trastuzumab Control NSABP B31 & NCCTG N9831a ACb → Paclitaxel + Trastuzumab 3.2% (64/2000)c 1.3% (21/1655) HERAd Chemotherapy →Trastuzumab 2% (30/1678) 0.3% (5/1708) BCIRG0 06 ACb → Docetaxel + Trastuzumab 2% (20/1068) 0.3% (3/1050) BCIRG0 06 Docetaxel + Carboplatin + Trastuzumab 0.4% (4/1056) 0.3% (3/1050) a Median follow-up duration for NSABP B31 & NCCTG N9831 combined was 8.3 years in the AC → paclitaxel + trastuzumab arm. bAnthracycline (doxorubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology. dIncludes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year trastuzumab arm. In HERA (one-year trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%. Reference ID: 5478075 9 Table 2:Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies Incidence NYHA I−IV NYHA III−IV Study Event Trastuzumab Control Trastuzumab Control H0648g (AC)b Cardiac Dysfunction 28% 7% 19% 3% H0648g (paclitaxel) Cardiac Dysfunction 11% 1% 4% 1% H0649g Cardiac Dysfunctionc 7% N/A 5% N/A a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy. In BCIRG006, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the trastuzumab containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T. 5.2 Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)]. In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Ogivri infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab products after experiencing a severe infusion reaction. Prior to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre medications. 5.3 Embryo-Fetal Toxicity Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post- marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and Reference ID: 5478075 10 -- -- oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Verify the pregnancy status of females of reproductive potential prior to the initiation of Ogivri. Advise pregnant women and females of reproductive potential that exposure to Ogivri during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Ogivri [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)]. 5.4 Pulmonary Toxicity Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. 5.5 Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not [see Adverse Reactions (6.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions (5.1)] • Infusion Reactions [see Warnings and Precautions (5.2)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)] • Pulmonary Toxicity [see Warnings and Precautions (5.4)] • Exacerbation of Chemotherapy-induced Neutropenia [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions in patients receiving trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.5)]. Reference ID: 5478075 11 In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. Adjuvant Breast Cancer The information below reflects exposure to one-year trastuzumab therapy across three randomized, open-label studies, NSABP B31, NCCTG N9831, and HERA, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer. HERA Table 3 reflects exposure to trastuzumab in 1678 patients in HERA; the median treatment duration was 51 weeks and median number of infusions was 18 [see Clinical Studies (14.1)]. Table 3: Adverse Reactions (>1%) in HERA (All Grades)a Adverse Reactions Trastuzumab (n = 1678) % Observation (n = 1708) % Nervous System Headache 10 3 Paresthesia 2 0.6 Musculoskeletal Arthralgia 8 6 Back pain 5 3 Myalgia 4 1 Bone pain 3 2 Muscle spasm 3 0.2 Infections Nasopharyngitis 8 3 Urinary tract infection 3 0.8 Gastrointestinal Diarrhea 7 1 Nausea 6 1 Vomiting 3.5 0.6 Constipation 2 1 Dyspepsia 2 0.5 Upper abdominal pain 2 1 General Pyrexia 6 0.4 Peripheral edema 5 2 Chills 5 0 Asthenia 4.5 2 Influenza-like illness 2 0.2 Respiratory Thoracic Mediastinal Cough 5 2 Influenza 4 0.5 Reference ID: 5478075 12 Dyspnea 3 2 URI 3 1 Rhinitis 2 0.4 Pharyngolaryngeal pain 2 0.5 Sinusitis 2 0.3 Epistaxis 2 0.06 Cardiac Hypertension 4 2 Dizziness 4 2 Ejection fraction decreased 3.5 0.6 Palpitations 3 0.7 Cardiac arrhythmiasb 3 1 Cardiac failure (congestive) 2 0.3 Skin & Subcutaneous Tissue Rash 4 0.6 Nail disorders 2 0 Pruritus 2 0.6 aThe incidence of Grade 3 or higher adverse reactions was < 1% in both arms for each listed term. b Higher level grouping term. Clinically relevant adverse reactions in < 1% of patients who received trastuzumab in HERA included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%), autoimmune thyroiditis (0.3%), and sudden death (0.06%). Adjuvant Treatment of Breast Cancer with Trastuzumab Beyond One Year Extending adjuvant treatment beyond one year is not recommended [see Dosage and Administration (2.3)]. In HERA, a comparison of trastuzumab administered once every 3 weeks for two years versus one year was performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab compared to the 1-year trastuzumab treatment arm (8.1% versus 4.6%, respectively). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%). NSABP B31 and NCCTG N9831 The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks [see Clinical Studies (14.1)]. In NSABP B31, only Grade 3 to 5 adverse events, treatment-related Grade 2 events, and Grade 2 to 5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3%), edema (4.7% vs. 2.7%) and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity. Reference ID: 5478075 13 In NCCTG N9831, data collection was limited to the following investigator-attributed treatment- related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3 to 5 non- hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1 to 5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The following non- cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs.6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity. BCIRG006 Safety data from BCIRG006reflect exposure to trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and once every three week dosing in the monotherapy period [see Clinical Studies (14.1)]. In BCIRG006, the toxicity profile was similar to that reported in NSABP B31, NCCTG N9831, and HERA with the exception of a lower incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The safety of trastuzumab was evaluated in one randomized, open-label study (H0648g) of chemotherapy with (n = 235) or without (n = 234) intravenous trastuzumab in patients with metastatic breast cancer and in one single-arm study (H0649g); in patients with metastatic breast cancer (n=222) [see Clinical Studies (14.1)]. Patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly. In H0648g, 58% of patients received trastuzumab for ≥ 6 months and 9% received trastuzumab ≥ 12 months, respectively. In H0649g, 31% of patients received trastuzumab for ≥ 6 months and 16% received trastuzumab for ≥ 12 months, respectively. Table 4 shows the adverse reactions (≥ 5%) in patients from H0648g and H0649g. Table 4: Adverse Reactions³ (5%) in the Trastuzumab Arms in H0648g and H0649g Trastuzuma ba n = 352 % Trastuzuma b + Paclitaxel n = 91 % Paclitaxel n = 95 % Trastuzum ab + ACb n = 143 % ACb n = 135 % General Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Reference ID: 5478075 14 Trastuzuma ba n = 352 % Trastuzuma b + Paclitaxel n = 91 % Paclitaxel n = 95 % Trastuzum ab + ACb n = 143 % ACb n = 135 % Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Gastrointestinal Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Anorexia 14 24 16 31 26 Nausea and vomiting 8 14 11 18 9 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 < 1 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Cardiovascular Congestive heart failure 7 11 1 28 7 Tachycardia 5 12 4 10 5 Reference ID: 5478075 15 Table 4: Adverse Reactions (> 5%) in the Trastuzumab Arms in H0648g and H0649g (continued) Trastuzumaba n = 352 % Trastuzumab + Paclitaxel n = 91 % Paclitaxel n = 95 % Trastuzumab + ACb n = 143 % ACb n =135 % Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Urogenital Urinary tract infection 5 18 14 13 7 Blood and Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 a Data for trastuzumab single agent were from 4 studies, including 213 patients from H0649g. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. Metastatic Gastric Cancer The safety of trastuzumab was evaluated in patients with previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma in an open label, multi-center trial (ToGA) [see Clinical Studies (14.3)]. Patients were randomized (1:1) to receive trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) (n=294) or chemotherapy alone (FC) (n=290) Patients in the trastuzumab plus chemotherapy arm received trastuzumab 8 mg/kg administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1 to 14 or 5 fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of trastuzumab treatment was 21 weeks and the median number of trastuzumab infusions administered was eight. Table 5: Adverse Reactions (All Grades > 5% or Grade 3-4 > 1% between Arms) in ToGA Adverse Reactions Trastuzumab + FC (N = 294) % FC (N = 290) % All Grades Grades 3 to 4 All Grades Grades 3 to 4 Investigations Neutropenia 78 34 73 29 Hypokalemia 28 10 24 6 Anemia 28 12 21 10 Thrombocytopenia 16 5 11 3 Blood and Lymphatic System Disorders Febrile Neutropenia - 5 - 3 Gastrointestinal Disorders Reference ID: 5478075 16 Adverse Reactions Trastuzumab + FC (N = 294) % FC (N = 290) % All Grades Grades 3 to 4 All Grades Grades 3 to 4 Diarrhea 37 9 28 4 Stomatitis 24 1 15 2 Dysphagia 6 2 3 < 1 General Fatigue 35 4 28 2 Fever 18 1 12 0 Mucosal Inflammation 13 2 6 1 Chills 8 < 1 0 0 Metabolism and Nutrition Disorders Weight Decrease 23 2 14 2 Infections and Infestations Upper Respiratory Tract Infections 19 0 10 0 Nasopharyngitis 13 0 6 0 Renal and Urinary Disorders Renal Failure and Impairment 18 3 15 2 Nervous System Disorders Dysgeusia 10 0 5 0 The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In HERA, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year trastuzumab arm); and in NSABP B31 and NCCTG N9831, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. Following initiation of trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in NSABP B31 and NCCTG N9831, and in patients receiving one-year trastuzumab monotherapy compared to observation in HERA (see Table 6, Figures 1 and 2). The incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery. Reference ID: 5478075 17 Table 6: Myocardial Dysfunction (by LVEF) in NSABP B31, NCCTG N9831, HERA and BCIRG006a Study and Arm LVEF <50% and Decrease from Baseline LVEF Decrease LVEF < 50% ≥ 10% decrease ≥ 16% decrease < 20% and ≥ 10% ≥ 20% NSABP B31 & NCCTGb,c AC → TH 23.1% 18.5% 11.2% 37.9% 8.9% (n = 1856) (428) (344) (208) (703) (166) AC → T 11.7% 7.0% 3.0% 22.1% 3.4% (n = 1170) (137) (82) (35) (259) (40) HERAd Trastuzumab 8.6% 7.0% 3.8% 22.4% 3.5% (n = 1678) (144) (118) (64) (376) (59) Observation 2.7% 2.0% 1.2% 11.9% 1.2% (n = 1708) (46) (35) (20) (204) (21) BCIRG006e TCH 8.5% 5.9% 3.3% 34.5% 6.3% (n = 1056) (90) (62) (35) (364) (67) AC → TH 17% 13.3% 9.8% 44.3% 13.2% (n = 1068) (182) (142) (105) (473) (141) AC → T 9.5% 6.6% 3.3% 34% 5.5% (n = 1050) (100) (69) (35) (357) (58) a For NSABP B31, NCCTG N9831, and HERA, events are counted from the beginning of trastuzumab treatment. For BCIRG006, events are counted from the date of randomization. b NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC → T) or paclitaxel plus trastuzumab (AC → TH). c Median duration of follow-up for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC → TH arm. d Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm. e BCIRG006regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC → T) or docetaxel plus trastuzumab (AC → TH); docetaxel and carboplatin plus trastuzumab (TCH). Reference ID: 5478075 18 a.so 0.45 0.40 0.35 g 0.30 i 0.25 ~ ~ 0.20 > ~ -s 0.1 5 § u 0.10 0.05 0.00 0.50 0.45 0.40 0.35 <1) u 0.30 C <1) :g 0.25 u != ., > 0.20 ~ 0.15 =i E 0.10 0 0.05 0.00 1678 1708 0 ~ f --~ r -- ___ _r - ~ ~ -- -- - - - - - - - ~ Number at Risk 1959 1670 951 492 481 221 139 AC - >T-tH 1316 1156 764 257 256 159 98 AC ->T nme from Initiation of PaclitaxelfTrastuzumab (Years) AC ->T AC - >T+H ~ I------- - - - I------~ 1142 1154 6 Numbe at Risk 873 538 831 498 12 18 Time from Randomization (Months) Observation Only 263 Trastuzumab 1-Year 245 Observation Only 24 Trastuzumab 1-Year Figure 1 NSABP B31 and NCCTG N9831: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and toBelow 50% with Death as a Competing Risk Event Time 0 is initiation of paclitaxel or trastuzumab + paclitaxel therapy. Figure 2 HERA: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. Reference ID: 5478075 19 0.50 0.45 0.40 <l) <.) 0.35 C <l) 0.30 cl ·u E <l) .2: '" 0.25 :i 0.20 E ::, (_) 0.15 0.10 0.05 .---- AC -> T (doxorubicin + cyclophosphamide -> docetaxel) AC-> TH (doxorubicin + cyclophosphamide -> docetaxel + trastuzumab) TCH (docetaxel + carboplatin + trastuzumab ... --•··-· .. ,---·------------·---------·--· .- • ---. ....---- 0.00 ~ - -----=--=::..a=--==------- ~ 0 6 12 18 24 36 Time (Months) Number at Risk AC->T 1050 947 836 523 359 259 AC->TH 1068 975 839 474 315 248 TCH 1056 975 877 535 350 271 Figure 3 BCIRG006: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. The incidence of congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I−IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received trastuzumab concurrently with anthracyclines. In ToGA, 5% of patients in the trastuzumab plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with trastuzumab, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of trastuzumab infusion); permanent discontinuation of trastuzumab for infusion reactions was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9% of patients, on second or subsequent trastuzumab infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Reference ID: 5478075 20 Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [H0648g]), of selected NCI-CTC Grade 2 to 5 anemia (12.3% vs. 6.7% [NSABP B31]), and of anemia requiring transfusions (0.1% vs. 0 patients [NCCTG N9831]) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of trastuzumab as a single agent (H0649g), the incidence of NCI-CTC Grade 3 anemia was < 1%. In ToGA (metastatic gastric cancer), on the trastuzumab containing arm as compared to the chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI-CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4 to 5 neutropenia (1.7% vs. 0.8% [NCCTG N9831]) and of selected Grade 2 to 5 neutropenia (6.4% vs. 4.3% [NSABP B31]) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic gastric cancer) on the trastuzumab containing arm as compared to the chemotherapy alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection The overall incidences of infection (46% vs. 30% [H0648g]), of selected NCI-CTC Grade 2 to 5 infection/febrile neutropenia (24.3% vs. 13.4% [NSABP B31]) and of selected Grade 3 to 5 infection/febrile neutropenia (2.9% vs. 1.4%) [NCCTG N9831]) were higher in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In BCIRG006, the overall incidence of infection was higher with the addition of trastuzumab to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3 to 4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2 to 5 pulmonary toxicity (14.3% vs. 5.4% [NSABP B31]) and of selected NCI-CTC Grade 3 to 5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4 % vs. 0.9% [NCCTG Reference ID: 5478075 21 N9831]) was higher in patients receiving trastuzumab and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2 to 5: 11.8% vs. 4.6% [NSABP B31]; NCI-CTC Grade 2 to 5: 2.4% vs. 0.2% [NCCTG N9831]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving trastuzumab, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In HERA, there were 4 cases of interstitial pneumonitis in the one-year trastuzumab treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months. Metastatic Breast Cancer Among women receiving trastuzumab for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post- marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions (5.4). Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [NSABP B31], 2.5% and 3.7% vs. 2.2% [BCIRG006] and 2.1% vs. 0% [H0648g]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2 to 5 diarrhea (6.7% vs. 5.4% [NSABP B31]) and of NCI-CTC Grade 3 to 5 diarrhea (2.2% vs. 0% [NCCTG N9831]), and of Grade 1 to 4 diarrhea (7% vs. 1% [HERA; one-year trastuzumab treatment at 12.6 months median duration of follow-up]) were higher in patients receiving trastuzumab as compared to controls. In BCIRG006, the incidence of Grade 3 to 4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1 to 4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab. Of patients receiving trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In ToGA (metastatic gastric cancer) on the trastuzumab-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the trastuzumab-containing arm compared to 1.7% on the Reference ID: 5478075 22 chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the trastuzumab-containing arm and 0.3% on the chemotherapy only arm. In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of trastuzumab therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of trastuzumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Infusion reaction [see Warnings and Precautions (5.2)] • Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions (5.3)] • Glomerulopathy [see Adverse Reactions (6.1)] • Immune thrombocytopenia • Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with trastuzumab products. Patients with significant tumor burden (e.g. bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated. 7 DRUG INTERACTIONS Anthracyclines Patients who receive anthracycline after stopping trastuzumab products may be at increased risk of cardiac dysfunction because of trastuzumab products estimated long washout period [see Clinical Pharmacology (12.3)]. If possible, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab products. If anthracyclines are used, closely monitor the patient’s cardiac function. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post- marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Data]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if a trastuzumab product is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of a trastuzumab product [see Clinical Considerations]. Reference ID: 5478075 23 The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received Ogivri during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal/neonatal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data In post-marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence. Fetal manifestations includedpulmonary hypoplasia, skeletal abnormalities and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In most reported cases, amniotic fluid index increased after trastuzumab was stopped. In reported cases where trastuzumab therapy was resumed after amniotic index improved, oligohydramnios recurred. Animal Data In studies where trastuzumab was administered to pregnant Cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects. 8.2 Lactation Risk Summary There is no information regarding the presence of trastuzumab products in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated with neonatal toxicity (see Data). Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Ogivri treatment and any potential adverse effects on the breastfed child from Ogivri or from the underlying maternal condition. This consideration should also take into account the trastuzumab product wash out period of 7 months [see Clinical Pharmacology (12.3)]. Reference ID: 5478075 24 Data In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre-(beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of trastuzumab products). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of Ogivri. Contraception Females Trastuzumab products can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Ogivri and for 7 months following the last dose of Ogivri [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of Ogivri in pediatric patients have not been established. 8.5 Geriatric Use Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in H0648g and H0649g, or adjuvant therapy in NSABP B31 and NCCTG N9831. Limitations in data collection and differences in study design of the 4 studies of trastuzumab in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of trastuzumab in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of trastuzumab treatment in older patients is different from that observed in patients < 65 years of age for metastatic disease and adjuvant treatment. In ToGA (metastatic gastric cancer), of the 294 patients treated with trastuzumab, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed. 11 DESCRIPTION Trastuzumab-dkst is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, Reference ID: 5478075 25 HER2. Trastuzumab-dkst is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. Ogivri (trastuzumab-dkst) for injection is a sterile, off-white to pale yellow, preservative-free lyophilized powder with a cake-like appearance, for injection, for intravenous administration. Each multiple-dose vial of Ogivri delivers 420 mg trastuzumab-dkst, D-sorbitol (322.6 mg), L- Histidine (6.0 mg), Histidine hydrochloride monohydrate (9.4 mg) and Polyethylene glycol 3350/Macrogol 3350 (94.1 mg). Hydrochloric acid or sodium hydroxide may be used to adjust the pH of the formulation buffer. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab-dkst that delivers 20 mL (420 mg trastuzumab-dkst), at a pH of approximately 6. If Ogivri is reconstituted with SWFI without preservative, the reconstituted solution is considered single-dose. Each single-dose vial of Ogivri delivers 150 mg trastuzumab-dkst, D-sorbitol (115.2 mg), L- Histidine (2.16 mg), L-Histidine hydrochloride monohydrate (3.36 mg) and Polyethylene glycol 3350/Macrogol 3350 (33.6 mg). Hydrochloric acid or sodium hydroxide may be used to adjust the pH of the formulation buffer. Reconstitution with 7.4 mL of sterile water for injection (SWFI) yields a solution containing 21 mg/mL trastuzumab-dkst that delivers 7.15 mL (150 mg trastuzumab-dkst), at a pH of approximately 6. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. 12.2 Pharmacodynamics Trastuzumab product exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized. Cardiac Electrophysiology The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors. Reference ID: 5478075 26 12.3 Pharmacokinetics The pharmacokinetics of trastuzumab were evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways. Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the once every three week schedule compared to the weekly schedule of trastuzumab, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first trastuzumab cycle and at steady state exposure are described in Tables 7 and 8, respectively. Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations in at least 95% of breast cancer patients and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Table 7 Population Predicted Cycle 1 PK Exposures (Median with 5th to 95th Percentiles) in Breast Cancer and MGC Patients Schedule Primary tumor type N Cmin (µg/mL) Cmax (µg/mL) AUC0-21days (µg.day/mL) 8 mg/kg + Breast cancer 1195 29.4 (5.8 to 59.5) 178 (117 to 291) 1373 (736 to 2245) 6 mg/kg q3w MGC 274 23.1 (6.1 to50.3) 132 (84.2 to 225) 1109 (588 to 1938) 4 mg/kg + 2 mg/kg qw Breast cancer 1195 37.7 (12.3 to 70.9) 88.3 (58 to 144) 1066 (586 to 1754) Table 8 Population Predicted Steady State PK Exposures (Median with 5th to 95th Percentiles) in Breast Cancer and MGC Patients Schedule Primary tumor type N Cmin,ssa (µg/mL) b Cmax,ss (µg/mL) AUCss,0-21days (µg.day/mL) Time to steady- state (week) Total CL range at steady-state (L/day) 8 mg/kg + 6 mg/kg q3w Breast cancer 1195 47.4 (5 to 115) 179 (107 to 309) 1794 (673 to 3618) 12 0.173 to 0.283 MGC 274 32.9 (6.1 to 88.9) 131 (72.5 to 251) 1338 (557 to 2875) 9 0.189 to 0.337 4 mg/kg + 2 mg/kg qw Breast cancer 1195 66.1 (14.9 to 142) 109 (51.0 to 209) 1765 (647 to 3578) 12 0.201 to 0.244 a Steady-state trough serum concentration of trastuzumab b Maximum steady-state serum concentration of trastuzumab Reference ID: 5478075 27 Specific Populations Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (<65 (n = 1294); ≥65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab products in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown. Drug Interaction Studies There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinically significant interactions between trastuzumab and concomitant medications used in clinical trials have not been observed. Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy. Docetaxel and carboplatin: When trastuzumab was administered in combination with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered. Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in ToGA, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with trastuzumab. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of trastuzumab or of other trastuzumab products. Among 903 women with metastatic breast cancer, human anti human antibody (HAHA) to trastuzumab was detected in one patient using an enzyme linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The clinical relevance of the development of anti-trastuzumab antibodies after treatment with trastuzumab is not known. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Trastuzumab products have not been tested for carcinogenic potential. Reference ID: 5478075 28 -- No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab. A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. 14 CLINICAL STUDIES 14.1 Adjuvant Breast Cancer The safety and efficacy of trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer were evaluated in an integrated analysis of two randomized, open- label, clinical trials (NSABP B31 and NCCTG N9831) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (HERA) with a total of 3386 women at definitive Disease-Free Survival analysis for one-year trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (BCIRG006). NSABP B31 and NCCTG N9831 In NSABP B31 and NCCTG N9831, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (NCCTG N9831) or was required to be performed at a reference laboratory (NSABP B31). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible. Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC → paclitaxel) alone or paclitaxel plus trastuzumab (AC → paclitaxel + trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks in NSABP B31; paclitaxel was administered only by the weekly schedule in NCCTG N9831. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline [see Dosage and Administration (2.5)]. Radiation therapy, if administered, was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The major efficacy outcome measure of the combined efficacy analysis was Disease-Free Survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. An additional efficacy outcome measure was overall survival (OS). A total of 3752 patients were included in the joint efficacy analysis of DFS following a median follow-up of 2.0 years in the AC → paclitaxel + trastuzumab arm. The pre-planned final OS Reference ID: 5478075 29 analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC → paclitaxel + trastuzumab arm. The data from both arms in NSABP B31 and two of the three study arms in NCCTG N9831 were pooled for efficacy analyses. The patients included in the DFS analysis had a median age of 49 years (range, 22 to 80 years; 6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+ tumors. HERA In HERA, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory. Patients with node-negative disease were required to have ≥ T1c primary tumor. Patients with a history of congestive heart failure or LVEF < 55%, uncontrolled arrhythmias, angina requiring medication, clinically significant valvular heart disease, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic > 180 mm Hg or diastolic > 100 mm Hg) were not eligible. Patients were randomized (1:1:1) upon completion of definitive surgery, and at least four cycles of chemotherapy to receive no additional treatment, or one year of trastuzumab treatment or two years of trastuzumab treatment. Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The major efficacy outcome measure was Disease-Free Survival (DFS), defined as in NSABP B31 and NCCTG N9831. HERA was designed to compare one and two years of once every three week trastuzumab treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). A protocol specified interim efficacy analysis comparing one-year trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the trastuzumab arm. Among the 3386 patients randomized to the observation (n = 1693) and trastuzumab one-year (n = 1693) treatment arms, the median age was 49 years (range 21 to 80), 83% were White, and 13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node positive, 32% node negative, and in 11% of patients, nodal status was not assessable due to prior neo-adjuvant chemotherapy. Ninety-six percent (1055/1098) of patients with node-negative disease had high-risk features: among the 1098 patients with node-negative disease, 49% (543) were ER− and PgR−, and 47% (512) were ER and/or PgR + and had at least one of the following high-risk features: pathological tumor size greater than 2 cm, Grade 2 to 3, or age <35 years. Prior to randomization, 94% of patients had received anthracycline-based chemotherapy regimens. After the DFS results comparing observation to one-year trastuzumab treatment were disclosed, a prospectively planned analysis that included comparison of one year versus two years of trastuzumab treatment at a median follow-up duration of 8 years was performed. Based on this analysis, extending trastuzumab treatment for a duration of two years did not show additional benefit over treatment for one year [Hazard Ratios of two-years trastuzumab versus one-year Reference ID: 5478075 30 trastuzumab treatment in the intent to treat (ITT) population for Disease-Free Survival (DFS) = 0.99 (95% CI: 0.87, 1.13), p-value = 0.90 and Overall Survival (OS) = 0.98 (0.83, 1.15); p- value = 0.78]. BCIRG006 In BCIRG006, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one of the following high-risk features: ER/PR negative, tumor size > 2 cm, age < 35 years, or histologic and/or nuclear Grade 2 or 3. Patients with a history of CHF, myocardial infarction, Grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic > 100 mm Hg), any T4 or N2 or known N3 or M1 breast cancer were not eligible. Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab (AC-TH), or docetaxel and carboplatin plus trastuzumab (TCH). In both the AC-T and AC-TH arms, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were administered every 3 weeks for four cycles; docetaxel 100 mg/m2 was administered every 3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m2 and carboplatin (at a target AUC of 6 mg/mL/min as a 30-to 60-minute infusion) were administered every 3 weeks for six cycles. Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg) concurrently with either T or TC, and then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. Disease-Free Survival (DFS) was the major efficacy outcome measure. Among 3222 patients, the median age was 49 (range 22 to 74 years; 6% ≥ 65 years). Disease characteristics included 54% ER+ and/or PR+ and 71% node positive. Prior to randomization, all patients underwent primary surgery for breast cancer. The results for DFS for the integrated analysis of NSABP B31 and NCCTG N9831, HERA, and BCIRG006 and OS results for the integrated analysis of NSABP B31 and NCCTG N9831, and HERA are presented in Table 9. For NSABP B31 and NCCTG N9831, the duration of DFS following a median follow-up of 2.0 years in the AC → TH arm is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC → TH arm is presented in Figure 5. The duration of DFS for BCIRG006is presented in Figure 6. For NSABP B31 and NCCTG N9831, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3 years of median follow-up [AC → TH], the survival rate was estimated to be 86.9% in the AC → TH arm and 79.4% in the AC → T arm. The final OS analysis results from NSABP B31 and NCCTG N9831 indicate that OS benefit by age, hormone receptor status, number of positive lymph nodes, tumor size and grade, and surgery/radiation therapy was consistent with the treatment effect in the overall population. In patients ≤ 50 years of age (n = 2197), the OS hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in patients > 50 years of age (n = 1866), the OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-positive disease (ER-positive and/or PR- positive) (n = 2223), the hazard ratio for OS was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-negative disease (ER-negative and PR-negative) (n = 1830), the hazard ratio for OS was 0.64 (95% CI: 0.52, 0.80). In the subgroup of patients with tumor size Reference ID: 5478075 31 ≤ 2 cm (n = 1604), the hazard ratio for OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size > 2 cm (n = 2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80). Table 9 Efficacy Results from Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831, HERA, and BCIRG006) DFS events DFS Hazard ratio (95% CI) p-value Deaths (OS events) OS Hazard ratio p-value NSABP B31 and NCCTG N9831a AC → TH (n = 1872)b (n = 2031)c 133b 0.48b,d (0.39, 0.59) p < 0.0001e 289c 0.64c,d (0.55, 0.74) p < 0.0001e AC → T (n = 1880)b (n = 2032)c 261b 418c HERAf Chemo → Trastuzumab (n = 1693) 127 0.54 (0.44, 0.67) p < 0.0001g 31 0.75 p = NSh Chemo → Observation (n = 1693) 219 40 BCIRG006i TCH (n = 1075) 134 0.67 (0.54 to 0.84) p = 0.0006e,j 56 AC → TH (n = 1074) 121 0.60 (0.48 to 0.76) p < 0.0001e,i 49 AC → T (n = 1073) 180 80 CI = confidence interval. a NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC → T) or paclitaxel plus trastuzumab (AC → TH). b Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC → TH arm. c Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the AC → TH arm). d Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes, and hormone receptor status. e stratified log-rank test. f At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm. g log-rank test. h NS = non-significant. i BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC → T) or docetaxel plus trastuzumab (AC → TH); docetaxel and carboplatin plus trastuzumab (TCH). j A two-sided alpha level of 0.025 for each comparison. Reference ID: 5478075 32 1.0 0.8 Q) ~ ½- 0.6 c Q) > UJ C 0 t 0 0.4 C. e Cl.. 0.2 0.0 00 - ... ...-.. -~ .... ----..-- AC-> TH (doxorubin + cyclophosphamide -> paclitaxel + trastuzumab ---- AC-> T (doxorubin + cyclophosphamide -> paclitaxel) 0.5 1.0 1.5 2.0 2.5 Disease-Free Survival (years) 3.0 3.5 Number at Risk AC -,T 1880 1490 1159 926 689 534 375 195 AC-,T+ H 1872 1529 1240 997 764 575 426 239 Figure 4 Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831) Reference ID: 5478075 33 1.0 0.8 Q) 0.6 -~ <( C 0 :e 0 a. 0 d: 0.4 0.2 AC->T (doxorubicin + cyclophosphamide -> paclitaxel AC->T + (doxorubicin + cyclophosphamide -> paclitaxel + trastuzumab) 00 0 Number at Risk AC->T 2032 AC->T + H "' "' u;: 2031 1.0 0.8 c 0.6 "' ,. w "' 0 ~ 0.4 a. e a.. 0.2 1961 1992 2 3 4 5 6 7 Overall Survival (years) 1883 1806 1732 1643 1538 1377 1957 1897 1843 1787 1714 1533 - - - - AC -> TH (doxorubicin + cyclophosphamide -> doc6taxel + trastuzumab) -- - TCH (docetaxel + carboplatin + trastuzumab) --- AC -> T (doxorubicin + cyclopho, phamide -> docetaxel) 0.0 0 2 3 Disease Free Survival (years) Number at Risk AC->T 1073 971 802 417 AC->TH 1074 1023 885 457 TCH 1075 1018 877 447 8 979 1127 9 10 630 399 787 485 4 103 126 126 AC=doxorubicin and cyclophosphamide; T=docetaxel; TCH=docetaxel, platinum salt. and trastuzumab; TH=docetaxel and trastuzumab. Kaplan-Meier estimates are shown. 11 151 159 5 Figure 5 Overall Survival in Patients with Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831) Figure 6 Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (BCIRG006) Reference ID: 5478075 34 Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were conducted for patients in NCCTG N9831 and HERA, where central laboratory testing data were available. The results are shown in Table 10. The number of events in NCCTG N9831 was small with the exception of the IHC 3+/FISH+ subgroup, which constituted 81% of those with data. Definitive conclusions cannot be drawn regarding efficacy within other subgroups due to the small number of events. The number of events in HERA was adequate to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and the FISH +/IHC unknown subgroups. Table 10: DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or Amplification NCCTG N9831 HERAc HER2 Assay Resulta Number of Patients Hazard Ratio DFS (95% CI) Number of Patients Hazard Ratio DFS (95% CI) IHC 3+ FISH (+) FISH (–) FISH Unknown 1170 51 51 0.42 (0.27, 0.64) 0.71 (0.04, 11.79) 0.69 (0.09, 5.14) 91 8 2258 0.56 (0.13, 2.50) — 0.53 (0.41, 0.69) IHC < 3+ / FISH (+) 174 1.01 (0.18, 5.65) 299b 0.53 (0.20, 1.42) IHC unknown / FISH (+) — — 724 0.59 (0.38, 0.93) a IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory. bAll cases in this category in HERA were IHC 2+. c Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm. 14.2 Metastatic Breast Cancer The safety and efficacy of trastuzumab in treatment of women with metastatic breast cancer were studied in a randomized, controlled clinical trial in combination with chemotherapy (H0648g, n = 469 patients) and an open-label single agent clinical trial (H0649g, n = 222 patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2 or 3 levels of overexpression (based on a 0 to 3 scale) by immunohistochemical assessment of tumor tissue performed by a central testing lab. Previously Untreated Metastatic Breast Cancer (H0648g) H0648g was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastatic breast cancer who had not been previously treated with chemotherapy for metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened). Patients were randomized to receive chemotherapy alone or in combination with trastuzumab given intravenously as a 4 mg/kg loading dose followed by weekly doses of trastuzumab at 2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles). Sixty-five percent of patients Reference ID: 5478075 35 randomized to receive chemotherapy alone in this study received trastuzumab at the time of disease progression as part of a separate extension study. Based upon the determination by an independent Response Evaluation Committee the patients randomized to trastuzumab and chemotherapy experienced a significantly longer median time to disease progression (TTP), a higher overall response rate (ORR), and a longer median duration of response (DoR), as compared with patients randomized to chemotherapy alone. Patients randomized to trastuzumab and chemotherapy also had a longer median overall survival (OS) (see Table 11). These treatment effects were observed both in patients who received trastuzumab plus paclitaxel and in those who received trastuzumab plus AC; however the magnitude of the effects was greater in the paclitaxel subgroup. Table 11 H0648g: Efficacy Results inFirst-Line Treatment for Metastatic Breast Cancer Combined Results Paclitaxel Subgroup ACa Subgroup trastuzumab + All Chemo therapy (n = 235) All Chemo therapy (n = 234) trastuzumab + Paclitaxel (n = 92) Paclitaxel (n = 96) trastuzumab + ACa (n = 143) ACa (n = 138) Time to Disease Progression (TTP) Median (months)b,c 7.2 4.5 6.7 2.5 7.6 5.7 95% CI 7, 8 4, 5 5, 10 2, 4 7, 9 5, 7 p-valued < 0.0001 < 0.0001 0.002 Overall Response Rate (ORR)b Events (n) 45 29 38 15 50 38 95% CI 39, 51 23, 35 28, 48 8, 22 42, 58 30, 46 p-valuee < 0.001 < 0.001 0.10 Duration of Response (DoR) Median (months)b,c 8.3 5.8 8.3 4.3 8.4 6.4 25%, 75% Quartile 6, 15 4, 8 5, 11 4, 7 6, 15 4, 8 Overall Survival (OS) Median (months)c 25.1 20.3 22.1 18.4 26.8 21.4 95% CI 22, 30 17, 24 17, 29 13, 24 23, 33 18, 27 p-valued 0.05 0.17 0.16 a AC = Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. bAssessed by an independent Response Evaluation Committee. c Kaplan-Meier Estimate. dlog-rank test. e χ2-test. Data from H0648g suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+) (see Table 12). Reference ID: 5478075 36 Table 12 Treatment Effects in H0648g as a Function of HER2 Overexpression or Amplification HER2 Assay Result Number of Patients (N) Relative Riskb for Time to Disease Progression (95% CI) Relative Riskb for Mortality (95% CI) CTA 2+ or 3+ 469 0.49 (0.40, 0.61) 0.80 (0.64, 1.00) FISH (+)a 325 0.44 (0.34, 0.57) 0.70 (0.53, 0.91) FISH (−)a 126 0.62 (0.42, 0.94) 1.06 (0.70, 1.63) CTA 2+ 120 0.76 (0.50, 1.15) 1.26 (0.82, 1.94) FISH (+) 32 0.54 (0.21, 1.35) 1.31 (0.53, 3.27) FISH (−) 83 0.77 (0.48, 1.25) 1.11 (0.68, 1.82) CTA 3+ 349 0.42 (0.33, 0.54) 0.70 (0.51, 0.90) FISH (+) 293 0.42 (0.32, 0.55) 0.67 (0.51, 0.89) FISH (−) 43 0.43 (0.20, 0.94) 0.88 (0.39, 1.98) a FISH testing results were available for 451 of the 469 patients enrolled on study. b The relative risk represents the risk of progression or death in the trastuzumab plus chemotherapy arm versus the chemotherapy arm. Previously Treated Metastatic Breast Cancer (H0649g) Trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical trial (H0649g) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of trastuzumab at 2 mg/kg IV. The ORR (complete response + partial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate. Complete responses were observed only in patients with disease limited to skin and lymph nodes. The overall response rate in patients whose tumors tested as CTA 3+ was 18% while in those that tested as CTA 2+, it was 6%. 14.3 Metastatic Gastric Cancer The safety and efficacy of trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma (ToGA). In this open-label, multi-center trial, 594 patients were randomized 1:1 to trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastric vs. gastroesophageal junction), tumor measurability (yes vs. no), ECOG performance status (0,1 vs. 2), and fluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene amplified (FISH+) or HER2 Reference ID: 5478075 37 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function (e.g., LVEF > 50%). On the trastuzumab-containing arm, trastuzumab was administered as an IV infusion at an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both study arms cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. On both study arms capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively, continuous intravenous infusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day from Day 1 through Day 5 every three weeks for 6 cycles. The median age of the study population was 60 years (range: 21 to 83); 76% were male; 53% were Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 82% had primary gastric cancer and 18% had primary gastroesophageal adenocarcinoma. Of these patients, 23% had undergone prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant therapy, and 2% had received prior radiotherapy. The main outcome measure of ToGA was overall survival (OS), analyzed by the unstratified log-rank test. The final OS analysis based on 351 deaths was statistically significant (nominal significance level of 0.0193). An updated OS analysis was conducted at one year after the final analysis. The efficacy results of both the final and the updated analyses are summarized in Table 13 and Figure 7. Table 13: Overall Survival in ToGA (ITT Population) FCa + Trastuzumab Arm N = 298 FCa Arm N = 296 Overall Survival (interim analysis) N (%) Median (months) 95% CI 167 (56.0%) 13.5 (11.7, 15.7) 184 (62.2%) 11.0 (9.4, 12.5) Hazard Ratio 95% CI p-valueb 0.73 (0.60, 0.91) 0.0038 Overall Survival (updated) N (%) Median (months) 95% CI 221 (74.2%) 13.1 (11.9, 15.1) 227 (76.7%) 11.7 (10.3, 13.0) Hazard Ratio 95% CI 0.80 (0.67, 0.97) a FC = capecitabine vs. 5-fluorouracil b Two sided p-value comparing with the nominal significance level of 0.0193. Reference ID: 5478075 38 1.0 0.8 >, ~ .c 0.6 n:s .c 0 ... a.. iii .2: 0.4 i::: :J Cl) 0.2 0.0 1 296 2 298 0 207 130 232 158 10 Product-Limit Survival Estimates With Number of Subjects at Risk 60 34 14 86 48 24 20 30 Duration of Survival (months) I + Censored I 3 2 0 11 5 0 40 50 Fluoropyrimidine + Cisplatin --- Fluoropyrimidine + Cisplatin + Trastuzumab Figure 7 Updated Overall Survival in Patients with Metastatic Gastric Cancer (ToGA) An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression (IHC) testing is summarized in Table 14. Table 14 Exploratory Analyses by HER2 Status Using Updated Overall survival Results FC (N = 296)a FC + H (N = 298)b FISH+ / IHC 0, 1+ subgroup (N = 133) No. Deaths (%) / n (%) 57/71 (80%) 56/62 (90%) Median OS Duration (mos.) 8.8 8.3 95% CI (mos.) (6.4, 11.7) (6.2, 10.7) Hazard Ratio (95% CI) 1.33 (0.92, 1.92) FISH+ / IHC2+ subgroup (N = 160) No. Deaths (%) / n (%) 65/80 (81%) 64/80 (80%) Median OS Duration (mos.) 10.8 12.3 95% CI (mos.) (6.8, 12.8) (9.5, 15.7) Hazard Ratio (95% CI) 0.78 (0.55, 1.10) FISH+ or FISH-/ IHC3+c subgroup (N = 294) Reference ID: 5478075 39 No. Deaths (%) / n (%) 104/143 (73%) 96/151 (64%) Median OS Duration (mos.) 13.2 18.0 95% CI (mos.) (11.5, 15.2) (15.5, 21.2) Hazard Ratio (95% CI) 0.66 (0.50, 0.87) a Two patients on the FC arm who were FISH+ but IHC status unknown were excluded from the exploratory subgroup analyses. b Five patients on the trastuzumab-containing arm who were FISH+, but IHC status unknown were excluded from the exploratory subgroup analyses. c Includes 6 patients on chemotherapy arm, 10 patients on trastuzumab arm with FISH–, IHC3+ and 8 patients on chemotherapy arm, 8 patients on trastuzumab arm with FISH status unknown, IHC 3+. 16 HOW SUPPLIED/STORAGE AND HANDLING Ogivri (trastuzumab-dkst) for injection 420 mg/vial is supplied in a multiple-dose vial as an off- white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial of Ogivri and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative. NDC 83257-004-12 Ogivri (trastuzumab-dkst) for injection 420 mg/vial is supplied in a multiple-dose vial as an off- white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial of Ogivri. No diluent is provided. NDC 83257-003-01 Ogivri (trastuzumab-dkst) for injection 150 mg/vial is supplied in a single-dose vial as an off- white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one single- dose vial of Ogivri. NDC 83257-001-11 Store Ogivri vials in the refrigerator at 2° to 8°C (36° to 46°F) until time of reconstitution. 17 PATIENT COUNSELING INFORMATION Cardiomyopathy • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential that Ogivri exposure during pregnancy or within 7 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Reference ID: 5478075 40 <$ Biocon Biologics™ • Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Ogivri [see Use in Specific Populations (8.3)]. Ogivri® is a registered trademark of Biosimilars New Co. Ltd.; a Biocon Biologics Company. Copyright © 2023 Biocon Biologics Inc. All rights reserved. Manufactured by and for: Biocon Biologics Inc. 245 Main st, 2nd floor Cambridge, MA 02142, U.S.A. U.S Licence No. 2324 KR/DRUGS/KTK/28D/07/2006 Reference ID: 5478075 41	custom-source	2025-02-12T15:46:37.685342	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761074s030lbl.pdf', 'application_number': 761074, 'submission_type': 'SUPPL ', 'submission_number': 30}
80,212	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SUNLENCA safely and effectively. See full prescribing information for SUNLENCA. SUNLENCA® (lenacapavir) tablets, for oral use SUNLENCA® (lenacapavir) injection, for subcutaneous use Initial U.S. Approval: 2022 ----------------------------RECENT MAJOR CHANGES------------------------- Dosage and Administration (2.3) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- SUNLENCA, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. (1) ------------------------DOSAGE AND ADMINISTRATION---------------------- • Recommended dosage – Initiation with one of two options followed by once every 6-months maintenance dosing. Tablets may be taken without regard to food. (2.1) Initiation Option 1 Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Initiation Option 2 Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Day 8 300 mg orally (1 x 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections) Maintenance 927 mg by subcutaneous injection (2 x 1.5 mL injections) every 6 months (26 weeks) from the date of the last injection +/-2 weeks. • Missed dose: If more than 28 weeks since last injection and clinically appropriate to continue SUNLENCA, restart initiation from Day 1, using either Option 1 or Option 2. (2.2) • Two 1.5 mL subcutaneous injections are required for complete dose. (2.3) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 300 mg Injection: 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials. (3) -------------------------------CONTRAINDICATIONS------------------------------ Concomitant administration of SUNLENCA is contraindicated with strong CYP3A inducers. (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.1) Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance. (5.2) May increase exposure and risk of adverse reactions to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA. (5.2) If discontinued, initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs, switch to an alternative regimen if possible. (5.2) Injection site reactions may occur, and nodules and indurations may be persistent. (5.3) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ • Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Missed Dose 2.3 Preparation and Administration of Subcutaneous Injection 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune Reconstitution Syndrome 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA 5.3 Injection Site Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on SUNLENCA 7.2 Effect of SUNLENCA on Other Drugs 7.3 Established and Other Potentially Significant Drug Interactions 7.4 Drugs without Clinically Significant Interactions with SUNLENCA 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5478130 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE SUNLENCA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage SUNLENCA can be initiated using one of two recommended dosage regimens, see Table 1 and Table 2 below. Healthcare providers should determine the appropriate initiation regimen for the patient [see Clinical Pharmacology (12.3)]. SUNLENCA oral tablets may be taken with or without food. Table 1 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 1 Treatment Time Dosage of SUNLENCA: Initiation Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) a +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) a. From the date of the last injection. Reference ID: 5478130 2 Table 2 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 2 Treatment Time Dosage of SUNLENCA: Initiation Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Day 8 300 mg orally (1 x 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) a +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) a. From the date of the last injection. 2.2 Missed Dose During the maintenance period, if more than 28 weeks have elapsed since the last injection and if clinically appropriate to continue SUNLENCA treatment, restart the initiation dosage regimen from Day 1, using either Option 1 or Option 2 [see Dosage and Administration (2.1)]. 2.3 Preparation and Administration of Subcutaneous Injection SUNLENCA injection is for administration into the abdomen by a healthcare provider. Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. SUNLENCA injection is a yellow solution. Do not use SUNLENCA injection if the solution is discolored or if it contains particulate matter. Once the solution is withdrawn from the vials, the subcutaneous injections should be administered as soon as possible [see How Supplied/Storage and Handling (16)]. There are two available injection kits, which differ only in how SUNLENCA injection is prepared (the components and associated method for withdrawal of the solution from the vials) [see How Supplied/Storage and Handling (16)]. Refer to the figures below for the relevant injection kit. The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose. Reference ID: 5478130 3 VIAL x2 VIAL ACCESS DEVICE x2 SYRINGE x2 NOTE: all components are for single use Prepare Vial Prepare Vial Access Device Make sure that: • Vial and prepared syringe contain a yellow solution with no particles • Contents are not damaged • Product is not expired Attach 22G Injection Needle to Syringe, Expel Air Bubbles, and Prime to 1.5 ml Clean an Injection Site on Patient's Abdomen e = Injection site options (at least 2 inches from navel) Push down Inject 1.5 ml ofSunlenca Subcutaneously Insert fully 22G, ½inch INJECTION NEEDLE x2 Attach and Fill Syringe Flip upside down and withdraw all contents Administer 2nd Injection Vial access device injection kit Figure 1 identifies the components for use in the administration steps for the vial access device injection kit, and the administration steps are provided in Figure 2. Use of a vial access device is required in this kit. Figure 1 SUNLENCA Vial Access Device Injection Kit Components Figure 2 SUNLENCA Injection Steps for Vial Access Device Injection Kit Withdrawal needle injection kit Figure 3 identifies the components for use in the administration steps for the withdrawal needle injection kit, and the administration steps are provided in Figure 4. The 18-gauge needle is for withdrawal only in this kit. Reference ID: 5478130 4 VIAL x2 tj SYRINGE ; 18G, 1½inch 1 U x 2 WITHDRAWAL NEEDLE x2 NOTE: all components are for single use. Fill Syringe 22G, ½ inch INJECTION NEEDLE x2 Make sure that: Attach 18G Withdrawal Needle to Syringe Earr---.----._ ----- Remove18G Withdrawal Needle from Syringe • Vial and prepared syringe contain a yellow solution with no particles • Contents are not damaged • Product is not expired Attach 22G Injection Needle to Syringe, Expel Air Bubbles, and Prime to 1 .5 ml Clean an Injection Site on Patient's Abdomen e = Injection site options (at least 2 inches from navel) Inject 1 .5 ml ofSunlenca Subcutaneously Administer 2nd Injection Figure 3 SUNLENCA Withdrawal Needle Injection Kit Components Figure 4 SUNLENCA Injection Steps for Withdrawal Needle Injection Kit 3 DOSAGE FORMS AND STRENGTHS SUNLENCA tablets: Each tablet contains 300 mg of lenacapavir (present as 306.8 mg of lenacapavir sodium). The tablets are beige, capsule-shaped, film-coated, and debossed with ‘GSI’ on one side of the tablet and ‘62L’ on the other side of the tablet. SUNLENCA injection: Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium). The lenacapavir injectable solution is sterile, preservative-free, clear, and yellow with no visible particles. Reference ID: 5478130 5 4 CONTRAINDICATIONS Concomitant administration of SUNLENCA with strong CYP3A inducers is contraindicated due to decreased lenacapavir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to SUNLENCA [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA Residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer after the last subcutaneous dose). It is important to counsel patients that maintenance dosing by injection is required every 6 months, because missed doses or non-adherence to injections could lead to loss of virologic response and development of resistance [see Dosage and Administration (2.1)]. Lenacapavir, a moderate CYP3A inhibitor, may increase the exposure to, and therefore potential risk of adverse reactions from, drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA [see Drug Interactions and Clinical Pharmacology (7.2, 12.3)]. If SUNLENCA is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible [see Dosage and Administration (2.2)]. Reference ID: 5478130 6 5.3 Injection Site Reactions Administration of SUNLENCA may result in local injection site reactions (ISRs). If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow up. Manifestations of ISRs may include swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass. Nodules and indurations at the injection site may take longer to resolve than other ISRs. In clinical studies, after a median follow-up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of subjects, respectively) associated with the first injections of SUNLENCA had not fully resolved. Measurements and qualitative assessments of ISRs were not routinely reported. Where described, the majority of the injection site nodules and indurations were palpable but not visible, and had a maximum size of approximately 1 to 4 cm [see Adverse Reactions (6.1)]. The mechanism driving the persistence of injection site nodules and indurations in some patients is not fully understood, but based on available data, they may be related to the presence of the subcutaneous drug depot. In some patients who had a skin biopsy performed of an injection site nodule or induration, dermatopathology revealed foreign body inflammation or granulomatous response. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Immune Reconstitution Syndrome [see Warnings and Precautions (5.1)] • Injection Site Reactions [see Warnings and Precautions (5.3)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The primary safety assessment of SUNLENCA was based on data from heavily treatment-experienced adult subjects with HIV who received SUNLENCA in a Phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks) [see Clinical Studies (14)], as well as supportive data in treatment-naïve adult subjects with HIV who received SUNLENCA in a Phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks). The most common adverse reactions (all Grades) reported in at least 3% of subjects in CAPELLA were nausea and injection site reactions. The proportion of subjects in CAPELLA who discontinued treatment with SUNLENCA due to adverse events, regardless of severity, was 1% (Grade 1 injection site nodule in 1 subject). Table 3 displays the frequency of adverse reactions (all Grades) greater than or equal to 3% in the SUNLENCA group. Reference ID: 5478130 7 Table 3 Adverse Reactions (All Grades) Reported in ≥ 3% a of Heavily Treatment Experienced Adults with HIV-1 Receiving SUNLENCA in CAPELLA (Week 52 Analysis) SUNLENCA + Background Regimen Adverse Reactions (N=72) Injection Site Reactions 65% Nausea 4% a. Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all subjects (cohorts 1 and 2) in CAPELLA. The majority (96%) of all adverse reactions associated with SUNLENCA were mild or moderate in severity. Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs): The most frequent adverse reactions were ISRs. Of the 72 subjects in CAPELLA, 65% had experienced an ISR attributed to study drug through at least the Week 52 visit. Most subjects had mild (Grade 1, 44%) or moderate (Grade 2, 17%) ISRs. Four percent of subjects experienced a severe (Grade 3) ISR (erythema, pain, swelling) that resolved within 15 days. The ISRs reported in more than 1% of subjects were swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%) and mass (3%). ISRs reported in 1% of subjects included discomfort, hematoma, edema, and ulcer. Nodules and indurations at the injection site took longer to resolve than other ISRs. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days (range: 1 to 183). The median time to resolution of nodules and indurations associated with the first injections of SUNLENCA was 148 (range: 41 to 727) and 70 (range: 3 to 252) days, respectively. After a median follow up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of subjects, respectively) associated with the first injections of SUNLENCA had not fully resolved. Qualitative descriptions of injection site nodules and indurations were not routinely reported, but, where reported, the majority of injection site nodules and indurations were palpable but not visible. Measurements of injection site nodules and indurations were not routinely performed or standardized, but where measurements were reported, the maximum size for the majority of injection site nodules and indurations was approximately 1 to 4 cm [see Warnings and Precautions (5.3)]. Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3 to 4) occurring in at least 2% of subjects in CAPELLA are presented in Table 4. A causal association between SUNLENCA and these laboratory abnormalities has not been established. Reference ID: 5478130 8 Table 4 Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥ 2% of Subjects Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Laboratory Parameter Abnormality SUNLENCA + Background Regimen (N=72) a Creatinine ( >1.8 x ULN or ≥1.5 x baseline) 13% Glycosuria (>2+) b 6% Hyperglycemia (fasting) (>250 mg/dL) 5% Proteinuria (>2+) b 4% ALT (≥5 x ULN) b 3% AST (≥5 x ULN) 3% Direct Bilirubin (>ULN) b 3% ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN = upper limit of normal a. Frequencies are based on treatment-emergent laboratory abnormalities in all subjects (cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of subjects with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except hyperglycemia fasting n=57). b. Grade 3 only (no Grade 4 values reported). 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on SUNLENCA Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A. Strong or Moderate CYP3A Inducers Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of lenacapavir [see Clinical Pharmacology (12.3)], which may result in loss of therapeutic effect of SUNLENCA and development of resistance. Concomitant administration of SUNLENCA with strong CYP3A inducers during SUNLENCA treatment is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with moderate CYP3A inducers during SUNLENCA treatment is not recommended. Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of SUNLENCA. Concomitant administration of SUNLENCA with these inhibitors is not recommended. Reference ID: 5478130 9 7.2 Effect of SUNLENCA on Other Drugs Lenacapavir is a moderate inhibitor of CYP3A. Due to the long half-life of lenacapavir following subcutaneous administration, SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A [see Clinical Pharmacology (12.3)] initiated within 9 months after the last subcutaneous dose of SUNLENCA, which may increase the potential risk of adverse reactions. See the prescribing information of the sensitive CYP3A substrate for dosing recommendations with moderate inhibitors of CYP3A. 7.3 Established and Other Potentially Significant Drug Interactions Table 5 provides a listing of clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with SUNLENCA or are drug interactions that may occur with SUNLENCA [see Contraindications (4) and Clinical Pharmacology (12.3)]. Table 5 Drug Interactions with SUNLENCA Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Antiarrhythmics: digoxin ↑ digoxin Use with caution and monitor digoxin therapeutic concentration. Anticoagulants: Direct Oral Anticoagulants (DOACs) rivaroxaban dabigatran edoxaban ↑ DOAC Refer to the DOAC prescribing information for concomitant administration with combined moderate CYP3A and P-gp inhibitors. Anticonvulsants: ↓ lenacapavir Concomitant administration of carbamazepine carbamazepine, oxcarbazepine, oxcarbazepine phenobarbital, or phenytoin may result in phenobarbital loss of therapeutic effect and development phenytoin of resistance. Concomitant administration of SUNLENCA with carbamazepine or phenytoin is contraindicated. Concomitant administration of SUNLENCA with oxcarbazepine or phenobarbital is not recommended. Consider use of alternative anticonvulsants. Antiretroviral Agents: atazanavir/cobicistat b atazanavir/ritonavir efavirenz b nevirapine tipranavir/ritonavir ↑ lenacapavir (atazanavir/cobicistat, atazanavir/ritonavir) ↓ lenacapavir (efavirenz, nevirapine, tipranavir/ritonavir) Concomitant administration of efavirenz, nevirapine, or tipranavir/ritonavir may result in loss of therapeutic effect and development of resistance. Concomitant administration with atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, or tipranavir/ritonavir is not recommended. Reference ID: 5478130 10 Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Antimycobacterials: ↓ lenacapavir Concomitant administration of rifabutin, rifabutin rifampin and rifapentine may result in loss rifampin b of therapeutic effect and development of rifapentine resistance. Concomitant administration of SUNLENCA with rifampin is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with rifabutin or rifapentine is not recommended. Corticosteroids (systemic): ↑ corticosteroids Concomitant administration with Dexamethasone (systemic) corticosteroids whose exposures are Hydrocortisone/cortisone significantly increased by CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Initiate with the lowest starting dose and titrate carefully while monitoring for safety. Ergot derivatives: dihydroergotamine ergotamine methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Concomitant administration of SUNLENCA with dihydroergotamine, ergotamine or methylergonovine is not recommended. Herbal Products: ↓ lenacapavir Concomitant administration of St. John’s St. John’s wort c wort may result in loss of therapeutic effect (Hypericum perforatum) and development of resistance. Concomitant administration of SUNLENCA with St. John’s wort is contraindicated. HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g., myopathy). Narcotic analgesics ↑ fentanyl Careful monitoring of therapeutic effects metabolized by CYP3A: e.g., fentanyl, oxycodone ↑ oxycodone and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co- administration. tramadol ↑ tramadol A decrease in dose may be needed for tramadol with concomitant use. Narcotic analgesic for buprenorphine: Initiation of buprenorphine or methadone in treatment of opioid effects unknown patients taking SUNLENCA: Carefully titrate dependence: the dose of buprenorphine or methadone to buprenorphine, methadone methadone: effects unknown the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SUNLENCA in patients taking buprenorphine or methadone: A dose adjustment for buprenorphine or methadone may be needed. Monitor clinical signs and symptoms. Reference ID: 5478130 11 Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Opioid Antagonist: naloxegol ↑ naloxegol Avoid use with SUNLENCA; if unavoidable, decrease the dosage of naloxegol and monitor for adverse reactions. Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil ↑ PDE-5 inhibitors Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Concomitant administration of SUNLENCA with tadalafil for the treatment of PAH is not recommended. Use of PDE-5 inhibitors for erectile dysfunction (ED): Refer to the prescribing information of PDE 5 inhibitors for dose recommendations. Sedatives/Hypnotics: midazolam (oral) b triazolam ↑ midazolam (oral) ↑ triazolam Use with caution when midazolam or triazolam is concomitantly administered with SUNLENCA a. ↑ = Increase, ↓ = Decrease. b. Drug-drug interaction study was conducted. c. The induction potency of St. John’s wort may vary widely based on preparation. 7.4 Drugs without Clinically Significant Interactions with SUNLENCA Based on drug interaction studies conducted with SUNLENCA, no clinically significant drug interactions have been observed with: darunavir/cobicistat, cobicistat, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SUNLENCA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258 4263. Risk Summary There are insufficient human data on the use of SUNLENCA during pregnancy to inform a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA (see Data). Reference ID: 5478130 12 The background risk of major birth defects and miscarriage for the indicated population is unknown. The background rate of major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. Data Animal Data Lenacapavir was administered intravenously to pregnant rabbits (up to 20 mg/kg/day on gestation days (GD) 7 to 19), orally to rats (up to 300 mg/kg/day on GD 6 to 17), and subcutaneously to rats (up to 300 mg/kg on GD 6). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at exposures (AUC) approximately 16 times (rats) and 39 times (rabbits) the exposure in humans at the RHD of SUNLENCA. 8.2 Lactation Risk Summary It is not known whether SUNLENCA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. After administration to pregnant rats, lenacapavir was detected in the plasma of nursing rat pups, without effects on these nursing pups (see Data). Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults. Data Animal Data Lenacapavir was detected at low levels in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10). 8.4 Pediatric Use The safety and effectiveness of SUNLENCA have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SUNLENCA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Reference ID: 5478130 13 8.6 Renal Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). SUNLENCA has not been studied in patients with ESRD (estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild (Child- Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUNLENCA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No data are available on overdose of SUNLENCA in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with SUNLENCA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis. 11 DESCRIPTION SUNLENCA tablets and SUNLENCA injection contain lenacapavir sodium, a capsid inhibitor. The chemical name of lenacapavir sodium is: Sodium (4-chloro-7-(2-((S)-1-(2 ((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6 (3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol 3-yl)(methylsulfonyl)amide. Lenacapavir sodium has a molecular formula of C39H31ClF10N7NaO5S2, a molecular weight of 990.3, and the following structural formula: N S Me H N N N N Cl CF3 O S Me N F F Na+ O O O O N F F F3C Lenacapavir sodium is a light yellow to yellow solid and is practically insoluble in water. Reference ID: 5478130 14 SUNLENCA tablets are for oral administration. Each film-coated tablet contains 300 mg of lenacapavir (present as 306.8 mg lenacapavir sodium) and the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection is for subcutaneous administration. Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium) as a sterile, preservative-free, clear, yellow solution and the following inactive ingredients: 896.3 mg of polyethylene glycol 300 (as solvent) and water for injection. The apparent pH range of the injection is 9.0-10.2. The vial stoppers are not made with natural rubber latex. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SUNLENCA is an HIV-1 antiretroviral agent [see Microbiology (12.4)]. 12.2 Pharmacodynamics Exposure-Response In CAPELLA, oral loading doses (600 mg on Day 1 and Day 2, 300 mg on Day 8) followed by subcutaneous doses (927 mg every 6 months starting on Day 15) of SUNLENCA in heavily treatment-experienced subjects with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of subjects with HIV-1 RNA less than 50 copies/mL at Week 26) were similar across the range of observed lenacapavir exposures. Cardiac Electrophysiology At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of SUNLENCA), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent. 12.3 Pharmacokinetics The pharmacokinetic (PK) properties of lenacapavir are provided in Table 6 and Table 7. The estimated lenacapavir exposures are comparable between the two recommended dosing regimens. Reference ID: 5478130 15 Table 6 Pharmacokinetic Properties of Lenacapavir Oral Subcutaneous Absorption % Absolute bioavailability 6 to 10 100 a b Tmax 4 hours 77 to 84 days c Effect of Food Effect of low- fat meal (relative to fasting) d AUCinf ratio 98.6 (58.2,167.2) - Cmax ratio 115.8 (55.4, 242.1) - Effect of high- fat meal (relative to fasting) e AUCinf ratio 115.2 (72.0, 184.5) - Cmax ratio 145.2 (77.9, 270.5) - Distribution Apparent volume of distribution (Vd/F, L) 19240 9500 to 11700 % bound to human plasma proteins >98.5 Blood-to-plasma ratio 0.5 to 0.7 f Elimination t1/2 10 to 12 days 8 to 12 weeks Clearance (mean apparent clearance, L/h) 55 4.2 % of dose of unchanged drug in plasma g 69 Metabolism Metabolic pathway(s) CYP3A (minor) UGT1A1 (minor) Excretion Major routes of elimination Excretion of unchanged drug into feces h % of dose excreted in urine g <1 % of dose excreted in feces (% unchanged) h 76 (33) a. Values reflect absolute bioavailability following subcutaneous administration of the 927 mg dose. b. Values reflect administration of lenacapavir with or without food. c. Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex. d. Values refer to geometric mean ratio [low-fat meal/fasting] in PK parameters and (90% confidence interval). Low fat meal is approximately 400 kcal, 25% fat. e. Values refer to geometric mean ratio [high-fat meal/fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 1000 kcal, 50% fat. f. Values reflect the blood-to-plasma ratio of lenacapavir following a single dose intravenous administration of [14C] lenacapavir through 336 hours postdose. g. Dosing in mass balance studies: single dose intravenous administration of [14C] lenacapair to subjects without HIV-1 infection. Reference ID: 5478130 16 h. Metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A and UGT1A1 and no single circulating metabolite accounted for >10% of plasma drug-related exposure. Table 7 Lenacapavir Exposures Following Oral and Subcutaneous Administration of SUNLENCA in Heavily Treatment Experienced Subjects with HIV Parameter Mean (%CV) Recommended Dosing Regimen, Option 1 a Recommended Dosing Regimen, Option 2 b Day 1: 600 mg (oral) + 927 mg (SC) Day 2: 600 mg (oral) Days 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC) Day 1 to end of Month 6 Days 1 to 15 Day 15 to end of Month 6 Cmax (ng/mL) 97.1 (61.6) 124.4 (85.1) 87.3 (49.4) AUCtau (h•ng/mL) 234294.8 (65.1) 25962.9 (67.8) 251907.2 (48.2) Ctrough (ng/mL) 29.2 (90.8) 48.6 (52.1) 35.1 (59.2) CV = coefficient of variation; NA = not applicable; SC = subcutaneous a. Predicted exposures. b. Post hoc exposures from CAPELLA (N=62). The estimated exposures of lenacapavir were 43% to 100% higher in subjects with HIV-1 infection compared to subjects without HIV-1 infection. Specific Populations There were no clinically significant differences in the pharmacokinetics of lenacapavir based on age (18 to 78 years), sex, ethnicity (hispanic or non-hispanic), race (white, black, asian or other), body weight (41.4 to 164 kg), severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir [see Use in Specific Populations (8.6)]. Drug Interaction Studies Clinical Studies Clinical drug-drug interaction study indicated that lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1. Table 8 summarizes the pharmacokinetic effects of other drugs on lenacapavir. 17 Reference ID: 5478130 Lenacapavir is a moderate inhibitor of CYP3A. Lenacapavir is an inhibitor of P-gp and BCRP but does not inhibit OATP. Table 9 summarizes the pharmacokinetic effects of lenacapavir on other drugs. Table 8 Effect of Other Drugs on Lenacapavir a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Ratio of Lenacapavir Pharmacokinetic Parameters (90% CI); No effect = 1.00 Cmax AUC Cobicistat (fed) (Inhibitor of CYP3A [strong] and P-gp) 150 once daily 2.10 (1.62, 2.72) 2.28 (1.75, 2.96) Darunavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and inhibitor and inducer of P-gp) 800/150 once daily 2.30 (1.79, 2.95) 1.94 (1.50, 2.52) Voriconazole (fasted) (Inhibitor of CYP3A [strong]) 400 twice daily, 200 twice daily c 1.09 (0.81, 1.47) 1.41 (1.10, 1.81) Atazanavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and UGT1A1 and P-gp) 300/150 once daily 6.60 (4.99, 8.73) 4.21 (3.19, 5.57) Rifampin (fasted) (Inducer of CYP3A [strong] and P-gp and UGT) 600 once daily 0.45 (0.34, 0.60) 0.16 (0.12, 0.20) Efavirenz (fasted) (Inducer of CYP3A [moderate] and P-gp) 600 once daily 0.64 (0.45, 0.92) 0.44 (0.32, 0.59) Famotidine (2 hours before, fasted) 40 once daily 1.01 (0.75, 1.34) 1.28 (1.00, 1.63) a. Single dose of lenacapavir 300 mg administered orally. b. All interaction studies conducted in subjects without HIV-1. c. 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily. Reference ID: 5478130 18 Table 9 Effect of Lenacapavir on Other Drugs a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI) c; No effect = 1.00 Cmax AUC Tenofovir alafenamide (fed) (substrate of P-gp) 25 single dose 1.24 (0.98, 1.58) 1.32 (1.09, 1.59) Tenofovir d (substrate of P-gp) 1.23 (1.05, 1.44) 1.47 (1.27, 1.71) Pitavastatin (simultaneous administration, fed) (substrate of OATP) 2 single dose 1.00 (0.84, 1.19) 1.11 (1.00, 1.25) Pitavastatin (3 days after lenacapavir, fed) (substrate of OATP) 2 single dose 0.85 (0.69, 1.05) 0.96 (0.87, 1.07) Rosuvastatin (fed) (substrate of BCRP and OATP) 5 single dose 1.57 (1.38, 1.80) 1.31 (1.19, 1.43) Midazolam (simultaneous administration, fed) (substrate of CYP3A) 2.5 single dose 1.94 (1.81, 2.08) 3.59 (3.30, 3.91) 1-hydroxymidazolam e (substrate of CYP3A) 0.54 (0.50, 0.59) 0.76 (0.72, 0.80) Midazolam (1 day after lenacapavir, fed) (substrate of CYP3A) 2.5 single dose 2.16 (2.02, 2.30) 4.08 (3.77, 4.41) 1-hydroxymidazolam e (substrate of CYP3A) 0.52 (0.48, 0.57) 0.84 (0.80, 0.88) a. All interaction studies conducted in subjects without HIV-1. b. Following 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each coadministered drug, resulting in lenacapavir exposures similar to or higher than those at the recommended dosage regimen. c. All No Effect Boundaries are 70% to 143%. d. Tenofovir alafenamide is converted to tenofovir in vivo. e. Major active metabolite of midazolam. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Lenacapavir is not a substrate, inducer, or inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Lenacapavir is not an inducer of CYP3A4. Reference ID: 5478130 19 Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Lenacapavir is not an inhibitor of UGT1A1. Transporter Systems: Lenacapavir is not an inhibitor of organic anion transporter 1 (OAT1), OAT3, organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion transporter (MATE) 1, or MATE 2-K. Lenacapavir is not a substrate of BCRP, OATP1B1, or OATP1B3. 12.4 Microbiology Mechanism of Action Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids). Antiviral Activity in Cell Culture Lenacapavir has antiviral activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2). The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes with EC50 values ranging from 30 to 190 pM. Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G with EC50 values ranging from 20 and 160 pM. The median EC50 value for subtype B isolates (n=8) was 40 pM. Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1. In a study of lenacapavir in combination with representatives from the major classes of anti-retroviral agents (INSTIs, NNRTIs, NRTIs, and PIs), no antagonism of antiviral activity was observed. Resistance In Cell Culture HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. Resistance selections with lenacapavir identified 7 substitutions in capsid: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination that conferred 4 to >3,226-fold reduced phenotypic susceptibility to lenacapavir relative to wild-type (WT) virus. The M66I substitution alone or in combination conferred >3,226-fold decreased Reference ID: 5478130 20 susceptibility to lenacapavir in a single-cycle infectivity assay; substitutions Q67H and T107N, conferred 4- to 6.3-fold decreased susceptibility; K70N, N74D and Q67H/N74S conferred 22- to 32-fold decreased susceptibility; and L56I conferred 239-fold decreased susceptibility. In Clinical Trials In CAPELLA, 31% (22/72) of heavily treatment-experienced subjects met the criteria for resistance analyses through Week 52 (HIV-1 RNA ≥ 50 copies/mL at confirmed virologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit]) and were analyzed for lenacapavir resistance-associated substitution emergence. Lenacapavir resistance-associated capsid substitutions were found in 41% (n=9) of subjects with confirmed virologic failure who had post-baseline capsid genotypic resistance data (n=22). The M66I CA substitution was observed in 27% (6/22) of subjects, alone or in combination with other lenacapavir resistance-associated capsid substitutions including Q67Q/H, Q67Q/H/K/N, K70K/R, K70N/S, N74D, N74N/H, A105T, and T107A. The other 3 subjects with virologic failure had emergent lenacapavir resistance-associated capsid substitutions Q67K+K70H, Q67H+K70R+T107S, and Q67Q/H. Phenotypic analyses of the confirmed virologic failure isolates with emergent lenacapavir resistance-associated substitutions showed 6- to >1428-fold decreases in lenacapavir susceptibility when compared to WT. Among the 9 subjects with virologic failure who developed lenacapavir resistance- associated substitutions in capsid, 4 received SUNLENCA in combination with a background regimen with no fully active antiretrovirals based on the baseline genotypic and/or phenotypic resistance. Therefore, given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to SUNLENCA in the treatment regimen. Four subjects with virologic failure had emergent resistance substitutions to components of the optimized background regimen (OBR): emergent NRTI substitution M184I/V and NNRTI substitution K103N/Y with emtricitabine and doravirine plus atazanavir, bictegravir, and tenofovir alafenamide in OBR; emergent NNRTI substitution V106M from a mixture at baseline (in addition to lenacapavir resistance-associated substitutions M66I + T107A) with doravirine plus emtricitabine and ibalizumab in OBR; emergent NRTI substitutions K65R and S68N from mixtures at baseline (in addition to lenacapavir resistance-associated substitution M66I) with tenofovir alafenamide, plus emtricitabine, dolutegravir, darunavir/cobicistat, and rilpivirine in OBR; and emergent NRTI substitution K65K/R with tenofovir disoproxil fumarate plus darunavir/cobicistat, dolutegravir, and emtricitabine in OBR. Cross-Resistance The antiviral activity in cell culture of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the four main classes of anti-retroviral agents (INSTI, NNRTI, NRTI, and PI; n=58), as well as to viruses resistant to the gp120-directed attachment inhibitor Reference ID: 5478130 21 fostemsavir, the CD4+-directed post-attachment inhibitor ibalizumab, the CCR5 co- receptor antagonist maraviroc, and the gp41 fusion inhibitor enfuvirtide (n=42). These data indicated that lenacapavir remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms and substitutions at protease cleavage sites. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study in males or females at doses of up to 300 mg/kg/dose once every 13 weeks. A 104-week carcinogenicity study was conducted in male and female rats at lenacapavir doses of 0, 102, 309, or 927 mg/kg by subcutaneous injection once every 13-weeks. A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg). This dose in rats resulted in an exposure approximately 34-times the human exposure at the RHD, based on AUC. These tumors are considered to be a secondary response to chronic tissue irritation and granulomatous inflammation, due to the depot effect of lenacapavir following subcutaneous injection. The clinical relevance of these findings are unknown. Mutagenesis Lenacapavir was not mutagenic in a battery of in vitro and in vivo genotoxicity assays, including microbial mutagenesis, chromosome aberration in human peripheral blood lymphocytes, and in in vivo rat micronucleus assays. Impairment of Fertility There were no effects on fertility, mating performance or early embryonic development when lenacapavir was administered to rats at systemic exposures (AUC) 5 times the exposure to humans at the RHD of SUNLENCA. 14 CLINICAL STUDIES The efficacy and safety of SUNLENCA in HIV-1 infected, heavily treatment-experienced subjects with multidrug resistance is based on 52-week data from CAPELLA, a randomized, placebo-controlled, double-blind, multicenter trial (NCT 04150068). CAPELLA was conducted in 72 heavily treatment-experienced subjects with multiclass resistant HIV-1. Subjects were required to have a viral load ≥ 400 copies/mL, documented resistance to at least two antiretroviral medications from each of at least Reference ID: 5478130 22 3 of the 4 classes of antiretroviral medications (NRTI, NNRTI, PI and INSTI), and ≤ 2 fully active antiretroviral medications from the 4 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, drug access, contraindication, or other safety concerns. The trial was composed of two cohorts. Subjects were enrolled into the randomized cohort (cohort 1, N=36) if they had a < 0.5 log10 HIV-1 RNA decline compared to the screening visit. Subjects were enrolled into the non-randomized cohort (cohort 2, N=36) if they had a ≥ 0.5 log10 HIV-1 RNA decline compared to the screening visit or after cohort 1 reached its planned sample size. In the 14-day functional monotherapy period, subjects in cohort 1 were randomized in a 2:1 ratio in a blinded fashion to receive either SUNLENCA or placebo, while continuing their failing regimen. This period was to establish the virologic activity of SUNLENCA. After the functional monotherapy period, subjects who had received SUNLENCA continued on SUNLENCA along with an optimized background regimen (OBR); subjects who had received placebo during this period initiated SUNLENCA along with an OBR. Subjects in cohort 1 had a mean age of 52 years (range: 24 to 71), 72% were male, 46% were White, 46% were Black, and 9% were Asian. 29% percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 2.3 to 5.4). 19% of subjects had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4+ cell count was 161 cells/mm3 (range: 6 to 827). 75% of subjects had CD4+ cell counts below 200 cells/mm3. The mean number of years since subjects first started HIV treatment was 24 years (range: 7 to 33); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 1 to 7). The percentage of subjects in the randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 97%, 94%, 78% and 75%, respectively. In cohort 1, 53% of subjects had no fully active agents, 31% had 1 fully active agent, and 17% had 2 or more fully active agents within their initial failing regimen, including 6% of subjects were who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial. Subjects in cohort 2 initiated SUNLENCA and an OBR on Day 1. Subjects in cohort 2 had a mean age of 48 years (range: 23 to 78), 78% were male, 36% were White, 31% were Black, 33% were Asian, and 14% of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 1.3 to 5.7). 19% of subjects had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4+ cell count was 258 cells/mm3 (range: 3 to 1296). 53% of subjects had CD4+ cell counts below 200 cells/mm3. The mean number of years since subjects first started HIV treatment was 19 years (range: 3 to 35); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 2 to 7). The percentage of subjects in the non-randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 100%, 100%, 83% and 64%, respectively. In cohort 2, 31% of subjects had no fully active agents, 42% had 1 fully active agent, and 28% had 2 or more fully active agents within their initial failing Reference ID: 5478130 23 regimen, including 6% of subjects who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial. The primary efficacy endpoint was the proportion of subjects in cohort 1 achieving ≥ 0.5 log10 copies/mL reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period. The results of the primary endpoint analysis are shown in Table 10. Table 10 Proportion of Subjects Achieving a ≥ 0.5 log10 Decrease in Viral Load at the End of the Functional Monotherapy Period in the CAPELLA Trial (Cohort 1) SUNLENCA (N=24) Placebo (N=12) Proportion of Subjects Achieving a ≥ 0.5 log10 Decrease in Viral Load 87.5% 16.7% Treatment Difference (95% CI) 70.8% (34.9% to 90.0%) a a. p < 0.0001 The results at Weeks 26 and 52 are provided in Table 11 and Table 12. Table 11 Virologic Outcomes (HIV-1 RNA < 50 copies/mL) at Weeks 26 a and 52 b with SUNLENCA plus OBR in the CAPELLA Trial (Cohort 1) SUNLENCA plus OBR (N=36) Week 26 Week 52 HIV-1 RNA < 50 copies/mL 81% 83% HIV-1 RNA ≥ 50 copies/mLc 19% 14% No virologic data in Week 26 or 52 Window 0 3% Discontinued Study Drug Due to AE or Death d 0 0 Discontinued Study Drug Due to Other Reasons e and Last Available HIV-1 RNA < 50 copies/mL 0 3% Missing Data During Window but on Study Drug 0 0 OBR = optimized background regimen a. Week 26 window was between Days 184 and 232 (inclusive). b. Week 52 window was between Days 324 and 414 (inclusive). c. Includes subjects who had ≥ 50 copies/mL in the Week 26 or 52 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL. d. Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. Reference ID: 5478130 24 e. Includes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. Table 12 Virologic Outcomes (HIV-1 RNA < 50 copies/mL) by Baseline Covariates at Weeks 26 a and 52 b with SUNLENCA plus OBR in the CAPELLA trial (Cohort 1) SUNLENCA plus OBR (N=36) Week 26 Week 52 Age (Years) < 50 100% (9/9) 89% (8/9) ≥ 50 74% (20/27) 81% (22/27) Gender Male 77% (20/26) 77% (20/26) Female 90% (9/10) 100% (10/10) Race Black 81% (13/16) 75% (12/16) Non-Black 84% (16/19) 89% (17/19) Baseline plasma viral load (copies/mL) ≤ 100,000 86% (25/29) 86% (25/29) > 100,000 57% (4/7) 71% (5/7) Baseline CD4+ (cells/mm3) < 200 78% (21/27) 78% (21/27) ≥ 200 89% (8/9) 100% (9/9) Baseline INSTI resistance profile With INSTI resistance 85% (23/27) 81% (22/27) Without INSTI resistance 63% (5/8) 88% (7/8) Number of fully active ARV agents in the OBR 0 67% (4/6) 67% (4/6) 1 86% (12/14) 79% (11/14) ≥ 2 81% (13/16) 94% (15/16) Use of DTG and/or DRV in the OBR With DTG and DRV 83% (10/12) 83% (10/12) With DTG, without DRV 83% (5/6) 83% (5/6) Without DTG, with DRV 78% (7/9) 89% (8/9) Without DTG or DRV 78% (7/9) 78% (7/9) ARV = antiretroviral; DRV=darunavir; DTG=dolutegravir; INSTI = integrase strand-transfer inhibitor; OBR = optimized background regimen; a. Week 26 window was between Days 184 and 232 (inclusive). b. Week 52 window was between Days 324 and 414 (inclusive). Reference ID: 5478130 25 In cohort 1, at Weeks 26 and 52, the mean change from baseline in CD4+ cell count was 81 cells/mm3 (range: -101 to 522) and 82 cells/mm3 (range: -194 to 467), respectively. In cohort 2, at Week 26 and 52, 81% (29/36) and 72% (26/36) of patients achieved HIV 1 RNA < 50 copies/mL, respectively, and the mean change from baseline in CD4+ cell count was 97 cells/mm3 (range: -103 to 459) and 113 cells/mm3 (range: -124 to 405), respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING SUNLENCA tablets, 300 mg are beige, capsule-shaped, and film-coated with “GSI” debossed on one side and “62L” on the other side. SUNLENCA tablets are available in a bottle and blister packs, packaged as follows: Bottle • SUNLENCA bottle contains 4 tablets (NDC 61958-3001-3). The bottle also contains a silica gel desiccant and polyester coil, and is closed with a child-resistant closure. Do not remove the desiccant packet. Keep bottle tightly closed. Blister Packs • SUNLENCA 4-Tablets™ blister pack contains 4 tablets (NDC 61958-3001-1) • SUNLENCA 5-Tablets™ blister pack contains 5 tablets (NDC 61958-3001-2) Within the blister packs, tablets are packaged in a clear blister film sealed to a foil lidding material. The blister card is fitted between two paperboard cards, and packaged with silica gel desiccant in a sealed child-resistant flexible laminated pouch. Store bottle and blister packs at 20 °C – 25 °C (68 °F – 77 °F), excursions permitted to 15 °C – 30 °C (59 °F – 86 °F) (see USP Controlled Room Temperature). Dispense and store only in original bottle or blister pack. SUNLENCA injection is packaged in one of two different injection kits containing the following: Vial access device injection kit (NDC 61958-3002-1): • 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. • 2 vial access devices, 2 disposable syringes, and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). Reference ID: 5478130 26 Withdrawal needle injection kit (NDC 61958-3005-1): • 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. • 2 disposable syringes, 2 withdrawal needles (18-gauge, 1.5 inch), and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). The vial stoppers are not made with natural rubber latex. Store at 20 °C – 25 °C (68 °F – 77 °F), excursions permitted to 15 °C – 30 °C (59 °F – 86 °F). Keep the vials in the original carton until just prior to preparation of the injections in order to protect from light. Once the solution has been drawn into the syringes, the injections should be administered as soon as possible. Discard any unused portion of the solution. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions SUNLENCA may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products, including St. John’s wort, during treatment with SUNLENCA [see Contraindications (4) and Drug Interactions (7)]. If SUNLENCA is discontinued, advise patients that SUNLENCA may remain in the body and affect certain other drugs for up to 9 months after receiving their last injection [see Drug Interactions (7.2, 7.3)]. Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.1)]. Adherence to SUNLENCA Counsel patients about the importance of continued medication adherence and scheduled visits to maintain viral suppression and to reduce risk of loss of virologic response and development of resistance. Advise patients to contact their healthcare provider immediately if they stop taking SUNLENCA or any other drug in their Reference ID: 5478130 27 antiretroviral regimen [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)]. Injection Site Reactions Inform patients that injection site reactions (ISRs), such as swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass, may occur. Nodules and indurations at the injection site may take longer to resolve than other ISRs and may be persistent. Instruct patients when to contact their healthcare provider about these reactions [see Warnings and Precautions (5.3)]. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to SUNLENCA [see Use in Specific Populations (8.1)]. Lactation Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2024 Gilead Sciences, Inc. All rights reserved. Reference ID: 5478130 28 Patient Information SUNLENCA® (sun-LEN-kuh) SUNLENCA® (sun-LEN-kuh) (lenacapavir) (lenacapavir) tablets injection What is SUNLENCA? SUNLENCA is a prescription medicine that is used with other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in adults: • who have received HIV-1 medicines in the past, and • who have HIV-1 virus that is resistant to many HIV-1 medicines, and • whose current HIV-1 medicines are failing. Your HIV-1 medicines may be failing because the HIV-1 medicines are not working or no longer work, you are not able to tolerate the side effects, or there are safety reasons why you cannot take them. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if SUNLENCA is safe and effective in children. Do not receive or take SUNLENCA if you also take certain other medicines called strong CYP3A inducers. Ask your healthcare provider if you are not sure. Before receiving or taking SUNLENCA, tell your healthcare provider about all your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if SUNLENCA can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with SUNLENCA. Pregnancy Registry: There is a pregnancy registry for women who take SUNLENCA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry. • are breastfeeding or plan to breastfeed. It is not known whether SUNLENCA will pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with SUNLENCA: o The HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection. o The HIV-1 virus may become harder to treat if your baby has HIV-1 infection. o Your baby may get side effects from SUNLENCA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements, including St. John’s wort. Some medicines may interact with SUNLENCA. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with SUNLENCA. • Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take SUNLENCA with other medicines. • SUNLENCA may affect certain other medicines for up to 9 months after your last injection. How should I receive and take SUNLENCA? • Your SUNLENCA treatment will consist of injections and tablets. o SUNLENCA injections will be given to you by your healthcare provider under the skin (subcutaneous injection) in your stomach-area (abdomen). o Take SUNLENCA tablets by mouth, with or without food. • There are two options (Option 1 and Option 2) to start treatment with SUNLENCA. Your healthcare provider will decide which starting option is for you. o If Option 1 is chosen: • On Day 1, you will receive 2 SUNLENCA injections and take 2 SUNLENCA tablets. • On Day 2, you will take 2 SUNLENCA tablets. o If Option 2 is chosen: • On Day 1 and Day 2, you will take 2 SUNLENCA tablets each day. • On Day 8, you will take 1 SUNLENCA tablet. • On Day 15, you will receive 2 SUNLENCA injections. • After completing Option 1 or Option 2, you will receive 2 SUNLENCA injections every 6 months (26 weeks) from the date of your last injection. 1 Reference ID: 5478130 • Stay under the care of a healthcare provider during treatment with SUNLENCA. It is important that you attend your planned appointments to receive your injections of SUNLENCA. • If you miss your scheduled injection appointment, call your healthcare provider right away to discuss your treatment options. Missing an injection of SUNLENCA may cause the HIV-1 virus to change (mutate) and become harder to treat (resistant). • Tell your healthcare provider right away if you stop receiving SUNLENCA or stop taking any other antiretroviral medicines. If you stop treatment with SUNLENCA you will need other medicines to treat your HIV-1 infection. If you do not take other HIV-1 medicines, the amount of virus in your blood may increase and the virus may become harder to treat. Call your healthcare provider right away to discuss your treatment options. • If you take too many SUNLENCA tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of SUNLENCA? SUNLENCA may cause serious side effects, including: • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. • Injection site reactions may happen when you receive SUNLENCA injections and may include swelling, pain, redness, skin hardening, small mass or lump, and itching. Hardened skin or lumps at the injection site usually can be felt but not seen. If you develop hardened skin or a lump, it may take longer than other reactions at the injection site to go away, and the injection site may not completely heal on its own. Tell your healthcare provider if you have any injection site reactions. The most common side effects of SUNLENCA are nausea and injection site reactions. These are not all of the possible side effects of SUNLENCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store SUNLENCA tablets? • Store SUNLENCA tablets at room temperature between 68 °F to 77 °F (20 °C to 25 °C). • SUNLENCA bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not eat the desiccant packet. • Keep SUNLENCA tablets in their original bottle or blister pack. • Keep the bottle tightly closed. Keep SUNLENCA and all medicines out of reach of children. General information about the safe and effective use of SUNLENCA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SUNLENCA for a condition for which it was not prescribed. Do not give SUNLENCA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SUNLENCA that is written for health professionals. What are the ingredients in SUNLENCA? Active ingredient: lenacapavir Inactive ingredients: SUNLENCA tablets: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection: polyethylene glycol 300 and water for injection. Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2024 Gilead Sciences, Inc. All rights reserved. 215973-GS-003/IFU-001 For more information, call 1-800-445-3235 or go to www.SUNLENCA.com. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 2 Reference ID: 5478130	custom-source	2025-02-12T15:46:38.334215	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215974s009lbl.pdf', 'application_number': 215974, 'submission_type': 'SUPPL ', 'submission_number': 9}
80,213	1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VERZENIO safely and effectively. See full prescribing information for VERZENIO. VERZENIO® (abemaciclib) tablets, for oral use Initial U.S. Approval: 2017 ---------------------------- INDICATIONS AND USAGE -------------------------- VERZENIO® is a kinase inhibitor indicated: • in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. (1.1, 14.1) • in combination with an aromatase inhibitor as initial endocrine- based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. (1.2) • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. (1.2) • as monotherapy for the treatment of adult patients with HR- positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. (1.2) ------------------------DOSAGE AND ADMINISTRATION---------------------- VERZENIO tablets are taken orally with or without food. (2.1) • Recommended starting dose in combination with fulvestrant, tamoxifen, or an aromatase inhibitor: 150 mg twice daily. (2.1) • Recommended starting dose as monotherapy: 200 mg twice daily. (2.1) • Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. (2.2) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 50 mg, 100 mg, 150 mg, and 200 mg. (3) ------------------------------- CONTRAINDICATIONS ----------------------------- None. (4) ------------------------WARNINGS AND PRECAUTIONS ---------------------- • Diarrhea: VERZENIO can cause severe cases of diarrhea, associated with dehydration and infection. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. (2.2, 5.1) • Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. (2.2, 5.2) • Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis. (2.2, 5.3) • Hepatotoxicity: Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with VERZENIO. Monitor LFTs every two weeks for the first two months, monthly for the next 2 months, and as clinically indicated. (2.2, 5.4) • Venous Thromboembolism: Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. (2.2, 5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.6, 8.1, 8.3) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence ≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------- DRUG INTERACTIONS ----------------------------- • CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the VERZENIO dose with concomitant use of other strong and moderate CYP3A inhibitors. (2.2, 7.1) • CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. (7.1) ------------------------USE IN SPECIFIC POPULATIONS---------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Early Breast Cancer 1.2 Advanced or Metastatic Breast Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule 2.2 Dose Modification 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Diarrhea 5.2 Neutropenia 5.3 Interstitial Lung Disease (ILD) or Pneumonitis 5.4 Hepatotoxicity 5.5 Venous Thromboembolism 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on VERZENIO 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Early Breast Cancer 14.2 Advanced or Metastatic Breast Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING Reference ID: 5478239 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Early Breast Cancer VERZENIO® (abemaciclib) is indicated: • in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node- positive, early breast cancer at high risk of recurrence [see Clinical Studies (14.1)]. 1.2 Advanced or Metastatic Breast Cancer VERZENIO (abemaciclib) is indicated: • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule • When used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen, or aromatase inhibitor being used. • Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with a gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards. • Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with a GnRH according to current clinical practice standards • When used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily. • For early breast cancer, continue VERZENIO until completion of 2 years of treatment or until disease recurrence, or unacceptable toxicity. • For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity. VERZENIO may be taken with or without food [see Clinical Pharmacology (12.3)]. Instruct patients to take their doses of VERZENIO at approximately the same times every day. If the patient vomits or misses a dose of VERZENIO, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow VERZENIO tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest VERZENIO tablets if broken, cracked, or otherwise not intact. 2.2 Dose Modification Dose Modifications for Adverse Reactions The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1-7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily. Reference ID: 5478239 Table 1: VERZENIO Dose Modification — Adverse Reactions Dose Level VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor VERZENIO Dose for Monotherapy Recommended starting dose 150 mg twice daily 200 mg twice daily First dose reduction 100 mg twice daily 150 mg twice daily Second dose reduction 50 mg twice daily 100 mg twice daily Third dose reduction not applicable 50 mg twice daily Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicitiesa Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Grade 3 Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required. Grade 3 recurrent, or Grade 4 Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose. Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events. a If blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines. Table 3: VERZENIO Dose Modification and Management — Diarrhea At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids. CTCAE Grade VERZENIO Dose Modifications Grade 1 No dose modification is required. Grade 2 If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required. Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose. Grade 3 or 4 or requires hospitalization Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose. Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. CTCAE Grade for ALT and AST VERZENIO Dose Modifications Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN No dose modification is required. Persistent or Recurrent Grade 2, or Grade 3 (>5.0 20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose. Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis Discontinue VERZENIO. Reference ID: 5478239 Grade 4 (>20.0 x ULN) Discontinue VERZENIO. Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal. Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose. Grade 3 or 4 Discontinue VERZENIO. Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs) CTCAE Grade VERZENIO Dose Modifications Early Breast Cancer Any Grade Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable. Advanced or Metastatic Breast Cancer Grade 1 or 2 No dose modification is required. Grade 3 or 4 Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable. Table 7: VERZENIO Dose Modification and Management — Other Toxicitiesa CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose. Grade 3 or 4 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose. a Excluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs. Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information. Dose Modification for Use with Strong and Moderate CYP3A Inhibitors Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary. Dose Modification for Patients with Severe Hepatic Impairment Reference ID: 5478239 For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment. 3 DOSAGE FORMS AND STRENGTHS 50 mg tablets: oval beige tablet with “Lilly” debossed on one side and “50” on the other side. 100 mg tablets: oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side. 150 mg tablets: oval yellow tablet with “Lilly” debossed on one side and “150” on the other side. 200 mg tablets: oval beige tablet with “Lilly” debossed on one side and “200” on the other side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Diarrhea Severe diarrhea associated with dehydration and infection occurred in patients treated with VERZENIO. Across four clinical trials in 3691 patients, diarrhea occurred in 81% to 90% of patients who received VERZENIO. Grade 3 diarrhea occurred in 8% to 20% of patients receiving VERZENIO [see Adverse Reactions (6.1)]. Most patients experienced diarrhea during the first month of VERZENIO treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19% to 26% of patients with diarrhea required a VERZENIO dose interruption and 13% to 23% required a dose reduction. Instruct patients to start antidiarrheal therapy such as loperamide at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up [see Patient Counseling Information (17)]. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue VERZENIO until toxicity resolves to ≤Grade 1, and then resume VERZENIO at the next lower dose [see Dosage and Administration (2.2)]. 5.2 Neutropenia Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with VERZENIO. Across four clinical trials in 3691 patients, neutropenia occurred in a 37% to 46% of patients receiving VERZENIO. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19% to 32% of patients receiving VERZENIO. Across trials, the median time to the first episode of Grade ≥3 neutropenia ranged from 29 days to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 days to 16 days [see Adverse Reactions (6.1)]. Febrile neutropenia has been reported in <1% of patients exposed to VERZENIO across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider [see Patient Counseling Information (17)]. Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2)]. 5.3 Interstitial Lung Disease (ILD) or Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with VERZENIO and other CDK4/6 inhibitors. In VERZENIO-treated patients in early breast cancer (monarchE, N=2791), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In VERZENIO- treated patients in advanced or metastatic breast cancer (N=900) (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of VERZENIO-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Adverse Reactions (6.2)]. Reference ID: 5478239 6 Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis [see Dosage and Administration (2.2)]. 5.4 Hepatotoxicity Grade ≥3 ALT (2% to 6%) and AST (2% to 3%) were reported in patients receiving VERZENIO. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days. Monitor liver function tests (LFTs) prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or Grade 4 hepatic transaminase elevation [see Dosage and Administration (2.2)]. 5.5 Venous Thromboembolism Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), venous thromboembolic events were reported in 2% to 5% of patients treated with VERZENIO. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to venous thromboembolism have been reported in patients treated with VERZENIO. VERZENIO has not been studied in patients with early breast cancer who had a history of venous thromboembolism. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for early breast cancer patients with any grade venous thromboembolic event and for advanced or metastatic breast cancer patients with a Grade 3 or 4 venous thromboembolic event [see Dosage and Administration (2.2)]. 5.6 Embryo-Fetal Toxicity Based on findings from animal studies and the mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VERZENIO and for 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Diarrhea [see Warnings and Precautions (5.1)]. • Neutropenia [see Warnings and Precautions (5.2)]. • Interstitial Lung Disease (ILD) or Pneumonitis [see Warnings and Precautions (5.3)]. • Hepatotoxicity [see Warnings and Precautions (5.4)]. • Venous Thromboembolism [see Warnings and Precautions (5.5)]. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Reference ID: 5478239 The safety population described in the Warnings and Precautions reflect exposure to VERZENIO in 3691 patients from four clinical trials: monarchE, MONARCH 1, MONARCH 2, and MONARCH 3. The safety population includes exposure to VERZENIO as a single agent at 200 mg twice daily in 132 patients in MONARCH 1 and to VERZENIO at 150 mg twice daily in 3559 patients administered in combination with fulvestrant, tamoxifen, or an aromatase inhibitor in monarchE, MONARCH 2, and MONARCH 3. The median duration of exposure ranged from 4.5 months in MONARCH 1 to 24 months in monarchE. The most common adverse reactions (incidence ≥20%) across clinical trials were: diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia. Early Breast Cancer monarchE: VERZENIO in Combination with Tamoxifen or an Aromatase Inhibitor as Adjuvant Treatment Adult patients with HR-positive, HER2-negative, node-positive early breast cancer at a high risk of recurrence The safety of VERZENIO was evaluated in monarchE, a study of 5591 adult patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor) or endocrine therapy (tamoxifen or an aromatase inhibitor) alone [see Clinical Studies (14.1)]. Patients were randomly assigned to receive 150 mg of VERZENIO orally, twice daily, plus tamoxifen or an aromatase inhibitor, or tamoxifen or an aromatase inhibitor, for two years or until discontinuation criteria were met. The median duration of VERZENIO treatment was 24 months. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, diarrhea, and lymphopenia. Fatal adverse reactions occurred in 0.8% of patients who received VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor), including: cardiac failure (0.1%), cardiac arrest, myocardial infarction, ventricular fibrillation, cerebral hemorrhage, cerebrovascular accident, pneumonitis, hypoxia, diarrhea, and mesenteric artery thrombosis (0.03% each). Permanent VERZENIO treatment discontinuation due to an adverse reaction was reported in 19% of patients receiving VERZENIO, plus tamoxifen or an aromatase inhibitor. Of the patients receiving tamoxifen or an aromatase inhibitor, 1% permanently discontinued due to an adverse reaction. The most common adverse reactions leading to VERZENIO discontinuations were diarrhea (5%), fatigue (2%), and neutropenia (0.9%). Dose interruption of VERZENIO due to an adverse reaction occurred in 62% of patients receiving VERZENIO plus tamoxifen or aromatase inhibitors. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were diarrhea (20%), neutropenia (16%), leukopenia (7%), and fatigue (5%). Dose reductions of VERZENIO due to an adverse reaction occurred in 44% of patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor). Adverse reactions leading to VERZENIO dose reductions in ≥5% were diarrhea (17%), neutropenia (8%), and fatigue (5%). The most common adverse reactions reported (≥20%) in the VERZENIO, plus tamoxifen or an aromatase inhibitor, arm and ≥2% higher than the tamoxifen or an aromatase inhibitor arm were: diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Adverse reactions are shown in Table 8 and laboratory abnormalities are shown in Table 9. Table 8: Adverse Reactions (≥10%) of Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2791 Tamoxifen or an Aromatase Inhibitor N=2800 All Gradesa % Grade 3 % Grade 4 % All Gradesb % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 84 8 0 9 0.2 0 Nausea 30 0.5 0 9 <0.1 0 Vomiting 18 0.5 0 4.6 0.1 0 Stomatitisc 14 0.1 0 5 0 0 Reference ID: 5478239 c Infections and Infestations Infectionsd 51 4.9 0.6 39 2.7 0.1 General Disorders and Administration Site Conditions Fatiguee 41 2.9 0 18 0.1 0 Nervous System Disorders Headache 20 0.3 0 15 0.2 0 Dizziness 11 0.1 0 7 <0.1 0 Metabolism and Nutrition Disorders Decreased appetite 12 0.6 0 2.4 <0.1 0 Skin and Subcutaneous Tissue Disorders Rashf 11 0.4 0 4.5 0 0 Alopecia 11 0 0 2.7 0 0 a Includes the following fatal adverse reactions: diarrhea (n=1), and infections (n=4) b Includes the following fatal adverse reactions: infections (n=5) Includes mouth ulceration, mucosal inflammation, oropharyngeal pain, stomatitis. d Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>5%) include upper respiratory tract infection, urinary tract infection, and nasopharyngitis. e Includes asthenia, fatigue. f Includes exfoliative rash, mucocutaneous rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash maculovesicular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash vesicular, vulvovaginal rash. Clinically relevant adverse reactions in <10% of patients who received VERZENIO in combination with tamoxifen or an aromatase inhibitor in monarchE include: • Pruritus-9% • Dyspepsia-8% • Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis) • Lacrimation increased-6% • Dysgeusia-5% • Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis – lung, lung opacity, sarcoidosis) • Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb) Table 9: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2791 Tamoxifen or an Aromatase Inhibitor N=2800 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 99 0.5 0 91 <0.1 0 White blood cell decreased 89 19 <0.1 28 1.1 0 Neutrophil count decreased 84 18 0.7 23 1.6 0.3 Anemia 68 1.0 0 17 0.1 0 Lymphocyte count decreased 59 13 0.2 24 2.4 0.1 Reference ID: 5478239 Platelet count decreased 37 0.7 0.2 10 0.1 0.1 Alanine aminotransferase increased 37 2.5 <0.1 24 1.2 0 Aspartate aminotransferase increased 31 1.5 <0.1 18 0.9 0 Hypokalemia 11 1.2 0.1 3.8 0.1 0.1 Advanced or Metastatic Breast Cancer MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine- Based Therapy Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting The safety of VERZENIO was evaluated in MONARCH 3, a study of 488 women receiving VERZENIO plus an aromatase inhibitor or placebo plus an aromatase inhibitor [see Clinical Studies (14.2)]. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physician’s choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: 3 (0.9%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction. Permanent treatment discontinuation due to an adverse reaction was reported in 13% of patients receiving VERZENIO plus an aromatase inhibitor and in 3% of patients receiving placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%). Dose interruption of VERZENIO due to an adverse reaction occurred in 56% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were neutropenia (16%) and diarrhea (15%). Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor. The most common adverse reactions reported (≥20%) in the VERZENIO arm and ≥2% than the placebo arm were: diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. Adverse reactions are shown in Table 10 and laboratory abnormalities in Table 11. Diarrhea incidence was greatest during the first month of VERZENIO dosing. The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions [see Dosage and Administration (2.2) and Patient Counseling Information (17)]. Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days. Table 10: Adverse Reactions (≥10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with a Difference between Arms of ≥2%] in MONARCH 3 VERZENIO plus Placebo plus Anastrozole or Letrozole Anastrozole or Letrozole N=327 N=161 Reference ID: 5478239 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 81 9 0 30 1.2 0 Nausea 39 0.9 0 20 1.2 0 Abdominal pain 29 1.2 0 12 1.2 0 Vomiting 28 1.2 0 12 1.9 0 Constipation 16 0.6 0 12 0 0 Infections and Infestations Infectionsa 39 4.0 0.9 29 2.5 0.6 General Disorders and Administration Site Conditions Fatigue 40 1.8 0 32 0 0 Influenza like illness 10 0 0 8 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 27 0 0 11 0 0 Rash 14 0.9 0 5 0 0 Pruritus 13 0 0 9 0 0 Metabolism and Nutrition Disorders Decreased appetite 24 1.2 0 9 0.6 0 Investigations Weight decreased 10 0.6 0 3.1 0.6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 9 0 0 Dyspnea 12 0.6 0.3 6 0.6 0 Nervous System Disorders Dizziness 11 0.3 0 9 0 0 a Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis. Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo. Table 11: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with a Difference Between Arms of ≥2%] in MONARCH 3 VERZENIO plus Anastrozole or Letrozole N=327 Placebo plus Anastrozole or Letrozole N=161 Laboratory Abnormality All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 2.2 0 84 0 0 White blood cell decreased 82 13 0 27 0.6 0 Anemia 82 1.6 0 28 0 0 Neutrophil count decreased 80 19 2.9 21 2.6 0 Lymphocyte count decreased 53 7 0.6 26 1.9 0 Platelet count decreased 36 1.3 0.6 12 0.6 0 Alanine aminotransferase increased 48 6 0.6 25 1.9 0 Aspartate aminotransferase increased 37 3.8 0 23 0.6 0 Reference ID: 5478239 Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired. MONARCH 2: VERZENIO in Combination with Fulvestrant Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2 [see Clinical Studies (14.2)]. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2. Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections. Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction. Permanent study treatment discontinuation due to an adverse reaction were reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%). Dose interruption of VERZENIO due to an adverse reaction occurred in 52% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were diarrhea (19%) and neutropenia (16%). Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant. The most common adverse reactions reported (≥20%) in the VERZENIO arm were: diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. Adverse reactions are shown in Table 12 and laboratory abnormalities in Table 13. Table 12: Adverse Reactions (≥10%) in Patients Receiving VERZENIO Plus Fulvestrant [with a Difference Between Arms of ≥2%] in MONARCH 2 VERZENIO plus Fulvestrant N=441 Placebo plus Fulvestrant N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Reference ID: 5478239 Diarrhea 86 13 0 25 0.4 0 Nausea 45 2.7 0 23 0.9 0 Abdominal paina 35 2.5 0 16 0.9 0 Vomiting 26 0.9 0 10 1.8 0 Stomatitis 15 0.5 0 10 0 0 Infections and Infestations Infectionsb 43 5 0.7 25 3.1 0.4 General Disorders and Administration Site Conditions Fatiguec 46 2.7 0 32 0.4 0 Edema peripheral 12 0 0 7 0 0 Pyrexia 11 0.5 0.2 6 0.4 0 Metabolism and Nutrition Disorders Decreased appetite 27 1.1 0 12 0.4 0 Respiratory, Thoracic and Mediastinal Disorders Cough 13 0 0 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 0 1.8 0 0 Pruritus 13 0 0 6 0 0 Rash 11 1.1 0 4.5 0 0 Nervous System Disorders Headache 20 0.7 0 15 0.4 0 Dysgeusia 18 0 0 2.7 0 0 Dizziness 12 0.7 0 6 0 0 Investigations Weight decreased 10 0.2 0 2.2 0.4 0 a Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness. b Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis. c Includes asthenia, fatigue. Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Table 13: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Fulvestrant [with a Difference Between Arms of ≥2%]in MONARCH 2 VERZENIO plus Fulvestrant N=441 Placebo plus Fulvestrant N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 1.2 0 74 0 0 White blood cell decreased 90 23 0.7 33 0.9 0 Neutrophil count decreased 87 29 3.5 30 3.7 0.5 Anemia 84 2.6 0 34 0.5 0 Lymphocyte count decreased 63 12 0.2 32 1.8 0 Platelet count decreased 53 0.9 1.2 15 0 0 Reference ID: 5478239 Alanine aminotransferase increased 41 3.9 0.7 32 1.4 0 Aspartate aminotransferase increased 37 3.9 0 25 3.7 0.5 Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired. MONARCH 1: VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting The safety of VERZENIO was evaluated in MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer [see Clinical Studies (14.2)]. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were diarrhea, neutropenia, fatigue, and leukopenia. Deaths due to adverse reactions during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient). Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each), abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Dose interruption of VERZENIO due to an adverse reaction occurred in 58% of patients. The most frequent (≥5%) adverse reactions leading to dose interruptions were diarrhea (24%), neutropenia (16%), fatigue (10%), vomiting (6%), and nausea (5%). Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%). The most common reported adverse reactions (≥20%) were: diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Adverse reactions are shown in Table 14 and laboratory abnormalities in Table 15. Table 14: Adverse Reactions (≥10%) of Patients in MONARCH 1 VERZENIO N=132 All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 90 20 0 Nausea 64 4.5 0 Abdominal pain 39 2.3 0 Vomiting 35 1.5 0 Constipation 17 0.8 0 Dry mouth 14 0 0 Stomatitis 14 0 0 Reference ID: 5478239 Infections and Infestations Infections 31 4.5 0 General Disorders and Administration Site Conditions Fatiguea 65 13 0 Pyrexia 11 0 0 Metabolism and Nutrition Disorders Decreased appetite 45 3.0 0 Dehydration 10 2.3 0 Respiratory, Thoracic and Mediastinal Disorders Cough 19 0 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 0 0 Nervous System Disorders Headache 20 0 0 Dysgeusia 12 0 0 Dizziness 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 12 0 0 Investigations Weight decreased 14 0 0 a Includes asthenia, fatigue. Table 15: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1 VERZENIO N=132 All Grades % Grade 3 % Grade 4 % Creatinine increased 99 0.8 0 White blood cell decreased 91 28 0 Neutrophil count decreased 88 22 4.6 Anemia 69 0 0 Lymphocyte count decreased 42 13 0.8 Platelet count decreased 41 2.3 0 ALT increased 31 3.1 0 AST increased 30 3.8 0 Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired. 6.2 Postmarketing Experience Reference ID: 5478239 The following adverse reactions have been identified during post-approval use of VERZENIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on VERZENIO CYP3A Inhibitors Strong and moderate CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Ketoconazole Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold [see Clinical Pharmacology (12.3)]. Other Strong CYP3A Inhibitors In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking VERZENIO discontinues a strong CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. Patients should avoid grapefruit products [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Moderate CYP3A Inhibitors With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary. Strong and Moderate CYP3A Inducers Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses ≥4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or Reference ID: 5478239 nodulated ribs. At 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose. 8.2 Lactation Risk Summary There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for 3 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating treatment with VERZENIO. Contraception Females Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose. Infertility Males Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of VERZENIO have not been established in pediatric patients. 8.5 Geriatric Use Of the 2791 VERZENIO-treated patients in monarchE, 15% were 65 years of age or older and 2.7% were 75 years of age or older. Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 were: neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients. 8.6 Renal Impairment No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 11 DESCRIPTION Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C27H32F2N8 and a molecular weight 506.59. Reference ID: 5478239 F ,::;' I F ""- ,::;' I Ny N HQO~ The chemical name for abemaciclib is 2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4 fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following structure: VERZENIO (abemaciclib) tablets are provided as immediate-release oval white, beige, or yellow tablets. Inactive ingredients are as follows: Excipients—microcrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide. Color mixture ingredients—polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size. 12.2 Pharmacodynamics Cardiac Electrophysiology Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval. 12.3 Pharmacokinetics The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including breast cancer, and in healthy subjects. Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively. Absorption The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). Effect of Food A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%. Distribution In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV). In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations. Reference ID: 5478239 Elimination The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). Metabolism Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. Excretion After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites. Specific Populations Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib. Patients with Renal Impairment In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min ≤ CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib [see Use in Specific Populations (8.6)]. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown. Patients with Hepatic Impairment Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) [see Use in Specific Populations (8.7)]. In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function. Drug Interaction Studies Effects of Other Drugs on Abemaciclib Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold. Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold relative to abemaciclib alone in cancer patients. Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively. Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects. Moderate CYP3A Inducers: Efavirenz, bosentan, and modafinil (moderate CYP3A inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively. Reference ID: 5478239 Loperamide: Co-administration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen on abemaciclib pharmacokinetics. Effects of Abemaciclib on Other Drugs Loperamide: In a clinical drug interaction study in healthy subjects, coadministration of a single 8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant. Metformin: In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen. CYP Metabolic Pathways: In a clinical drug interaction study in patients with cancer, multiple doses of abemaciclib (200 mg twice daily for 7 days) did not result in clinically meaningful changes in the pharmacokinetics of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a result of autoinhibition of its metabolism were not observed. In Vitro Studies Transporter Systems: Abemaciclib and its major active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage. The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K [see Adverse Effects (6.1)]. Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3. Abemaciclib is a substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3. Abemaciclib inhibits P-gp and BCRP. The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown. P-gp and BCRP Inhibitors: In vitro, abemaciclib is a substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Abemaciclib was assessed for carcinogenicity in a 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to 3 mg/kg/day (approximately 1 time the exposure at the maximum recommended human dose based on AUC). Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes. Abemaciclib, M2, and M20 were not clastogenic in an in vivo rat bone marrow micronucleus assay. Abemaciclib may impair fertility in males of reproductive potential. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis. These doses in rats and dogs resulted in approximately 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In a rat male fertility study, Reference ID: 5478239 abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately 2 times the exposure at the maximum recommended human dose based on AUC). In a rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately 3 times the exposure at the maximum recommended human dose based on AUC). 13.2 Animal Toxicology and/or Pharmacology In repeat-dose toxicity studies up to 6-months duration, oral administration of abemaciclib resulted in retinal atrophy of the eyes in mice at a dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at a dose of 30 mg/kg/day (approximately 5 times the exposure at the maximum recommended human dose based on AUC). In a 2-year rat carcinogenicity study, oral administration of abemaciclib resulted in retinal atrophy in the eyes at doses ≥0.3 mg/kg/day (approximately 0.05 times the exposure at the maximum recommended human dose based on AUC). 14 CLINICAL STUDIES 14.1 Early Breast Cancer VERZENIO in Combination with Standard Endocrine Therapy (monarchE) Patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence monarchE (NCT03155997) was a randomized (1:1), open-label, two cohort, multicenter study in adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence. To be enrolled, patients had to have HR-positive HER2-negative early breast cancer with tumor involvement in at least 1 axillary lymph node (pALN) and to be enrolled in cohort 1 had to have either: • ≥4 pALN or • 1-3 pALN and at least one of: – tumor grade 3 or – tumor size ≥50 mm Patients enrolled in cohort 2 could not have met the eligibility criteria for cohort 1. To be enrolled in cohort 2, patients had to have 1-3 pALN and Ki-67 score ≥20%. Breast tumor samples were tested at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was ≥20%. Patients were randomized to receive 2 years of VERZENIO plus physician's choice of standard endocrine therapy or standard endocrine therapy alone. Randomization to treatment was stratified by prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy); menopausal status (premenopausal versus postmenopausal); and region (North America/Europe versus Asia versus other). Men were stratified as postmenopausal. After the end of the study treatment period, standard adjuvant endocrine therapy was continued for a duration of at least 5 years if deemed medically appropriate. The major efficacy outcome measure was invasive disease–free survival (IDFS). IDFS was defined as the time from randomization to the first occurrence of: ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, second primary non-breast invasive cancer, or death attributable to any cause. Overall survival (OS) was an additional outcome measure. A statistically significant difference in IDFS was observed in the intent-to-treat (ITT) population which was primarily attributed to the patients treated in cohort 1. While the OS data in cohort 2 remains immature, more deaths were observed among those receiving VERZENIO plus standard endocrine therapy compared to those receiving standard endocrine therapy alone (10/253 vs. 5/264). Of 5637 patients randomized, 5120 (91%) were randomized in cohort 1. Patient median age was 51 years (range, 22-89 years), 99% were women, 70% were White, 24% were Asian, 1.7% were Black or African American, 2.1% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Other Pacific Islander. Forty-three percent of patients were premenopausal. Most patients received prior chemotherapy (37% neoadjuvant, 59% adjuvant) and prior radiotherapy (96%). Sixty-five percent of the patients had 4 or more positive lymph nodes with 22% having ≥10 positive lymph nodes, 41% had Grade 3 tumor, and 24% had pathological tumor size ≥50 mm. The majority of patients (99%) had estrogen receptor positive disease and 87% had progesterone receptor positive disease. Initial endocrine therapy received by patients included letrozole (39%), tamoxifen (31%), anastrozole (22%), or exemestane (8%). Reference ID: 5478239 100 - 'cft-_, 90 >, :!:: .c 80 cu .c 0 I... 0.. 70 cu > "> 60 I... :J Cf) Q.) ~ 50 LL I 40 Q.) Cl) cu Q.) 30 Cl) 0 ~ 20 Censored observations ·u5 cu > C 10 VERZENIO plus Tamoxifen or Aromatase Inhibitors (N=2555) Tamoxifen or Aromatase Inhibitors (N=2565) 0 0 6 12 18 24 30 36 Patients at risk Time (months) VERZENIO plus Tamoxifen or Aromatase Inhibitors 2555 2387 2322 2256 2189 2129 2023 Tamoxifen or Aromatase Inhibitors 2565 2404 2327 2236 2143 2059 1920 42 1162 1134 48 520 511 54 79 82 I, 11-•••· I◄ 60 0 0 Efficacy results for cohort 1 are summarized in Table 16 and Figure 1. At the time of OS interim analysis 2, OS was immature and a total of 315 (6%) of patients had died in cohort 1. Table 16: Efficacy Results in monarchE in Cohort 1 VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2555 Tamoxifen or an Aromatase Inhibitor N=2565 Invasive Disease–Free Survival (IDFS) Number of patients with an event, n (%) 317 (12) 474 (18) Hazard ratio (95% CI) 0.65 (0.57, 0.75) IDFS at 48 months, % (95% CI) 85.5 (83.8, 87.0) 78.6 (76.7, 80.4) Abbreviation: CI = confidence interval. Figure 1: Kaplan-Meier Curves of Invasive Disease–Free Survival VERZENIO plus Tamoxifen or an Aromatase Inhibitor versus Tamoxifen or an Aromatase Inhibitor in Cohort 1 (monarchE) 14.2 Advanced or Metastatic Breast Cancer Reference ID: 5478239 VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) (MONARCH 3) Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease setting MONARCH 3 (NCT02246621) was a randomized (2:1), double-blinded, placebo-controlled, multicenter study in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with a nonsteroidal aromatase inhibitor as initial endocrine-based therapy, including patients not previously treated with systemic therapy for breast cancer. Randomization was stratified by disease site (visceral, bone only, or other) and by prior (neo)adjuvant endocrine therapy (aromatase inhibitor versus other versus no prior endocrine therapy). A total of 493 patients were randomized to receive 150 mg VERZENIO or placebo orally twice daily, plus physician’s choice of letrozole (80% of patients) or anastrozole (20% of patients). Patient median age was 63 years (range, 32-88 years) and the majority were White (58%) or Asian (30%). A total of 51% had received prior systemic therapy and 39% of patients had received chemotherapy, 53% had visceral disease, and 22% had bone-only disease. Efficacy results are summarized in Table 17 and Figure 2. PFS was evaluated according to RECIST version 1.1 and PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent PFS results were observed across patient stratification subgroups of disease site and prior (neo)adjuvant endocrine therapy. Table 17: Efficacy Results in MONARCH 3 (Investigator Assessment, Intent-to-Treat Population) VERZENIO plus Anastrozole or Letrozole Placebo plus Anastrozole or Letrozole Progression-Free Survival N=328 N=165 Number of patients with an event, n (%) 138 (42) 108 (65) Median in months (95% CI) 28.2 (23.5, NR) 14.8 (11.2, 19.2) Hazard ratio (95% CI) 0.54 (0.42, 0.70) p-value <0.0001 Overall Survival N=328 N=165 Number of patients with an event, n (%) 198 (60) 116 (70) Median in months (95% CI) 66.8 (59.2, 74.8) 53.7 (44.7 59.3) Hazard ratio (95% CI) 0.80 (0.64, 1.02) p-value NS Objective Response for Patients with Measurable Diseasea N=267 N=132 Objective response rate, n (%)a,b 148 (55) 53 (40) 95% CI 49, 61 32, 49 Abbreviations: CI = confidence interval; OS = overall survival; NR = not reached; NS = not statistically significant. a Complete response + partial response. b Based upon confirmed responses. Reference ID: 5478239 100 Censored observations - VERZENIO + NSAI (N=328) ~ 0 Placebo + NSAI (N=165) - >- l ~ 80 :.0 IV .c 0 --. ... LL c.. .... \ IV 60 ~- > .... - ·s; ... ... l :::, ... en .. +- ... Q) - - ~ 40 - -H+1 '+ 1- H1-1+t LL HH!ff-, I ., C: -~ .2 Ill t- Ill 20 t-, ~ - ++, C, Lt--, e c.. I 0 I 0 4 8 12 16 20 24 28 32 36 Patients at risk: Time (months) VERZENIO + NSAI 328 272 236 208 181 164 106 40 0 0 Placebo + NSAI 165 126 105 84 66 58 42 7 0 0 Figure 2: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Anastrozole or Letrozole versus Placebo plus Anastrozole or Letrozole in Intent-to-Treat Population (MONARCH 3) VERZENIO in Combination with Fulvestrant (MONARCH 2) Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multicenter study in women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. A total of 669 patients were randomized to receive VERZENIO or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity. Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal. The efficacy results from the MONARCH 2 study are summarized in Table 18, Figure 3, and Figure 4. PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance for PFS and OS. Reference ID: 5478239 c Table 18: Efficacy Results in MONARCH 2 (Intent-to-Treat Population) VERZENIO plus Fulvestrant Placebo plus Fulvestrant Progression-Free Survival (Investigator Assessment) N=446 N=223 Number of patients with an event, n (%) 222 (50) 157 (70) Median in months (95% CI) 16.4 (14.4, 19.3) 9.3 (7.4, 12.7) Hazard ratio (95% CI)a 0.55 (0.45, 0.68) p-valuea p<.0001 Overall Survivalb Number of deaths, n (%) 211 (47) 127 (57) Median OS in months (95% CI) 46.7 (39.2, 52.2) 37.3 (34.4, 43.2) Hazard ratio (95% CI)a 0.76 (0.61, 0.95) p-valuea p=.0137 Objective Response for Patients with Measurable Disease N=318 N=164 Objective response rate, n (%)c 153 (48) 35 (21) 95% CI 43, 54 15, 28 Abbreviation: CI = confidence interval, OS = overall survival. a Stratified by disease site (visceral metastases vs. bone-only metastases vs. other) and endocrine therapy resistance (primary resistance vs. secondary resistance) b Data from a pre-specified interim analysis (77% of the number of events needed for the planned final analysis) with the p-value compared with the allocated alpha of 0.021. Complete response + partial response. Reference ID: 5478239 100 - ~ 0 - >. - :.a 80 Cll .c 0 ... a. Cll 60 > > ... ::::J Cl) Cl) 40 Cl) ... u. I C: 0 en en 20 Cl) ... C) 0 ... a. 0 0 3 6 9 12 Patients at risk: VERZENIO plus fulvestrant 446 367 314 281 234 Placebo plus fulvestrant 223 165 123 103 80 15 Censored observations VERZENIO plus fulvestrant (N=446) Placebo plus fulvestrant (N=223) 18 21 ' • I ·- 1 24 27 30 Time (months) 171 101 61 32 65 13 32 4 2 0 0 Figure 3: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2) Reference ID: 5478239 100 -80 ~ 0 - .C 60 ca .c 0 ... a.. ~ 40 > ... ::::, Cl) 20 Censored observations - VERZEN 10 plus fulvestrant (N=446) - - Placebo plus fulvestrant (N=223) o-----------.------------....---------..--------------- 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Patients at risk: Time (months) VERZENIO plus fulvestrant 446 422 410 397 384 364 339 321 302 284 265 246 234 214 202 157 101 58 23 0 Placebo plus fulvestrant 223 214 201 195 191 178 170 158 148 135 122 115 99 92 82 62 42 15 3 0 Figure 4: Kaplan-Meier Curves of Overall Survival: VERZENIO plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2) VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1) Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting MONARCH 1 (NCT02102490) was a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg VERZENIO orally twice daily on a continuous schedule until development of progressive disease or unmanageable toxicity. Patient median age was 58 years (range, 36-89 years), and the majority of patients were White (85%). Patients had an Eastern Cooperative Oncology Group performance status of 0 (55% of patients) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of patients had had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received a taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting. Table 19 provides the efficacy results from MONARCH 1. Reference ID: 5478239 Table 19: Efficacy Results in MONARCH 1 (Intent-to-Treat Population) VERZENIO 200 mg N=132 Investigator Assessed Independent Review Objective Response Ratea,b, n (%) 26 (20) 23 (17) 95% CI 13, 28 11, 25 Median Duration of Response in months 8.6 7.2 95% CI 5.8, 10.2 5.6, NR Abbreviations: CI = confidence interval, NR = not reached. a All responses were partial responses. b Based upon confirmed responses. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied VERZENIO 50 mg tablets are oval beige tablet with “Lilly” debossed on one side and “50” on the other side. VERZENIO 100 mg tablet are oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side. VERZENIO 150 mg tablets are oval yellow tablet with “Lilly” debossed on one side and “150” on the other side. VERZENIO 200 mg tablets are oval beige tablet with “Lilly” debossed on one side and “200” on the other side. VERZENIO tablets are supplied in 7-day dose pack configurations as follows: • 200 mg dose pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily) NDC 0002-6216-54 • 150 mg dose pack (14 tablets) – each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily) NDC 0002-5337-54 • 100 mg dose pack (14 tablets) – each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily) NDC 0002-4815-54 • 50 mg dose pack (14 tablets) – each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily) NDC 0002-4483-54 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). 17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved Patient Information. Diarrhea VERZENIO may cause diarrhea, which may be severe in some cases [see Warnings and Precautions (5.1)]. • Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up. • Encourage patients to increase oral fluids. • If diarrhea does not resolve with antidiarrheal therapy within 24 hours to ≤Grade 1, suspend VERZENIO dosing [see Dosage and Administration (2.2)]. Neutropenia Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)]. Reference ID: 5478239 Interstitial Lung Disease/Pneumonitis Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)]. Hepatotoxicity Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.4)]. Venous Thromboembolism Advise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions (5.5)]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)]. Lactation Advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2)]. Infertility Inform males of reproductive potential that VERZENIO may impair fertility [see Use in Specific Populations (8.3)]. Drug Interactions • Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors or for moderate CYP3A inhibitors [see Dosage and Administration (2.2) and Drug Interactions (7)]. • Grapefruit may interact with VERZENIO. Advise patients not to consume grapefruit products while on treatment with VERZENIO. • Advise patients to avoid concomitant use of strong and moderate CYP3A inducers and to consider alternative agents [see Dosage and Administration (2.2) and Drug Interactions (7)]. • Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Dosage and Administration (2.2) and Drug Interactions (7)]. Dosing • Instruct patients to take the doses of VERZENIO at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing) [see Dosage and Administration (2.1)]. • If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time [see Dosage and Administration (2.1)]. • Advise the patient that VERZENIO may be taken with or without food [see Dosage and Administration 2.1)]. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2017, 202X, Eli Lilly and Company. All rights reserved. VER-000X-USPI-0000-00-00 Reference ID: 5478239 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VERZENIO safely and effectively. See full prescribing information for VERZENIO. VERZENIO® (abemaciclib) tablets, for oral use Initial U.S. Approval: 2017 ---------------------------- INDICATIONS AND USAGE -------------------------- VERZENIO® is a kinase inhibitor indicated: • in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. (1.1, 14.1) • in combination with an aromatase inhibitor as initial endocrine- based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. (1.2) • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. (1.2) • as monotherapy for the treatment of adult patients with HR- positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. (1.2) ------------------------DOSAGE AND ADMINISTRATION---------------------- VERZENIO tablets are taken orally with or without food. (2.1) • Recommended starting dose in combination with fulvestrant, tamoxifen, or an aromatase inhibitor: 150 mg twice daily. (2.1) • Recommended starting dose as monotherapy: 200 mg twice daily. (2.1) • Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. (2.2) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 50 mg, 100 mg, 150 mg, and 200 mg. (3) ------------------------------- CONTRAINDICATIONS ----------------------------- None. (4) ------------------------WARNINGS AND PRECAUTIONS ---------------------- • Diarrhea: VERZENIO can cause severe cases of diarrhea, associated with dehydration and infection. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. (2.2, 5.1) • Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. (2.2, 5.2) • Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis. (2.2, 5.3) • Hepatotoxicity: Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with VERZENIO. Monitor LFTs every two weeks for the first two months, monthly for the next 2 months, and as clinically indicated. (2.2, 5.4) • Venous Thromboembolism: Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. (2.2, 5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.6, 8.1, 8.3) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence ≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------- DRUG INTERACTIONS ----------------------------- • CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the VERZENIO dose with concomitant use of other strong and moderate CYP3A inhibitors. (2.2, 7.1) • CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. (7.1) ------------------------USE IN SPECIFIC POPULATIONS---------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Early Breast Cancer 1.2 Advanced or Metastatic Breast Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule 2.2 Dose Modification 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Diarrhea 5.2 Neutropenia 5.3 Interstitial Lung Disease (ILD) or Pneumonitis 5.4 Hepatotoxicity 5.5 Venous Thromboembolism 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on VERZENIO 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Early Breast Cancer 14.2 Advanced or Metastatic Breast Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING Reference ID: 5478239 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Early Breast Cancer VERZENIO® (abemaciclib) is indicated: • in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node- positive, early breast cancer at high risk of recurrence [see Clinical Studies (14.1)]. 1.2 Advanced or Metastatic Breast Cancer VERZENIO (abemaciclib) is indicated: • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule • When used in combination with fulvestrant, tamoxifen, or an aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen, or aromatase inhibitor being used. • Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with a gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards. • Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with a GnRH according to current clinical practice standards • When used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily. • For early breast cancer, continue VERZENIO until completion of 2 years of treatment or until disease recurrence, or unacceptable toxicity. • For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity. VERZENIO may be taken with or without food [see Clinical Pharmacology (12.3)]. Instruct patients to take their doses of VERZENIO at approximately the same times every day. If the patient vomits or misses a dose of VERZENIO, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow VERZENIO tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest VERZENIO tablets if broken, cracked, or otherwise not intact. 2.2 Dose Modification Dose Modifications for Adverse Reactions The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1-7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily. Reference ID: 5478239 Table 1: VERZENIO Dose Modification — Adverse Reactions Dose Level VERZENIO Dose Combination with Fulvestrant, Tamoxifen, or an Aromatase Inhibitor VERZENIO Dose for Monotherapy Recommended starting dose 150 mg twice daily 200 mg twice daily First dose reduction 100 mg twice daily 150 mg twice daily Second dose reduction 50 mg twice daily 100 mg twice daily Third dose reduction not applicable 50 mg twice daily Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicitiesa Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Grade 3 Suspend dose until toxicity resolves to ≤Grade 2. Dose reduction is not required. Grade 3 recurrent, or Grade 4 Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose. Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events. a If blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines. Table 3: VERZENIO Dose Modification and Management — Diarrhea At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids. CTCAE Grade VERZENIO Dose Modifications Grade 1 No dose modification is required. Grade 2 If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required. Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose. Grade 3 or 4 or requires hospitalization Suspend dose until toxicity resolves to ≤Grade 1. Resume at next lower dose. Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. CTCAE Grade for ALT and AST VERZENIO Dose Modifications Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN No dose modification is required. Persistent or Recurrent Grade 2, or Grade 3 (>5.0 20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose. Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis Discontinue VERZENIO. Reference ID: 5478239 Grade 4 (>20.0 x ULN) Discontinue VERZENIO. Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal. Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose. Grade 3 or 4 Discontinue VERZENIO. Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs) CTCAE Grade VERZENIO Dose Modifications Early Breast Cancer Any Grade Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable. Advanced or Metastatic Breast Cancer Grade 1 or 2 No dose modification is required. Grade 3 or 4 Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable. Table 7: VERZENIO Dose Modification and Management — Other Toxicitiesa CTCAE Grade VERZENIO Dose Modifications Grade 1 or 2 No dose modification is required. Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose. Grade 3 or 4 Suspend dose until toxicity resolves to baseline or ≤Grade 1. Resume at next lower dose. a Excluding diarrhea, hematologic toxicity, hepatotoxicity, ILD/pneumonitis, and VTEs. Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen, or an aromatase inhibitor for dose modifications and other relevant safety information. Dose Modification for Use with Strong and Moderate CYP3A Inhibitors Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary. Dose Modification for Patients with Severe Hepatic Impairment Reference ID: 5478239 For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen, or aromatase inhibitor for dose modification requirements for severe hepatic impairment. 3 DOSAGE FORMS AND STRENGTHS 50 mg tablets: oval beige tablet with “Lilly” debossed on one side and “50” on the other side. 100 mg tablets: oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side. 150 mg tablets: oval yellow tablet with “Lilly” debossed on one side and “150” on the other side. 200 mg tablets: oval beige tablet with “Lilly” debossed on one side and “200” on the other side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Diarrhea Severe diarrhea associated with dehydration and infection occurred in patients treated with VERZENIO. Across four clinical trials in 3691 patients, diarrhea occurred in 81% to 90% of patients who received VERZENIO. Grade 3 diarrhea occurred in 8% to 20% of patients receiving VERZENIO [see Adverse Reactions (6.1)]. Most patients experienced diarrhea during the first month of VERZENIO treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19% to 26% of patients with diarrhea required a VERZENIO dose interruption and 13% to 23% required a dose reduction. Instruct patients to start antidiarrheal therapy such as loperamide at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up [see Patient Counseling Information (17)]. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue VERZENIO until toxicity resolves to ≤Grade 1, and then resume VERZENIO at the next lower dose [see Dosage and Administration (2.2)]. 5.2 Neutropenia Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with VERZENIO. Across four clinical trials in 3691 patients, neutropenia occurred in a 37% to 46% of patients receiving VERZENIO. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19% to 32% of patients receiving VERZENIO. Across trials, the median time to the first episode of Grade ≥3 neutropenia ranged from 29 days to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 days to 16 days [see Adverse Reactions (6.1)]. Febrile neutropenia has been reported in <1% of patients exposed to VERZENIO across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider [see Patient Counseling Information (17)]. Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2)]. 5.3 Interstitial Lung Disease (ILD) or Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with VERZENIO and other CDK4/6 inhibitors. In VERZENIO-treated patients in early breast cancer (monarchE, N=2791), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In VERZENIO- treated patients in advanced or metastatic breast cancer (N=900) (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of VERZENIO-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Adverse Reactions (6.2)]. Reference ID: 5478239 6 Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis [see Dosage and Administration (2.2)]. 5.4 Hepatotoxicity Grade ≥3 ALT (2% to 6%) and AST (2% to 3%) were reported in patients receiving VERZENIO. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days. Monitor liver function tests (LFTs) prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or Grade 4 hepatic transaminase elevation [see Dosage and Administration (2.2)]. 5.5 Venous Thromboembolism Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), venous thromboembolic events were reported in 2% to 5% of patients treated with VERZENIO. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to venous thromboembolism have been reported in patients treated with VERZENIO. VERZENIO has not been studied in patients with early breast cancer who had a history of venous thromboembolism. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for early breast cancer patients with any grade venous thromboembolic event and for advanced or metastatic breast cancer patients with a Grade 3 or 4 venous thromboembolic event [see Dosage and Administration (2.2)]. 5.6 Embryo-Fetal Toxicity Based on findings from animal studies and the mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VERZENIO and for 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Diarrhea [see Warnings and Precautions (5.1)]. • Neutropenia [see Warnings and Precautions (5.2)]. • Interstitial Lung Disease (ILD) or Pneumonitis [see Warnings and Precautions (5.3)]. • Hepatotoxicity [see Warnings and Precautions (5.4)]. • Venous Thromboembolism [see Warnings and Precautions (5.5)]. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Reference ID: 5478239 The safety population described in the Warnings and Precautions reflect exposure to VERZENIO in 3691 patients from four clinical trials: monarchE, MONARCH 1, MONARCH 2, and MONARCH 3. The safety population includes exposure to VERZENIO as a single agent at 200 mg twice daily in 132 patients in MONARCH 1 and to VERZENIO at 150 mg twice daily in 3559 patients administered in combination with fulvestrant, tamoxifen, or an aromatase inhibitor in monarchE, MONARCH 2, and MONARCH 3. The median duration of exposure ranged from 4.5 months in MONARCH 1 to 24 months in monarchE. The most common adverse reactions (incidence ≥20%) across clinical trials were: diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia. Early Breast Cancer monarchE: VERZENIO in Combination with Tamoxifen or an Aromatase Inhibitor as Adjuvant Treatment Adult patients with HR-positive, HER2-negative, node-positive early breast cancer at a high risk of recurrence The safety of VERZENIO was evaluated in monarchE, a study of 5591 adult patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor) or endocrine therapy (tamoxifen or an aromatase inhibitor) alone [see Clinical Studies (14.1)]. Patients were randomly assigned to receive 150 mg of VERZENIO orally, twice daily, plus tamoxifen or an aromatase inhibitor, or tamoxifen or an aromatase inhibitor, for two years or until discontinuation criteria were met. The median duration of VERZENIO treatment was 24 months. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, diarrhea, and lymphopenia. Fatal adverse reactions occurred in 0.8% of patients who received VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor), including: cardiac failure (0.1%), cardiac arrest, myocardial infarction, ventricular fibrillation, cerebral hemorrhage, cerebrovascular accident, pneumonitis, hypoxia, diarrhea, and mesenteric artery thrombosis (0.03% each). Permanent VERZENIO treatment discontinuation due to an adverse reaction was reported in 19% of patients receiving VERZENIO, plus tamoxifen or an aromatase inhibitor. Of the patients receiving tamoxifen or an aromatase inhibitor, 1% permanently discontinued due to an adverse reaction. The most common adverse reactions leading to VERZENIO discontinuations were diarrhea (5%), fatigue (2%), and neutropenia (0.9%). Dose interruption of VERZENIO due to an adverse reaction occurred in 62% of patients receiving VERZENIO plus tamoxifen or aromatase inhibitors. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were diarrhea (20%), neutropenia (16%), leukopenia (7%), and fatigue (5%). Dose reductions of VERZENIO due to an adverse reaction occurred in 44% of patients receiving VERZENIO plus endocrine therapy (tamoxifen or an aromatase inhibitor). Adverse reactions leading to VERZENIO dose reductions in ≥5% were diarrhea (17%), neutropenia (8%), and fatigue (5%). The most common adverse reactions reported (≥20%) in the VERZENIO, plus tamoxifen or an aromatase inhibitor, arm and ≥2% higher than the tamoxifen or an aromatase inhibitor arm were: diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Adverse reactions are shown in Table 8 and laboratory abnormalities are shown in Table 9. Table 8: Adverse Reactions (≥10%) of Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2791 Tamoxifen or an Aromatase Inhibitor N=2800 All Gradesa % Grade 3 % Grade 4 % All Gradesb % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 84 8 0 9 0.2 0 Nausea 30 0.5 0 9 <0.1 0 Vomiting 18 0.5 0 4.6 0.1 0 Stomatitisc 14 0.1 0 5 0 0 Reference ID: 5478239 c Infections and Infestations Infectionsd 51 4.9 0.6 39 2.7 0.1 General Disorders and Administration Site Conditions Fatiguee 41 2.9 0 18 0.1 0 Nervous System Disorders Headache 20 0.3 0 15 0.2 0 Dizziness 11 0.1 0 7 <0.1 0 Metabolism and Nutrition Disorders Decreased appetite 12 0.6 0 2.4 <0.1 0 Skin and Subcutaneous Tissue Disorders Rashf 11 0.4 0 4.5 0 0 Alopecia 11 0 0 2.7 0 0 a Includes the following fatal adverse reactions: diarrhea (n=1), and infections (n=4) b Includes the following fatal adverse reactions: infections (n=5) Includes mouth ulceration, mucosal inflammation, oropharyngeal pain, stomatitis. d Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>5%) include upper respiratory tract infection, urinary tract infection, and nasopharyngitis. e Includes asthenia, fatigue. f Includes exfoliative rash, mucocutaneous rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash maculovesicular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash vesicular, vulvovaginal rash. Clinically relevant adverse reactions in <10% of patients who received VERZENIO in combination with tamoxifen or an aromatase inhibitor in monarchE include: • Pruritus-9% • Dyspepsia-8% • Nail disorder-6% (includes nail bed disorder, nail bed inflammation, nail discoloration, nail disorder, nail dystrophy, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis) • Lacrimation increased-6% • Dysgeusia-5% • Interstitial lung disease (ILD)/pneumonitis-3% (includes pneumonitis, radiation pneumonitis, interstitial lung disease, pulmonary fibrosis, organizing pneumonia, radiation fibrosis – lung, lung opacity, sarcoidosis) • Venous thromboembolic events (VTEs)-3% (includes catheter site thrombosis, cerebral venous thrombosis, deep vein thrombosis, device related thrombosis, embolism, hepatic vein thrombosis, jugular vein occlusion, jugular vein thrombosis, ovarian vein thrombosis, portal vein thrombosis, pulmonary embolism, subclavian vein thrombosis, venous thrombosis limb) Table 9: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Tamoxifen or an Aromatase Inhibitor [with a Difference between Arms of ≥2%] in monarchE VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2791 Tamoxifen or an Aromatase Inhibitor N=2800 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 99 0.5 0 91 <0.1 0 White blood cell decreased 89 19 <0.1 28 1.1 0 Neutrophil count decreased 84 18 0.7 23 1.6 0.3 Anemia 68 1.0 0 17 0.1 0 Lymphocyte count decreased 59 13 0.2 24 2.4 0.1 Reference ID: 5478239 Platelet count decreased 37 0.7 0.2 10 0.1 0.1 Alanine aminotransferase increased 37 2.5 <0.1 24 1.2 0 Aspartate aminotransferase increased 31 1.5 <0.1 18 0.9 0 Hypokalemia 11 1.2 0.1 3.8 0.1 0.1 Advanced or Metastatic Breast Cancer MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine- Based Therapy Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting The safety of VERZENIO was evaluated in MONARCH 3, a study of 488 women receiving VERZENIO plus an aromatase inhibitor or placebo plus an aromatase inhibitor [see Clinical Studies (14.2)]. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physician’s choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: 3 (0.9%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction. Permanent treatment discontinuation due to an adverse reaction was reported in 13% of patients receiving VERZENIO plus an aromatase inhibitor and in 3% of patients receiving placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%). Dose interruption of VERZENIO due to an adverse reaction occurred in 56% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were neutropenia (16%) and diarrhea (15%). Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor. The most common adverse reactions reported (≥20%) in the VERZENIO arm and ≥2% than the placebo arm were: diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. Adverse reactions are shown in Table 10 and laboratory abnormalities in Table 11. Diarrhea incidence was greatest during the first month of VERZENIO dosing. The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions [see Dosage and Administration (2.2) and Patient Counseling Information (17)]. Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days. Table 10: Adverse Reactions (≥10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with a Difference between Arms of ≥2%] in MONARCH 3 VERZENIO plus Placebo plus Anastrozole or Letrozole Anastrozole or Letrozole N=327 N=161 Reference ID: 5478239 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 81 9 0 30 1.2 0 Nausea 39 0.9 0 20 1.2 0 Abdominal pain 29 1.2 0 12 1.2 0 Vomiting 28 1.2 0 12 1.9 0 Constipation 16 0.6 0 12 0 0 Infections and Infestations Infectionsa 39 4.0 0.9 29 2.5 0.6 General Disorders and Administration Site Conditions Fatigue 40 1.8 0 32 0 0 Influenza like illness 10 0 0 8 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 27 0 0 11 0 0 Rash 14 0.9 0 5 0 0 Pruritus 13 0 0 9 0 0 Metabolism and Nutrition Disorders Decreased appetite 24 1.2 0 9 0.6 0 Investigations Weight decreased 10 0.6 0 3.1 0.6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 9 0 0 Dyspnea 12 0.6 0.3 6 0.6 0 Nervous System Disorders Dizziness 11 0.3 0 9 0 0 a Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis. Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo. Table 11: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Anastrozole or Letrozole [with a Difference Between Arms of ≥2%] in MONARCH 3 VERZENIO plus Anastrozole or Letrozole N=327 Placebo plus Anastrozole or Letrozole N=161 Laboratory Abnormality All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 2.2 0 84 0 0 White blood cell decreased 82 13 0 27 0.6 0 Anemia 82 1.6 0 28 0 0 Neutrophil count decreased 80 19 2.9 21 2.6 0 Lymphocyte count decreased 53 7 0.6 26 1.9 0 Platelet count decreased 36 1.3 0.6 12 0.6 0 Alanine aminotransferase increased 48 6 0.6 25 1.9 0 Aspartate aminotransferase increased 37 3.8 0 23 0.6 0 Reference ID: 5478239 Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired. MONARCH 2: VERZENIO in Combination with Fulvestrant Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2 [see Clinical Studies (14.2)]. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2. Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections. Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction. Permanent study treatment discontinuation due to an adverse reaction were reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%). Dose interruption of VERZENIO due to an adverse reaction occurred in 52% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to VERZENIO dose interruptions in ≥5% of patients were diarrhea (19%) and neutropenia (16%). Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant. The most common adverse reactions reported (≥20%) in the VERZENIO arm were: diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. Adverse reactions are shown in Table 12 and laboratory abnormalities in Table 13. Table 12: Adverse Reactions (≥10%) in Patients Receiving VERZENIO Plus Fulvestrant [with a Difference Between Arms of ≥2%] in MONARCH 2 VERZENIO plus Fulvestrant N=441 Placebo plus Fulvestrant N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Reference ID: 5478239 Diarrhea 86 13 0 25 0.4 0 Nausea 45 2.7 0 23 0.9 0 Abdominal paina 35 2.5 0 16 0.9 0 Vomiting 26 0.9 0 10 1.8 0 Stomatitis 15 0.5 0 10 0 0 Infections and Infestations Infectionsb 43 5 0.7 25 3.1 0.4 General Disorders and Administration Site Conditions Fatiguec 46 2.7 0 32 0.4 0 Edema peripheral 12 0 0 7 0 0 Pyrexia 11 0.5 0.2 6 0.4 0 Metabolism and Nutrition Disorders Decreased appetite 27 1.1 0 12 0.4 0 Respiratory, Thoracic and Mediastinal Disorders Cough 13 0 0 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 0 1.8 0 0 Pruritus 13 0 0 6 0 0 Rash 11 1.1 0 4.5 0 0 Nervous System Disorders Headache 20 0.7 0 15 0.4 0 Dysgeusia 18 0 0 2.7 0 0 Dizziness 12 0.7 0 6 0 0 Investigations Weight decreased 10 0.2 0 2.2 0.4 0 a Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness. b Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis. c Includes asthenia, fatigue. Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Table 13: Laboratory Abnormalities (≥10%) in Patients Receiving VERZENIO Plus Fulvestrant [with a Difference Between Arms of ≥2%]in MONARCH 2 VERZENIO plus Fulvestrant N=441 Placebo plus Fulvestrant N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 1.2 0 74 0 0 White blood cell decreased 90 23 0.7 33 0.9 0 Neutrophil count decreased 87 29 3.5 30 3.7 0.5 Anemia 84 2.6 0 34 0.5 0 Lymphocyte count decreased 63 12 0.2 32 1.8 0 Platelet count decreased 53 0.9 1.2 15 0 0 Reference ID: 5478239 Alanine aminotransferase increased 41 3.9 0.7 32 1.4 0 Aspartate aminotransferase increased 37 3.9 0 25 3.7 0.5 Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired. MONARCH 1: VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting The safety of VERZENIO was evaluated in MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer [see Clinical Studies (14.2)]. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were diarrhea, neutropenia, fatigue, and leukopenia. Deaths due to adverse reactions during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient). Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each), abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Dose interruption of VERZENIO due to an adverse reaction occurred in 58% of patients. The most frequent (≥5%) adverse reactions leading to dose interruptions were diarrhea (24%), neutropenia (16%), fatigue (10%), vomiting (6%), and nausea (5%). Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%). The most common reported adverse reactions (≥20%) were: diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Adverse reactions are shown in Table 14 and laboratory abnormalities in Table 15. Table 14: Adverse Reactions (≥10%) of Patients in MONARCH 1 VERZENIO N=132 All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 90 20 0 Nausea 64 4.5 0 Abdominal pain 39 2.3 0 Vomiting 35 1.5 0 Constipation 17 0.8 0 Dry mouth 14 0 0 Stomatitis 14 0 0 Reference ID: 5478239 Infections and Infestations Infections 31 4.5 0 General Disorders and Administration Site Conditions Fatiguea 65 13 0 Pyrexia 11 0 0 Metabolism and Nutrition Disorders Decreased appetite 45 3.0 0 Dehydration 10 2.3 0 Respiratory, Thoracic and Mediastinal Disorders Cough 19 0 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 0 0 Nervous System Disorders Headache 20 0 0 Dysgeusia 12 0 0 Dizziness 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 12 0 0 Investigations Weight decreased 14 0 0 a Includes asthenia, fatigue. Table 15: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1 VERZENIO N=132 All Grades % Grade 3 % Grade 4 % Creatinine increased 99 0.8 0 White blood cell decreased 91 28 0 Neutrophil count decreased 88 22 4.6 Anemia 69 0 0 Lymphocyte count decreased 42 13 0.8 Platelet count decreased 41 2.3 0 ALT increased 31 3.1 0 AST increased 30 3.8 0 Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired. 6.2 Postmarketing Experience Reference ID: 5478239 The following adverse reactions have been identified during post-approval use of VERZENIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory disorders: Interstitial lung disease (ILD)/pneumonitis [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on VERZENIO CYP3A Inhibitors Strong and moderate CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Ketoconazole Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold [see Clinical Pharmacology (12.3)]. Other Strong CYP3A Inhibitors In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking VERZENIO discontinues a strong CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. Patients should avoid grapefruit products [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Moderate CYP3A Inhibitors With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary. Strong and Moderate CYP3A Inducers Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses ≥4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or Reference ID: 5478239 nodulated ribs. At 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose. 8.2 Lactation Risk Summary There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for 3 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating treatment with VERZENIO. Contraception Females Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose. Infertility Males Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of VERZENIO have not been established in pediatric patients. 8.5 Geriatric Use Of the 2791 VERZENIO-treated patients in monarchE, 15% were 65 years of age or older and 2.7% were 75 years of age or older. Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 were: neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients. 8.6 Renal Impairment No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 11 DESCRIPTION Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C27H32F2N8 and a molecular weight 506.59. Reference ID: 5478239 F ,::;' I F ""- ,::;' I Ny N HQO~ The chemical name for abemaciclib is 2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4 fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following structure: VERZENIO (abemaciclib) tablets are provided as immediate-release oval white, beige, or yellow tablets. Inactive ingredients are as follows: Excipients—microcrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide. Color mixture ingredients—polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size. 12.2 Pharmacodynamics Cardiac Electrophysiology Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval. 12.3 Pharmacokinetics The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including breast cancer, and in healthy subjects. Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively. Absorption The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). Effect of Food A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%. Distribution In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV). In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations. Reference ID: 5478239 Elimination The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). Metabolism Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. Excretion After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites. Specific Populations Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib. Patients with Renal Impairment In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min ≤ CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib [see Use in Specific Populations (8.6)]. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown. Patients with Hepatic Impairment Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) [see Use in Specific Populations (8.7)]. In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function. Drug Interaction Studies Effects of Other Drugs on Abemaciclib Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold. Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a single 50 mg dose of VERZENIO (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold relative to abemaciclib alone in cancer patients. Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively. Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of VERZENIO decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects. Moderate CYP3A Inducers: Efavirenz, bosentan, and modafinil (moderate CYP3A inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively. Reference ID: 5478239 Loperamide: Co-administration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen on abemaciclib pharmacokinetics. Effects of Abemaciclib on Other Drugs Loperamide: In a clinical drug interaction study in healthy subjects, coadministration of a single 8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant. Metformin: In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C. Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, exemestane, or tamoxifen. CYP Metabolic Pathways: In a clinical drug interaction study in patients with cancer, multiple doses of abemaciclib (200 mg twice daily for 7 days) did not result in clinically meaningful changes in the pharmacokinetics of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 substrates. Abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a result of autoinhibition of its metabolism were not observed. In Vitro Studies Transporter Systems: Abemaciclib and its major active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage. The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K [see Adverse Effects (6.1)]. Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3. Abemaciclib is a substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3. Abemaciclib inhibits P-gp and BCRP. The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown. P-gp and BCRP Inhibitors: In vitro, abemaciclib is a substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Abemaciclib was assessed for carcinogenicity in a 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to 3 mg/kg/day (approximately 1 time the exposure at the maximum recommended human dose based on AUC). Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes. Abemaciclib, M2, and M20 were not clastogenic in an in vivo rat bone marrow micronucleus assay. Abemaciclib may impair fertility in males of reproductive potential. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis. These doses in rats and dogs resulted in approximately 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In a rat male fertility study, Reference ID: 5478239 abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately 2 times the exposure at the maximum recommended human dose based on AUC). In a rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately 3 times the exposure at the maximum recommended human dose based on AUC). 13.2 Animal Toxicology and/or Pharmacology In repeat-dose toxicity studies up to 6-months duration, oral administration of abemaciclib resulted in retinal atrophy of the eyes in mice at a dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at a dose of 30 mg/kg/day (approximately 5 times the exposure at the maximum recommended human dose based on AUC). In a 2-year rat carcinogenicity study, oral administration of abemaciclib resulted in retinal atrophy in the eyes at doses ≥0.3 mg/kg/day (approximately 0.05 times the exposure at the maximum recommended human dose based on AUC). 14 CLINICAL STUDIES 14.1 Early Breast Cancer VERZENIO in Combination with Standard Endocrine Therapy (monarchE) Patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence monarchE (NCT03155997) was a randomized (1:1), open-label, two cohort, multicenter study in adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence. To be enrolled, patients had to have HR-positive HER2-negative early breast cancer with tumor involvement in at least 1 axillary lymph node (pALN) and to be enrolled in cohort 1 had to have either: • ≥4 pALN or • 1-3 pALN and at least one of: – tumor grade 3 or – tumor size ≥50 mm Patients enrolled in cohort 2 could not have met the eligibility criteria for cohort 1. To be enrolled in cohort 2, patients had to have 1-3 pALN and Ki-67 score ≥20%. Breast tumor samples were tested at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was ≥20%. Patients were randomized to receive 2 years of VERZENIO plus physician's choice of standard endocrine therapy or standard endocrine therapy alone. Randomization to treatment was stratified by prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy); menopausal status (premenopausal versus postmenopausal); and region (North America/Europe versus Asia versus other). Men were stratified as postmenopausal. After the end of the study treatment period, standard adjuvant endocrine therapy was continued for a duration of at least 5 years if deemed medically appropriate. The major efficacy outcome measure was invasive disease–free survival (IDFS). IDFS was defined as the time from randomization to the first occurrence of: ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, second primary non-breast invasive cancer, or death attributable to any cause. Overall survival (OS) was an additional outcome measure. A statistically significant difference in IDFS was observed in the intent-to-treat (ITT) population which was primarily attributed to the patients treated in cohort 1. While the OS data in cohort 2 remains immature, more deaths were observed among those receiving VERZENIO plus standard endocrine therapy compared to those receiving standard endocrine therapy alone (10/253 vs. 5/264). Of 5637 patients randomized, 5120 (91%) were randomized in cohort 1. Patient median age was 51 years (range, 22-89 years), 99% were women, 70% were White, 24% were Asian, 1.7% were Black or African American, 2.1% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Other Pacific Islander. Forty-three percent of patients were premenopausal. Most patients received prior chemotherapy (37% neoadjuvant, 59% adjuvant) and prior radiotherapy (96%). Sixty-five percent of the patients had 4 or more positive lymph nodes with 22% having ≥10 positive lymph nodes, 41% had Grade 3 tumor, and 24% had pathological tumor size ≥50 mm. The majority of patients (99%) had estrogen receptor positive disease and 87% had progesterone receptor positive disease. Initial endocrine therapy received by patients included letrozole (39%), tamoxifen (31%), anastrozole (22%), or exemestane (8%). Reference ID: 5478239 100 - 'cft-_, 90 >, :!:: .c 80 cu .c 0 I... 0.. 70 cu > "> 60 I... :J Cf) Q.) ~ 50 LL I 40 Q.) Cl) cu Q.) 30 Cl) 0 ~ 20 Censored observations ·u5 cu > C 10 VERZENIO plus Tamoxifen or Aromatase Inhibitors (N=2555) Tamoxifen or Aromatase Inhibitors (N=2565) 0 0 6 12 18 24 30 36 Patients at risk Time (months) VERZENIO plus Tamoxifen or Aromatase Inhibitors 2555 2387 2322 2256 2189 2129 2023 Tamoxifen or Aromatase Inhibitors 2565 2404 2327 2236 2143 2059 1920 42 1162 1134 48 520 511 54 79 82 I, 11-•••· I◄ 60 0 0 Efficacy results for cohort 1 are summarized in Table 16 and Figure 1. At the time of OS interim analysis 2, OS was immature and a total of 315 (6%) of patients had died in cohort 1. Table 16: Efficacy Results in monarchE in Cohort 1 VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2555 Tamoxifen or an Aromatase Inhibitor N=2565 Invasive Disease–Free Survival (IDFS) Number of patients with an event, n (%) 317 (12) 474 (18) Hazard ratio (95% CI) 0.65 (0.57, 0.75) IDFS at 48 months, % (95% CI) 85.5 (83.8, 87.0) 78.6 (76.7, 80.4) Abbreviation: CI = confidence interval. Figure 1: Kaplan-Meier Curves of Invasive Disease–Free Survival VERZENIO plus Tamoxifen or an Aromatase Inhibitor versus Tamoxifen or an Aromatase Inhibitor in Cohort 1 (monarchE) 14.2 Advanced or Metastatic Breast Cancer Reference ID: 5478239 VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) (MONARCH 3) Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease setting MONARCH 3 (NCT02246621) was a randomized (2:1), double-blinded, placebo-controlled, multicenter study in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with a nonsteroidal aromatase inhibitor as initial endocrine-based therapy, including patients not previously treated with systemic therapy for breast cancer. Randomization was stratified by disease site (visceral, bone only, or other) and by prior (neo)adjuvant endocrine therapy (aromatase inhibitor versus other versus no prior endocrine therapy). A total of 493 patients were randomized to receive 150 mg VERZENIO or placebo orally twice daily, plus physician’s choice of letrozole (80% of patients) or anastrozole (20% of patients). Patient median age was 63 years (range, 32-88 years) and the majority were White (58%) or Asian (30%). A total of 51% had received prior systemic therapy and 39% of patients had received chemotherapy, 53% had visceral disease, and 22% had bone-only disease. Efficacy results are summarized in Table 17 and Figure 2. PFS was evaluated according to RECIST version 1.1 and PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent PFS results were observed across patient stratification subgroups of disease site and prior (neo)adjuvant endocrine therapy. Table 17: Efficacy Results in MONARCH 3 (Investigator Assessment, Intent-to-Treat Population) VERZENIO plus Anastrozole or Letrozole Placebo plus Anastrozole or Letrozole Progression-Free Survival N=328 N=165 Number of patients with an event, n (%) 138 (42) 108 (65) Median in months (95% CI) 28.2 (23.5, NR) 14.8 (11.2, 19.2) Hazard ratio (95% CI) 0.54 (0.42, 0.70) p-value <0.0001 Overall Survival N=328 N=165 Number of patients with an event, n (%) 198 (60) 116 (70) Median in months (95% CI) 66.8 (59.2, 74.8) 53.7 (44.7 59.3) Hazard ratio (95% CI) 0.80 (0.64, 1.02) p-value NS Objective Response for Patients with Measurable Diseasea N=267 N=132 Objective response rate, n (%)a,b 148 (55) 53 (40) 95% CI 49, 61 32, 49 Abbreviations: CI = confidence interval; OS = overall survival; NR = not reached; NS = not statistically significant. a Complete response + partial response. b Based upon confirmed responses. Reference ID: 5478239 100 Censored observations - VERZENIO + NSAI (N=328) ~ 0 Placebo + NSAI (N=165) - >- l ~ 80 :.0 IV .c 0 --. ... LL c.. .... \ IV 60 ~- > .... - ·s; ... ... l :::, ... en .. +- ... Q) - - ~ 40 - -H+1 '+ 1- H1-1+t LL HH!ff-, I ., C: -~ .2 Ill t- Ill 20 t-, ~ - ++, C, Lt--, e c.. I 0 I 0 4 8 12 16 20 24 28 32 36 Patients at risk: Time (months) VERZENIO + NSAI 328 272 236 208 181 164 106 40 0 0 Placebo + NSAI 165 126 105 84 66 58 42 7 0 0 Figure 2: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Anastrozole or Letrozole versus Placebo plus Anastrozole or Letrozole in Intent-to-Treat Population (MONARCH 3) VERZENIO in Combination with Fulvestrant (MONARCH 2) Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multicenter study in women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. A total of 669 patients were randomized to receive VERZENIO or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity. Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal. The efficacy results from the MONARCH 2 study are summarized in Table 18, Figure 3, and Figure 4. PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance for PFS and OS. Reference ID: 5478239 c Table 18: Efficacy Results in MONARCH 2 (Intent-to-Treat Population) VERZENIO plus Fulvestrant Placebo plus Fulvestrant Progression-Free Survival (Investigator Assessment) N=446 N=223 Number of patients with an event, n (%) 222 (50) 157 (70) Median in months (95% CI) 16.4 (14.4, 19.3) 9.3 (7.4, 12.7) Hazard ratio (95% CI)a 0.55 (0.45, 0.68) p-valuea p<.0001 Overall Survivalb Number of deaths, n (%) 211 (47) 127 (57) Median OS in months (95% CI) 46.7 (39.2, 52.2) 37.3 (34.4, 43.2) Hazard ratio (95% CI)a 0.76 (0.61, 0.95) p-valuea p=.0137 Objective Response for Patients with Measurable Disease N=318 N=164 Objective response rate, n (%)c 153 (48) 35 (21) 95% CI 43, 54 15, 28 Abbreviation: CI = confidence interval, OS = overall survival. a Stratified by disease site (visceral metastases vs. bone-only metastases vs. other) and endocrine therapy resistance (primary resistance vs. secondary resistance) b Data from a pre-specified interim analysis (77% of the number of events needed for the planned final analysis) with the p-value compared with the allocated alpha of 0.021. Complete response + partial response. Reference ID: 5478239 100 - ~ 0 - >. - :.a 80 Cll .c 0 ... a. Cll 60 > > ... ::::J Cl) Cl) 40 Cl) ... u. I C: 0 en en 20 Cl) ... C) 0 ... a. 0 0 3 6 9 12 Patients at risk: VERZENIO plus fulvestrant 446 367 314 281 234 Placebo plus fulvestrant 223 165 123 103 80 15 Censored observations VERZENIO plus fulvestrant (N=446) Placebo plus fulvestrant (N=223) 18 21 ' • I ·- 1 24 27 30 Time (months) 171 101 61 32 65 13 32 4 2 0 0 Figure 3: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2) Reference ID: 5478239 100 -80 ~ 0 - .C 60 ca .c 0 ... a.. ~ 40 > ... ::::, Cl) 20 Censored observations - VERZEN 10 plus fulvestrant (N=446) - - Placebo plus fulvestrant (N=223) o-----------.------------....---------..--------------- 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Patients at risk: Time (months) VERZENIO plus fulvestrant 446 422 410 397 384 364 339 321 302 284 265 246 234 214 202 157 101 58 23 0 Placebo plus fulvestrant 223 214 201 195 191 178 170 158 148 135 122 115 99 92 82 62 42 15 3 0 Figure 4: Kaplan-Meier Curves of Overall Survival: VERZENIO plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2) VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1) Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting MONARCH 1 (NCT02102490) was a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg VERZENIO orally twice daily on a continuous schedule until development of progressive disease or unmanageable toxicity. Patient median age was 58 years (range, 36-89 years), and the majority of patients were White (85%). Patients had an Eastern Cooperative Oncology Group performance status of 0 (55% of patients) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of patients had had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received a taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting. Table 19 provides the efficacy results from MONARCH 1. Reference ID: 5478239 Table 19: Efficacy Results in MONARCH 1 (Intent-to-Treat Population) VERZENIO 200 mg N=132 Investigator Assessed Independent Review Objective Response Ratea,b, n (%) 26 (20) 23 (17) 95% CI 13, 28 11, 25 Median Duration of Response in months 8.6 7.2 95% CI 5.8, 10.2 5.6, NR Abbreviations: CI = confidence interval, NR = not reached. a All responses were partial responses. b Based upon confirmed responses. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied VERZENIO 50 mg tablets are oval beige tablet with “Lilly” debossed on one side and “50” on the other side. VERZENIO 100 mg tablet are oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side. VERZENIO 150 mg tablets are oval yellow tablet with “Lilly” debossed on one side and “150” on the other side. VERZENIO 200 mg tablets are oval beige tablet with “Lilly” debossed on one side and “200” on the other side. VERZENIO tablets are supplied in 7-day dose pack configurations as follows: • 200 mg dose pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily) NDC 0002-6216-54 • 150 mg dose pack (14 tablets) – each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily) NDC 0002-5337-54 • 100 mg dose pack (14 tablets) – each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily) NDC 0002-4815-54 • 50 mg dose pack (14 tablets) – each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily) NDC 0002-4483-54 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). 17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved Patient Information. Diarrhea VERZENIO may cause diarrhea, which may be severe in some cases [see Warnings and Precautions (5.1)]. • Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up. • Encourage patients to increase oral fluids. • If diarrhea does not resolve with antidiarrheal therapy within 24 hours to ≤Grade 1, suspend VERZENIO dosing [see Dosage and Administration (2.2)]. Neutropenia Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)]. Reference ID: 5478239 Interstitial Lung Disease/Pneumonitis Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)]. Hepatotoxicity Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.4)]. Venous Thromboembolism Advise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions (5.5)]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)]. Lactation Advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2)]. Infertility Inform males of reproductive potential that VERZENIO may impair fertility [see Use in Specific Populations (8.3)]. Drug Interactions • Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors or for moderate CYP3A inhibitors [see Dosage and Administration (2.2) and Drug Interactions (7)]. • Grapefruit may interact with VERZENIO. Advise patients not to consume grapefruit products while on treatment with VERZENIO. • Advise patients to avoid concomitant use of strong and moderate CYP3A inducers and to consider alternative agents [see Dosage and Administration (2.2) and Drug Interactions (7)]. • Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Dosage and Administration (2.2) and Drug Interactions (7)]. Dosing • Instruct patients to take the doses of VERZENIO at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing) [see Dosage and Administration (2.1)]. • If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time [see Dosage and Administration (2.1)]. • Advise the patient that VERZENIO may be taken with or without food [see Dosage and Administration 2.1)]. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2017, 202X, Eli Lilly and Company. All rights reserved. VER-000X-USPI-0000-00-00 Reference ID: 5478239	custom-source	2025-02-12T15:46:39.697670	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208716s017lbl.pdf', 'application_number': 208716, 'submission_type': 'SUPPL ', 'submission_number': 17}
80,220	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LEUPROLIDE ACETATE FOR DEPOT SUSPENSION safely and effectively. See full prescribing information for LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Initial U.S. Approval: 2018 ---------------------------RECENT MAJOR CHANGES-------------------------- Warnings and Precautions (5.2) 12/2023 Warnings and Precautions (5.6) 11/2024 ----------------------------INDICATIONS AND USAGE-------------------------- LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is a gonadotropin releasing hormone (GnRH) agonist indicated for:  Treatment of advanced prostate cancer. (1) ----------------------DOSAGE AND ADMINISTRATION---------------------- Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule (2).  LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3 months administration, given as a single intramuscular injection every 12 weeks. (2.1) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- For Injection: 22.5 mg of leuprolide acetate in a single dose vial as a kit with a prefilled syringe containing diluent and a MIXJECT transfer device. (3). -------------------------------CONTRAINDICATIONS-----------------------------  Hypersensitivity to GnRH, GnRH agonist or any of the excipients in LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. (4). -----------------------WARNINGS AND PRECAUTIONS-----------------------  Tumor Flare: Increased serum testosterone (~50% above baseline) during first week of treatment; monitor serum testosterone and PSA. (5.7) o Transient worsening of symptoms, or additional signs and symptoms of prostate cancer during the first few weeks of treatment. (5.1) o Patients may experience a temporary increase in bone pain which can be managed symptomatically. (5.1) o Ureteral obstruction and spinal cord compression have been reported with GnRH agonists, which may contribute to paralysis with or without fatal complications. (5.1)  Metabolic Syndrome: The use of GnRH agonists may lead to an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease. Monitor for signs and symptoms of metabolic syndrome including lipids, blood glucose level and/or HbA1c and manage according to current treatment guidelines. (5.2)  Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice. (5.3)  Effect on QT/QTc Interval: Androgen deprivation therapy may prolong QT interval. Consider risks and benefits (5.4)  Convulsions have been observed in patients with or without a history of predisposing factors. Manage convulsions according to the current clinical practice. (5.5)  Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), may occur in patients treated with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Interrupt LEUPROLIDE ACETATE FOR DEPOT SUSPENSION if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. (5.6)  Monitor serum levels of testosterone following injection of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration. (5.7)  Embryo-Fetal Toxicity: LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may cause fetal harm. (5.8, 8.1) ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions (incidence > 10%) are hot flushes, upper respiratory infection, fatigue, diarrhea, pollakiuria, arthralgia, and injection site pain (6). As with other GnRH agonist, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy may occur (6). To report SUSPECTED ADVERSE REACTIONS, contact Cipla at 1-866- 604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS-----------------------  Females and males of reproductive potential: LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may impair fertility. Counsel patients on pregnancy planning and prevention. (8.3)  Pediatric: The use of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION formulations are not indicated for use in children (8.4)  Geriatric: This label reflects clinical trials for LEUPROLIDE ACETATE FOR DEPOT SUSPENSION in prostate cancer in which the majority of the subjects studied were at least 65 years of age. (8.5) See 17 for PATIENT COUNSELING INFORMATION. Date: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration 2.2 Reconstitution Instructions for LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tumor flare 5.2 Metabolic Syndrome 5.3 Cardiovascular Diseases 5.4 Effect on QT/QTc Interval 5.5 Convulsions 5.6 Severe Cutaneous Adverse Reactions 5.7 Laboratory Tests 5.8 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-marketing Experience 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5478850 1 FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration (leuprolide acetate) is indicated for treatment of advanced prostate cancer. 2. DOSAGE AND ADMINISTRATION 2.1 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration LEUPROLIDE ACETATE FOR DEPOT SUSPENSION must be administered under the supervision of a physician. In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration- resistant prostate cancer. Table 1. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION Recommended Dosing Dosage 22.5 mg for 3-Month Administration Recommended Dose 1 injection every 12 weeks The recommended dose of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and administered every 12 weeks as a single intramuscular injection. 2.2 Reconstitution Instructions for LEUPROLIDE ACETATE FOR DEPOT SUSPENSION  Reconstitute and administer the lyophilized microspheres as a single intramuscular injection.  The suspension should be administered immediately after reconstitution.  As with other drugs administered by intramuscular injection, the injection site should be alternated periodically.  Visually inspect LEUPROLIDE ACETATE FOR DEPOT SUSPENSION powder (white to off-white powder). DO NOT USE the vial if clumping or caking is evident. A thin layer of powder on the wall of the vial is considered normal prior to mixing with the diluent. The diluent contained in the prefilled syringe should appear clear and colorless.  Use ONLY the provided diluent for reconstitution of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. DO NOT use other diluents.  The reconstituted product is a suspension of milky, white color appearance. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is packaged in a commercial kit. Each kit contains:  One vial containing 22.5 mg of leuprolide acetate as lyophilized microspheres.  One prefilled syringe containing 2 mL of mannitol for injection.  One MIXJECT transfer device including one needle. Reference ID: 5478850 2 t ' PLUNGER BACKSTOP ROD SYRINGE BARREL VIAL ADAPTER NEEDLE FLIP-OFF'. BUTTON ' VIAL--1 ... ~ Please read the instructions completely before you begin. MIXJECT Preparation Wash your hands with soap and hot water and put on gloves1 immediately prior to preparing the injection. Place the tray on a clean, flat surface that is covered with a sterile pad or cloth. Remove the MIXJECT device, the backstop, the prefilled syringe containing the solvent for reconstitution and the LEUPROLIDE ACETATE FOR DEPOT SUSPENSION vial. Remove the Flip-Off button from the top of the vial, revealing the rubber stopper. Place the vial in a standing upright position on the prepared surface. Disinfect the rubber stopper with the alcohol wipe. Discard the alcohol wipe and allow the stopper to dry. Insert the backstop to the flange of the syringe until you feel it snap in place. Proceed to MIXJECT Activation. Reference ID: 5478850 3 MIXJECT Activation 1. Peel the cover away from the blister pack containing the vial adapter (MIXJECT). Do not remove the vial adapter from the blister pack. Place the blister pack containing the vial adapter firmly on the vial top, piercing the vial. Push down gently until you feel it snap in place. 2. Remove the cap from the syringe barrel and then, remove the blister pack from the vial adapter. Connect the syringe to the vial adapter by screwing it clockwise into the opening on the side of the vial adapter. Be sure to gently twist the syringe until it stops turning to ensure a tight connection. 3. While holding the vial, place your thumb on the plunger rod and push the plunger rod in all the way to transfer the diluent from the pre-filled syringe into the vial. Do not release the plunger rod. Reference ID: 5478850 4 4. Keeping the plunger rod depressed, gently swirl the vial for approximately one minute until a uniform milky-white suspension is obtained. This will ensure complete mixing of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION and the sterile mannitol solution diluent. The suspension will now have a milky appearance. In order to avoid separation of the suspension, proceed to the next steps without delay. 5. Invert the MIXJECT system so that the vial is at the top. Grasp the MIXJECT system firmly by the syringe and pull back the plunger rod slowly to draw the reconstituted LEUPROLIDE ACETATE FOR DEPOT SUSPENSION into the syringe. Return the vial to its upright position, and disconnect the vial adapter from the MIXJECT syringe assembly by grabbing firmly the syringe and turning the plastic cap of the vial adapter clockwise. Grasp only the plastic cap when removing. Reference ID: 5478850 5 6. Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward. Advance the plunger to expel the air from the syringe. The syringe containing LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is now ready for administration. The suspension should be administered immediately after reconstitution. 7. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see Figure). NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock. If blood is present, remove the needle immediately. Do not inject the medication. 8. Inject the entire contents of the syringe intramuscularly. 9. Withdraw the needle. Once the syringe has been withdrawn, immediately discard the needle into a suitable sharps container. Dispose the syringe according to local regulations/procedures. 3. DOSAGE FORMS AND STRENGTHS LEUPROLIDE ACETATE FOR DEPOT SUSPENSION For Injection: 22.5 mg of leuprolide acetate for 3-month administration as lyophilized microspheres in a single dose vial as a kit with a prefilled syringe containing 2mL 0.8% mannitol solution and a MIXJECT transfer device for a single dose injection. Reference ID: 5478850 6 4. CONTRAINDICATIONS LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is contraindicated in:  Hypersensitivity LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the excipients in LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature. 5. WARNINGS AND PRECAUTIONS 5.1 Tumor Flare Initially, LEUPROLIDE ACETATE FOR DEPOT SUSPENSION, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first weeks of treatment. Ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. Patients may experience a temporary increase in bone pain, which can be managed symptomatically. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. 5.2 Metabolic Syndrome The use of GnRH agonists may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving a GnRH agonist, and manage according to current treatment guidelines. 5.3 Cardiovascular Diseases Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. 5.4 Effect on QT/QTc Interval Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. 5.5 Convulsions Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Patients receiving a GnRH agonist who experience convulsion should be managed according to current clinical practice. Reference ID: 5478850 7 5.6 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), may occur in patients receiving LEUPROLIDE ACETATE FOR DEPOT SUSPENSION; including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions (6.2)]. Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt LEUPROLIDE ACETATE FOR DEPOT SUSPENSION until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. 5.7 Laboratory Tests Monitor serum levels of testosterone following injection of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3 month administration. In the majority of patients, testosterone levels increased above baseline during the first week, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks. [see Clinical Studies (14) and Adverse Reactions (6)]. 5.8 Embryo-Fetal Toxicity Based on findings in animal studies, LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose, based on body surface area, using an estimated daily dose. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)]. 6. ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling:  Tumor Flare [see Warnings and Precautions (5.1)]  Metabolic Syndrome [see Warnings and Precautions (5.2)]  Cardiovascular Disease [see Warnings and Precautions (5.3)]  Effect on QT/QTc Interval [see Warnings and Precautions (5.4)]  Convulsions [see Warnings and Precautions (5.5)]  Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration In a clinical trial of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration, patients were treated for 24 weeks with 157/163 receiving two injections. The table includes adverse reactions were reported in 5% or more of the patients during the treatment period as well as the incidence of these adverse reaction that were considered, by the treating physician, to be at least possibly related to LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Grade 3-4 adverse reactions reported as treatment- emergent in 13% of patients and treatment-related 4% of patients. Reference ID: 5478850 8 Table 2. Adverse Reactions Reported in ≥ 5% of Patients LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 2.5 mg for 3-Month Administration N = 163 (%) Grade 1-4 Treatment-Emergent Treatment-Related Hot Flush/Flushing1 128 (79) 127 (78) Upper Respiratory Infection2 28 (17) 0 Fatigue/Asthenia 24 (15) 22 (13) Diarrhea 21 (13) 2 (1) Pollakiuria 20 (12) 3 (2) Arthralgia/Arthritis 18 (11) 2 (1) Injection Site Pain/Discomfort 18 (11) 15 (9) Constipation 15 (9) 1 (0.6) Extremity Pain 14 (9) 0 Nausea 14 (9) 4 (2) Nocturia 14 (9) 3 (2) Abdominal Pain/Discomfort 13 (8) 1 (0.6) Urinary Tract Pain 13 (8) 2 (1) Dizziness 12 (7) 2 (1) Headache/Sinus Headache 12 (7) 1 (0.6) Urinary Tract Infection 12 (7) 0 Bone Pain 11 (7) 4 (2) Back Pain 10 (6) 1 (0.6) Hypertension/Blood Pressure Increased 10 (6) 0 Pruritus/Generalized Pruritus 9 (6) 3 (2) CTCAE v.3 1Includes cold sweat, flushing, hot flush, hyperhidrosis, and night sweats 2Includes influenza, influenza-like illness, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection and congestion In the same study, erectile dysfunction and testicular atrophy were reported in patients on LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg. Laboratory abnormalities During the treatment period, at least a one grade change in laboratory values was seen (>10%) in the following: anemia, increased triglyceride, hyperglycemia, increased cholesterol, increased creatine kinase, leukopenia, increased AST, increased creatinine, and increased ALT. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of gonadotropin-releasing hormone agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Mood swings, including depression, have been reported. There have been very rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Pituitary apoplexy: During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Localized reactions including induration and abscess have been reported at the site of injection. Reference ID: 5478850 9 Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide acetate-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Immune Disorders: Anaphylaxis Psychiatric Disorders: Depression Cardiovascular System - hypotension, myocardial infarction, pulmonary embolism Respiratory, Thoracic and Mediastinal disorder - Pneumonitis, interstitial lung disease Hepato-biliary disorder - serious drug-induced liver injury, non-alcoholic fatty liver disease Skin reactions – rash, urticaria, photosensitivity, erythema multiforme, bullous dermatitis, exfoliative dermatitis, DRESS, SJS/ TEN, and AGEP Blood and Lymphatic System - decreased WBC Central/Peripheral Nervous System - convulsion, peripheral neuropathy, spinal fracture/paralysis Endocrine System - diabetes mellitus Musculoskeletal System - tenosynovitis-like symptoms Urogenital System - prostate pain 7. DRUG INTERACTIONS No pharmacokinetic-based drug-drug interaction studies have been conducted with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. 7.1 Drug/Laboratory Test Interactions Administration of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION in therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LEUPROLIDE ACETATE FOR DEPOT SUSPENSION, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may be affected. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Risk summary Based on findings in animal studies and mechanism of action, LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose based on body surface area using an estimated daily dose (see data). Advise pregnant patients and females of reproductive potential of the potential risk to the fetus. Animal Data Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy at doses of 0.00024, 0.0024, and 0.024 mg/kg (approximately 1/1600 to 1/16 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot formulation was utilized in the study, a sustained exposure to leuprolide was expected throughout the period of organogenesis and to the end of gestation. Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats. Reference ID: 5478850 10 8.2. Lactation The safety and efficacy of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION have not been established in females. There is no information regarding the presence of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfed child from LEUPROLIDE ACETATE FOR DEPOT SUSPENSION, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. 8.3. Females and Males of Reproductive Potential Infertility Males Based on findings in animals and mechanism of action, LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric use The safety and effectiveness of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION in pediatric patients have not been established. 8.5 Geriatric use In the clinical trials for LEUPROLIDE ACETATE FOR DEPOT SUSPENSION in prostate cancer 74% of the patients studied were at least 65 years of age. Hot flushes occurred with equal frequency in those less than or at least 65 years of age. 10. OVERDOSAGE There is no experience of over dosage in clinical trials. In rats, a single subcutaneous dose of 100 mg/kg (approximately 4,000 times the estimated daily human dose based on body surface area), resulted in dyspnea, decreased activity, and excessive scratching. In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up two years caused no adverse effects differing from those observed with the 1 mg/day dose. 11. DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: Where: n=1 or 2 Reference ID: 5478850 11 Leuprolide acetate has a molecular weight of 1209.41 as ‘’free base”. Leuprolide is freely soluble in water. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration is available in a vial containing white to off white sterile lyophilized microspheres together with the corresponding sterile reconstitution diluent in a pre-filled syringe. When LEUPROLIDE ACETATE FOR DEPOT SUSPENSION and the diluent are mixed together they become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS as a single dose. Each vial of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration delivers leuprolide acetate (22.5 mg), polylactic acid (188.4 mg), triethylcitrate (10.4 mg), polysorbate 80 (3.8 mg), mannitol (88.4 mg) and carmellose sodium (25 mg). The prefilled syringe containing the clear reconstitution diluent (2 mL) contains mannitol (16 mg), water for injections, and sodium hydroxide and hydrochloric acid to control pH. Leuprolide acetate for depot suspension is an extended release sterile, single dose injection in suspension form for intramuscular administration. 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostate tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. 12.2 Pharmacodynamics In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for more than five years. Leuprolide acetate is not active when given orally. 12.3 Pharmacokinetics Absorption Following two sequential injections of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg administered with a 3 month interval, plasma leuprolide acetate concentrations were similar among both cycles. After first administration, mean plasma leuprolide concentration of 46.8 ng/mL was observed at approximately 2 hours and the mean concentration then declined until next injection. Distribution The mean steady-state volume of distribution of leuprolide acetate following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Elimination The mean systemic clearance of leuprolide acetate following intravenous bolus administration to healthy male volunteers was 7.6 L/h, and terminal elimination half-life was approximately 3 hours based on a two-compartment model. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M- 1) metabolite. Reference ID: 5478850 12 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Genotoxicity studies were conducted with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of mutagenic effects or chromosomal aberrations. Leuprolide acetate may reduce male and female fertility. Administration of leuprolide acetate to male and female rats at dose of 0.024, 0.24, and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive function. These changes were reversible upon cessation of treatment. 14 CLINICAL STUDIES 14.1 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration The efficacy of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg was evaluated in an open-label, multicenter, non- controlled, multiple dose clinical trial which enrolled 162 evaluable patients with prostate cancer. Patients were administered LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg intramuscularly in 2 doses (157 received 2 injections) with a 3-month interval. The median age was 71 years (range; 47-91), 62% White, and 30% Black or African-American. Castrate levels of serum testosterone (<50 ng/dL) were achieved and maintained from Day 28 to 168 in 94.3% (95% CI:89.4, 97.0) of patients. On Day 28, 160 of the 162 (98.8%) patients had castrate testosterone levels. One patient did not achieve a castrate level and one had a missing value. Testosterone escapes (any value > 50 ng/dL after castrate levels were achieved) occurred in four patients. In addition, three patients had a single unevaluable testosterone level after Day 28 that was considered to be non-castrate in this analysis. Figure 1. Mean testosterone plasma levels during treatment with two three-month IM injections of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg 700 600 500 400 300 200 100 0 0 14 28 42 56 70 84 Time (days) 98 112 126 140 154 168 Testosterone concentration (ng/dL) Reference ID: 5478850 13 15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 16 HOW SUPPLIED/STORAGE AND HANDLING LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is supplied as a kit consisting of a LEUPROLIDE ACETATE MIXJECT single-dose delivery system consisting of a vial with a Flip-Off seal containing sterile, white to off white lyophilized leuprolide acetate microspheres incorporated in a biodegradable polymer, a MIXJECT vial adapter containing the needle, and a pre-filled syringe containing clear sterile mannitol solution for injection, USP, 2 mL, pH 4.5 to 7.0. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg – NDC 69097-909-50 Storage Store at controlled room temperature at 20o-25oC (68o-77oF); excursions permitted between 15ºC and 30ºC (59ºC and 86ºF) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Hypersensitivity  Inform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like LEUPROLIDE ACETATE FOR DEPOT SUSPENSION, LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is contraindicated [see Contraindications (4)]. Tumor Flare  Inform patients that LEUPROLIDE ACETATE FOR DEPOT SUSPENSION can cause tumor flare during the first weeks of treatment. Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if urethral obstruction, spinal cord compression, paralysis, or new or worsened symptoms occur after beginning LEUPROLIDE ACETATE FOR DEPOT SUSPENSION treatment [see Warnings and Precautions (5.1)]. Metabolic Syndrome  Advise patients that there is an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non alcoholic fatty liver disease with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION therapy. Inform patients that periodic monitoring for metabolic changes is required when being treated with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION [see Warnings and Precautions (5.2)]. Cardiovascular Disease  Inform patients that there is an increased risk of myocardial infarction, sudden cardiac death, and stroke with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION treatment. Advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.3)]. Severe Cutaneous Adverse Reactions  Inform patients that severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life threatening or fatal, may occur during treatment with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION.  Advise patients to contact their healthcare provider or seek medical attention right away if they experience signs or symptoms of SCARs [see Warnings and Precautions (5.6)]. Urogenital Disorders  Advise patients that LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may cause impotence [(see Use In Specific Populations (8.3)]. Infertility  Inform patients that LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may cause infertility [(see Use In Specific Populations (8.3)]. Reference ID: 5478850 14 Continuation of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION Treatment  Inform patients that LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is usually continued, often with additional medication, after the development of metastatic castration-resistant prostate cancer [see Dosage and Administration (2.1)]. For more information or a video demonstration on how to use, scan the code below or call 1-866-604-3268. Manufactured by: GP-PHARM, S.A. 08777 Sant Quintí de Mediona Spain Distributed by: Cipla USA, Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059 21105644 Reference ID: 5478850 15	custom-source	2025-02-12T15:46:39.829010	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205054s007lbl.pdf', 'application_number': 205054, 'submission_type': 'SUPPL ', 'submission_number': 7}
80,219	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LEQEMBI® safely and effectively. See full prescribing information for LEQEMBI®. LEQEMBI® (lecanemab-irmb) injection, for intravenous use Initial U.S. Approval: 2023 WARNING: AMYLOID RELATED IMAGING ABNORMALITIES See full prescribing information for complete boxed warning. Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). ARIA is usually asymptomatic, although rarely serious and life-threatening events can occur. Serious intracerebral hemorrhages greater than 1 cm have occurred in patients treated with this class of medications. ARIA-E can cause focal neurologic deficits that can mimic ischemic stroke. (5.1, 6.1) ApoE ε4 Homozygotes Patients treated with this class of medications, including LEQEMBI, who are ApoE ε4 homozygotes have a higher incidence of ARIA, including symptomatic and serious ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. (5.1) Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI. (5.1, 14) --------------------------- RECENT MAJOR CHANGES -------------------------- Boxed Warning 11/2024 Warnings and Precautions (5.1) 11/2024 --------------------------- INDICATIONS AND USAGE ---------------------------- LEQEMBI is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. (1) ----------------------- DOSAGE AND ADMINISTRATION ----------------------  Confirm the presence of amyloid beta pathology prior to initiating treatment. (2.1)  The recommended dosage is 10 mg/kg that must be diluted then administered as an intravenous infusion over approximately one hour, once every two weeks. (2.2)  Obtain a recent baseline brain MRI prior to initiating treatment. (2.3, 5.1)  Obtain an MRI prior to the 5th, 7th, and 14th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms. (2.3, 5.1)  Dilution in 250 mL of 0.9% Sodium Chloride Injection, USP, is required prior to administration. (2.4)  Administer as an intravenous infusion over approximately one hour via a terminal low-protein binding 0.2 micron in-line filter. (2.5) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Injection:  500 mg/5 mL (100 mg/mL) solution in a single-dose vial (3)  200 mg/2 mL (100 mg/mL) solution in a single-dose vial (3) ------------------------------ CONTRAINDICATIONS ----------------------------- LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------  Amyloid Related Imaging Abnormalities (ARIA): Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. Risk of ARIA, including symptomatic ARIA, was increased in apolipoprotein E ε4 homozygotes compared to heterozygotes and noncarriers. The risk of ARIA-E and ARIA-H is increased in patients with pretreatment microhemorrhages and/or superficial siderosis. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI scanning if indicated. (2.3, 5.1)  Infusion-Related Reactions: The infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy administered as clinically indicated. Consider pre-medication at subsequent dosing with antihistamines, non-steroidal anti-inflammatory drugs, or corticosteroids. (5.3) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (at approximately 10% and higher incidence compared to placebo): infusion-related reactions, amyloid related imaging abnormality-microhemorrhages, amyloid related imaging abnormality edema/effusion, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: AMYLOID RELATED IMAGING ABNORMALITIES 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Dosing Instructions 2.3 Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities 2.4 Dilution Instructions 2.5 Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Amyloid Related Imaging Abnormalities 5.2 Hypersensitivity Reactions 5.3 Infusion-Related Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5478605 FULL PRESCRIBING INFORMATION WARNING: AMYLOID RELATED IMAGING ABNORMALITIES Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events rarely can occur. Serious intracerebral hemorrhages > 1 cm, some of which have been fatal, have been observed in patients treated with this class of medications. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy to a patient being treated with LEQEMBI [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. ApoE ε4 Homozygotes Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer’s disease patients) treated with this class of medications, including LEQEMBI, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA [see Warnings and Precautions (5.1)]. Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI [see Warnings and Precautions (5.1) and Clinical Studies (14)]. 1 INDICATIONS AND USAGE LEQEMBI is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Confirm the presence of amyloid beta pathology prior to initiating treatment [see Clinical Pharmacology (12.1)]. 2.2 Dosing Instructions The recommended dosage of LEQEMBI is 10 mg/kg that must be diluted then administered as an intravenous infusion over approximately one hour, once every two weeks. 2 Reference ID: 5478605 If an infusion is missed, administer the next dose as soon as possible. 2.3 Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities LEQEMBI can cause amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H) [see Warnings and Precautions (5.1)]. Monitoring for ARIA Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 5th, 7th, and 14th infusions. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated. Recommendations for Dosing Interruptions in Patients with ARIA ARIA-E The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 1. Table 1: Dosing Recommendations for Patients with ARIA-E Clinical Symptom Severity1 ARIA-E Severity on MRI2 Mild Moderate Severe Asymptomatic May continue dosing Suspend dosing3 Suspend dosing3 Mild May continue dosing based on clinical judgment Suspend dosing3 Moderate or Severe Suspend dosing3 1 Clinical Symptom Severity Categories: Mild: discomfort noticed, but no disruption of normal daily activity. Moderate: discomfort sufficient to reduce or affect normal daily activity. Severe: incapacitating, with inability to work or to perform normal daily activity. 2 See Table 3 for MRI radiographic severity [Warnings and Precautions (5.1)]. 3 Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment. ARIA-H The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 2. 3 Reference ID: 5478605 Table 2: Dosing Recommendations for Patients with ARIA-H Clinical Symptom Severity ARIA-H Severity on MRI1 Mild Moderate Severe Asymptomatic May continue dosing Suspend dosing2 Suspend dosing3 Symptomatic Suspend dosing2 Suspend dosing2 1 See Table 3 for MRI radiographic severity [Warnings and Precautions (5.1)]. 2 Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification. 3 Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue LEQEMBI. In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with LEQEMBI, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue LEQEMBI. 2.4 Dilution Instructions  Prior to administration, LEQEMBI must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP.  Use aseptic technique when preparing the LEQEMBI diluted solution for intravenous infusion.  Calculate the dose (mg), the total volume (mL) of LEQEMBI solution required, and the number of vials needed based on the patient’s actual body weight and the recommended dose of 10 mg/kg. Each vial contains a LEQEMBI concentration of 100 mg/mL.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check that the LEQEMBI solution is clear to opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present.  Remove the flip-off cap from the vial. Insert the sterile syringe needle into the vial through the center of the rubber stopper.  Withdraw the required volume of LEQEMBI from the vial(s) and add to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.  Each vial is for one-time use only. Discard any unused portion.  Gently invert the infusion bag containing the LEQEMBI diluted solution to mix completely. Do not shake.  After dilution, immediate use is recommended [see Description (11)]. If not administered immediately, store LEQEMBI refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours, or at room temperature up to 30°C (86°F) for up to 4 hours. Do not freeze. 2.5 Administration Instructions  Visually inspect the LEQEMBI diluted solution for particles or discoloration prior to administration. Do not use if it is discolored, opaque, or foreign particles are seen. 4 Reference ID: 5478605  Prior to infusion, allow the LEQEMBI diluted solution to warm to room temperature.  Infuse the entire volume of the LEQEMBI diluted solution intravenously over approximately one hour through an intravenous line containing a terminal low-protein binding 0.2 micron in-line filter. Flush infusion line to ensure all LEQEMBI is administered.  Monitor for any signs or symptoms of an infusion-related reaction. The infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy administered as clinically indicated. Consider pre-medication at subsequent dosing with antihistamines, non-steroidal anti-inflammatory drugs, or corticosteroids [see Warnings and Precautions (5.3)]. 3 DOSAGE FORMS AND STRENGTHS LEQEMBI is a clear to opalescent and colorless to pale yellow solution, available as:  Injection: 500 mg/5 mL (100 mg/mL) in a single-dose vial  Injection: 200 mg/2 mL (100 mg/mL) in a single-dose vial 4 CONTRAINDICATIONS LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Amyloid Related Imaging Abnormalities Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA E. ARIA-H of any cause and ARIA-E can occur together. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. When present, reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with LEQEMBI. Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI. Incidence of ARIA 5 Reference ID: 5478605 Symptomatic ARIA occurred in 3% (29/898) of patients treated with LEQEMBI in Study 2 [see Clinical Studies (14)]. Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation. Similar findings were observed in Study 1. Including asymptomatic radiographic events, ARIA was observed in 21% (191/898) of patients treated with LEQEMBI, compared to 9% (84/897) of patients on placebo in Study 2. ARIA-E was observed in 13% (113/898) of patients treated with LEQEMBI, compared to 2% (15/897) of patients on placebo. ARIA-H was observed in 17% (152/898) of patients treated with LEQEMBI, compared to 9% (80/897) of patients on placebo. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for LEQEMBI compared to placebo. Incidence of Intracerebral Hemorrhage Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI, compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been observed. Risk Factors for ARIA and Intracerebral Hemorrhage ApoE ε4 Carrier Status The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes. Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on LEQEMBI vs. 22% on placebo) than in heterozygotes (19% on LEQEMBI vs 9% on placebo) and noncarriers (13% on LEQEMBI vs 4% on placebo). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared to 2% of heterozygotes and 1% noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers [see Dosage and Administration (2.3)]. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with LEQEMBI is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design. Radiographic Findings of Cerebral Amyloid Angiopathy (CAA) Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy. The baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, have been identified as risk factors for ARIA. Patients were excluded from enrollment in Study 2 for the presence of more than 4 microhemorrhages and additional findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage greater than 1 cm in greatest diameter, 6 Reference ID: 5478605 superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage. Concomitant Antithrombotic or Thrombolytic Medication In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event, compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients), compared to none in patients who received placebo. Fatal cerebral hemorrhage has occurred in a patient taking an anti-amyloid monoclonal antibody in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent. Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy in a patient being treated with LEQEMBI. Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy, or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy. Radiographic Severity The radiographic severity of ARIA associated with LEQEMBI was classified by the criteria shown in Table 3. 7 Reference ID: 5478605 Table 3: ARIA MRI Classification Criteria ARIA Type Radiographic Severity Mild Moderate Severe ARIA-E FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring <10 cm FLAIR hyperintensity >10 cm with associated gyral swelling and sulcal effacement. One or more separate/ independent sites of involvement may be noted. ARIA-H microhemorrhage ≤ 4 new incident microhemorrhages 5 to 9 new incident microhemorrhages 10 or more new incident microhemorrhages ARIA-H superficial siderosis 1 focal area of superficial siderosis 2 focal areas of superficial siderosis > 2 areas of superficial siderosis The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898) of patients, moderate in 7% (66/898) of patients, and severe in 1% (9/898) of patients. Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with LEQEMBI was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278). Monitoring and Dose Management Guidelines Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity [see Dosage and Administration (2.3)]. Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity [see Dosage and Administration (2.3)]. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E. Baseline brain MRI and periodic monitoring with MRI are recommended [see Dosage and Administration (2.3)]. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment. There is no experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic but radiographically severe ARIA-E. There is limited experience in patients who continued 8 Reference ID: 5478605 6 dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E. Providers should encourage patients to participate in real world data collection (e.g., registries) to help further the understanding of Alzheimer’s disease and the impact of Alzheimer’s disease treatments. Providers and patients can contact Eisai at 888-274-2378 for a list of currently enrolling programs. 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in patients who were treated with LEQEMBI. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy. LEQEMBI is contraindicated in patients with a history of serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. 5.3 Infusion-Related Reactions In Study 2, infusion-related reactions were observed in 26% (237/898) of patients treated with LEQEMBI, compared to 7% (66/897) of patients on placebo; and the majority (75%, 178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity. Infusion-related reactions resulted in discontinuations in 1% (12/898) of patients treated with LEQEMBI. Symptoms of infusion-related reactions include fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation. After the first infusion in Study 1, 38% of patients treated with LEQEMBI had transient decreased lymphocyte counts to less than 0.9 x109/L, compared to 2% in patients on placebo, and 22% of patients treated with LEQEMBI had transient increased neutrophil counts to greater than 7.9 x109/L, compared to 1% of patients on placebo. Lymphocyte and neutrophil counts were not obtained after the first infusion in Study 2. In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions may be considered. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:  Amyloid Related Imaging Abnormalities [see Warnings and Precautions (5.1)]  Hypersensitivity Reactions [see Warnings and Precautions (5.2)]  Infusion-Related Reactions [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 9 Reference ID: 5478605 The safety of LEQEMBI has been evaluated in 2090 patients who received at least one dose of LEQEMBI. In Studies 1 and 2 in patients with Alzheimer’s disease, 1059 patients received LEQEMBI 10 mg/kg every two weeks [see Clinical Studies (14)]. Of these 1059 patients, 50% were female, 79% were White, 15% were Asian, 12% were of Hispanic or Latino ethnicity, and 2% were Black. The mean age at study entry was 72 years (range from 50 to 90 years). In the combined double-blind, placebo-controlled period and long-term extension period of Studies 1 and 2, 1604 patients received LEQEMBI for at least 6 months, 1261 patients for at least 12 months, and 965 patients for 18 months. In the double-blind, placebo-controlled period in Study 1, patients stopped study treatment because of an adverse reaction in 15% of patients treated with LEQEMBI, compared to 6% patients on placebo; in Study 2, patients stopped study treatment because of an adverse reaction in 7% of patients treated with LEQEMBI, compared to 3% patients on placebo. In Study 1, the most common adverse reaction leading to discontinuation of LEQEMBI was infusion-related reactions that led to discontinuation in 2% (4/161) of patients treated with LEQEMBI, compared to 1% (2/245) of patients on placebo. In Study 2, the most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI, compared to <1% (1/897) of patients on placebo. Table 4 shows adverse reactions that were reported in at least 5% of patients treated with LEQEMBI and at least 2% more frequently than in patients on placebo in Study 1. Table 4: Adverse Reactions Reported in at Least 5% of Patients Treated with LEQEMBI 10 mg/kg Every Two Weeks and at least 2% Higher than Placebo in Study 1 Adverse Reaction LEQEMBI 10 mg/kg Every Two Weeks N=161 % Placebo N=245 % Infusion-related reactions 20 3 Headache 14 10 ARIA-E 10 1 Cough 9 5 Diarrhea 8 5 Table 5 shows adverse reactions that were reported in at least 5% of patients treated with LEQEMBI and at least 2% more frequently than in patients on placebo in Study 2. Table 5: Adverse Reactions Reported in at Least 5% of Patients Treated with LEQEMBI 10 mg/kg Every Two Weeks and at least 2% Higher than Placebo in Study 2 Adverse Reaction LEQEMBI 10 mg/kg Every Two Weeks N=898 % Placebo N=897 % Infusion-related reactions 26 7 ARIA-H 14 8 ARIA-E 13 2 10 Reference ID: 5478605 8 Adverse Reaction LEQEMBI 10 mg/kg Every Two Weeks N=898 % Placebo N=897 % Headache 11 8 Superficial siderosis of central nervous system 6 3 Rash1 6 4 Nausea/Vomiting 6 4 1 Rash includes acne, erythema, infusion site rash, injection site rash, rash, rash erythematous, rash pruritic, skin reactions, and urticaria. Less Common Adverse Reactions Atrial fibrillation occurred in 3% of patients treated with LEQEMBI, compared to 2% in patients on placebo. In Study 1, lymphopenia or decreased lymphocyte count was reported in 4% of patients treated with LEQEMBI after the first dose, compared to less than 1% of patients on placebo [see Warnings and Precautions (5.3)]; lymphocytes were not measured after the first dose in Study 2. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on LEQEMBI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal studies have been conducted to assess the potential reproductive or developmental toxicity of LEQEMBI. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 8.2 Lactation Risk Summary There are no data on the presence of lecanemab-irmb in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Published data from other monoclonal antibodies generally indicate low passage of monoclonal antibodies into human milk and limited systemic exposure in the breastfed infant. The effects of this limited exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEQEMBI and any potential adverse effects on the breastfed infant from LEQEMBI or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of LEQEMBI in pediatric patients have not been established. 11 Reference ID: 5478605 8.5 Geriatric Use In Studies 1 and 2, the age of patients exposed to LEQEMBI 10 mg/kg every two weeks (n=1059) ranged from 50 to 90 years, with a mean age of 72 years; 81% were 65 years and older, and 39% were 75 years and older. No overall differences in safety or effectiveness of LEQEMBI have been observed between patients 65 years of age and older and younger adult patients. 11 DESCRIPTION Lecanemab-irmb is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta, and is expressed in a Chinese hamster ovary cell line. Lecanemab-irmb has an approximate molecular weight of 150 kDa. LEQEMBI (lecanemab-irmb) injection is a preservative-free, sterile, clear to opalescent and colorless to pale yellow solution for intravenous use by infusion after dilution. LEQEMBI is supplied in single-dose vials available in concentrations of 500 mg/5 mL (100 mg/mL) or 200 mg/2 mL (100 mg/mL). Each mL of solution contains 100 mg of lecanemab-irmb and arginine hydrochloride (42.13 mg), histidine (0.18 mg), histidine hydrochloride monohydrate (4.99 mg), polysorbate 80 (0.50 mg), and Water for Injection at an approximate pH of 5.0. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. LEQEMBI reduces amyloid beta plaques, as evaluated in Study 1 and Study 2 [see Clinical Studies (14)]. 12.2 Pharmacodynamics Effect of LEQEMBI on Amyloid Beta Pathology The effect of LEQEMBI on amyloid beta plaque levels in the brain was evaluated using Positron Emission Tomography (PET) imaging. The PET signal was quantified using both the Standard Uptake Value Ratio (SUVR) and Centiloid scale to estimate levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer’s disease pathology (frontal, parietal, lateral temporal, sensorimotor, and anterior and posterior cingulate cortices), compared to a brain region expected to be spared of such pathology (cerebellum). LEQEMBI reduced amyloid beta plaque in a dose- and time-dependent manner in the dose-ranging study (Study 1) and in a time-dependent manner in single-dosing regimen study (Study 2) compared with placebo [see Clinical Studies (14)]. In Study 1, treatment with LEQEMBI 10 mg/kg every two weeks reduced amyloid beta plaque levels in the brain, producing reductions in PET SUVR compared to placebo at both Weeks 53 and 79 (P<0.0001). The magnitude of the reduction was time- and dose-dependent. 12 Reference ID: 5478605 During an off-treatment period in Study 1 (range from 9 to 59 months; mean of 24 months), SUVR and Centiloid values began to increase with a mean rate of increase of 2.6 Centiloids/year, however, treatment difference relative to placebo at the end of the double-blind, placebo-controlled period in Study 1 was maintained. In Study 2, treatment with LEQEMBI 10 mg/kg every two weeks reduced amyloid beta plaque levels in the brain, producing reductions compared to placebo starting at Week 13 and continuing through Week 79 (P<0.0001). An increase in plasma Aβ42/40 ratio (Table 6) and CSF Aβ[1-42] was observed with LEQEMBI 10 mg/kg every two weeks dosing compared to placebo. Effect of LEQEMBI on Tau Pathophysiology A reduction in plasma p-tau181 (Table 6), CSF p-tau181, and CSF t-tau was observed with LEQEMBI 10 mg/kg every two weeks compared to placebo. Table 6: Effect of LEQEMBI on Plasma Aβ42/40 and Plasma p-tau181 in Study 1 and Study 2 Biomarker Endpoints Study 1 Study 2 LEQEMBI 10 mg/kg Every Two Weeks Placebo LEQEMBI 10 mg/kg Every Two Weeks Placebo Plasma Aβ42/402 N=43 N=88 N=797 N=805 Mean baseline 0.0842 0.0855 0.088 0.088 Adjusted mean change from baseline at Month 183 0.0075 0.0021 0.008 0.001 Difference from placebo 0.0054 (P=0.0036) 1 0.007 (P<0.0001) 1 Plasma p-tau181 (pg/mL)2 N=84 N=179 N=746 N=752 Mean baseline 4.6474 4.435 3.696 3.740 Adjusted mean change from baseline at Month 183 -1.1127 0.0832 -0.575 0.201 Difference from placebo -1.1960 (P<0.0001) 1 -0.776 (P<0.0001) 1 N is the number of patients with baseline value. 1 P values were not statistically controlled for multiple comparisons. 2 Results should be interpreted with caution due to uncertainties in bioanalysis. 3 Month 18 represents Week 79 in Study 1 and Week 77 in Study 2. A substudy was conducted in Study 2 to evaluate the effect of LEQEMBI on neurofibrillary tangles composed of tau protein using PET imaging (18F-MK6240 tracer). The PET signal was quantified using the SUVR method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer’s disease pathology (whole cortical gray matter, meta-temporal, frontal, cingulate, parietal, occipital, medial temporal, and temporal) in the study population, compared to a brain region expected to be spared of such pathology (cerebellum). The adjusted mean change from baseline in tau PET SUVR, relative to placebo, was in favor of LEQEMBI in the medial temporal (P<0.01), meta temporal (P<0.05), and temporal (P<0.05) regions. No statistically significant differences were observed for the whole cortical gray matter, frontal, cingulate, parietal, or occipital regions. 13 Reference ID: 5478605 Exposure-Response Relationships Model-based exposure-response analyses demonstrated that higher exposures to lecanemab-irmb were associated with greater reduction in clinical decline on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) and Alzheimer Disease Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14). In addition, higher exposures to lecanemab-irmb were associated with greater reduction in amyloid beta plaque. An association between reduction in amyloid beta plaque and clinical decline on CDR-SB and ADAS-Cog14 was also observed. Higher exposures to lecanemab-irmb were also associated with greater increase in plasma Aβ42/40 ratio and greater reduction in plasma p-tau181. 12.3 Pharmacokinetics Steady-state concentrations of lecanemab-irmb were reached after 6 weeks of 10 mg/kg administered every 2 weeks and systemic accumulation was 1.4-fold. The peak concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of lecanemab-irmb increased dose proportionally in the dose range of 0.3 to 15 mg/kg following single dose. Distribution The mean value (95% CI) for central volume of distribution at steady state is 3.24 (3.18-3.30) L. Elimination Lecanemab-irmb is degraded by proteolytic enzymes in the same manner as endogenous IgGs. The clearance of lecanemab-irmb (95% CI) is 0.370 (0.353-0.384) L/day. The terminal half-life is 5 to 7 days. Specific Populations Sex, body weight, and albumin were found to impact exposure to lecanemab-irmb. However, none of these covariates were found to be clinically significant. Patients with Renal or Hepatic Impairment No clinical studies were conducted to evaluate the pharmacokinetics of lecanemab-irmb in patients with renal or hepatic impairment. Lecanemab-irmb is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of lecanemab-irmb or of other lecanemab products. During the 18-month treatment period in Study 1, 63/154 (40.9%) of patients treated with LEQEMBI 10 mg/kg every two weeks developed anti-lecanemab-irmb antibodies. Of these patients, neutralizing anti-lecanemab irmb antibodies were detected in 16/63 (25.4%) patients. However, the assays used to measure anti-lecanemab irmb antibodies and neutralizing antibodies are subject to interference by serum lecanemab concentrations, 14 Reference ID: 5478605 possibly resulting in an underestimation of the incidence of antibody formation. Therefore, there is insufficient information to characterize the effects of anti-lecanemab-irmb antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of LEQEMBI. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies have not been conducted. Mutagenesis Genotoxicity studies have not been conducted. Impairment of Fertility No studies in animals have been conducted to assess the effects of lecanemab-irmb on male or female fertility. No adverse effects on male or female reproductive organs were observed in a 39-week intravenous toxicity study in monkeys administered lecanemab-irmb weekly at doses up to 100 mg/kg. The highest dose tested was associated with plasma exposures (Cave) approximately 27 times that in humans at the recommended human dose (10 mg/kg every two weeks). 14 CLINICAL STUDIES The efficacy of LEQEMBI was evaluated in two double-blind, placebo-controlled, parallel-group, randomized studies (Study 1, NCT01767311; Study 2 NCT03887455) in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment [64% of patients in Study 1; 62% of patients in Study 2] or mild dementia stage of disease [36% of patients in Study 1; 38% of patients in Study 2], consistent with Stage 3 and Stage 4 Alzheimer’s disease). In both studies, patients were enrolled with a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0 and a Memory Box score of 0.5 or greater. All patients had a Mini-Mental State Examination (MMSE) score of ≥22 and ≤30, and had objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the Wechsler-Memory Scale- IV Logical Memory II (subscale) (WMS-IV LMII). Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer’s disease. Patients in each study could enroll in an optional long-term extension. Study 1 In Study 1, 856 patients were randomized to receive one of 5 doses (161 of which were randomized to the recommended dosing regimen of 10 mg/kg every two weeks) of LEQEMBI or placebo (n=247). Of the total number of patients randomized, 71.4% were ApoE ε4 carriers and 28.6% were ApoE ε4 non-carriers. During the study, the protocol was amended to no longer randomize ApoE ε4 carriers to the 10 mg/kg every two weeks dose arm. ApoE ε4 carriers who had been receiving LEQEMBI 10 mg/kg every two weeks for 6 months or less were discontinued from study drug. As a result, in the LEQEMBI 10 mg/kg every two weeks arm, 30.3% of patients were ApoE ε4 carriers and 69.7% were ApoE ε4 non-carriers. At baseline, the mean age of randomized patients was 71 years, with a range of 50 to 90 years. Fifty percent of patients were male and 90% were White. 15 Reference ID: 5478605 I ■ Placebo £ IO mg/kg every two weeks I [ 0.0 ~ I I 0 ' ~ ' 1,1.l <fl ' i: ' .. ·= -0.1 ' -25 .;; ' "' ., -" ' E ' 0 <= .. ' .,, ' ~ -0.2 .c u ' -50 = ' .., .. = ' -; :[. --- ~ :: 1 -0.3 • --- -I -75 * Baseline Weck 53 Week 79 wnber of patients Analysis Visit (Weck) Placebo 98 96 88 10 mg/kg every two weeks 44 43 37 ***P<0_00l In Study 1, a subgroup of 315 patients were enrolled in the amyloid PET substudy; of these, 277 were evaluated at Week 79. Results from the amyloid beta PET substudy are described in Figure 1 and Table 7. Plasma biomarkers are described in Table 6. Figure 1: Reduction in Brain Amyloid Beta Plaque (Adjusted Mean Change from Baseline in Amyloid Beta PET Composite, SUVR and Centiloids) in Study 1 Table 7: Results for Amyloid Beta PET in Study 1 Biomarker Endpoints LEQEMBI 10 mg/kg Every Two Weeks Placebo Amyloid Beta PET Composite SUVR N=44 N=98 Mean baseline 1.373 1.402 Adjusted mean change from baseline at Week 79 Difference from placebo -0.306 -0.310 (P<0.001) 1 0.004 Amyloid Beta PET Centiloid N=44 N=98 Mean baseline 78.0 84.8 Adjusted mean change from baseline at Week 79 Difference from placebo -72.5 -73.5 (P<0.001) 1 1.0 N is the number of patients with baseline value. 1 P values were not statistically controlled for multiple comparisons. The primary endpoint was change from baseline on a weighted composite score consisting of selected items from the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), MMSE, and Alzheimer Disease Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14) at Week 53. LEQEMBI had a 64% likelihood of 25% or greater 16 Reference ID: 5478605 slowing of progression on the primary endpoint relative to placebo at Week 53, which did not meet the prespecified success criterion of 80%. Key secondary efficacy endpoints included the change from baseline in amyloid PET SUVR composite at Week 79 and change from baseline in the CDR-SB and ADAS-Cog14 at Week 79. Results for clinical assessments showed less change from baseline in CDR-SB and ADAS-Cog14 scores at Week 79 in the LEQEMBI group than in patients on placebo (CDR-SB: -0.40 [26%], 90% CI [-0.82, 0.03]; ADAS-Cog14: -2.31 [47%], 90% CI [-3.91, -0.72]. After the 79-week double-blind, placebo-controlled period of Study 1, patients could enroll in an open-label extension period for up to 260 weeks, which was initiated after a gap period (range 9 to 59 months; mean 24 months) off treatment. Study 2 In Study 2, 1795 patients were enrolled and randomized 1:1 to receive LEQEMBI 10 mg/kg or placebo once every 2 weeks. Of the total number of patients randomized, 69% were ApoE ε4 carriers and 31% were ApoE ε4 non-carriers. Overall median age of patients was 72 years, with a range of 50 to 90 years. Fifty-two percent were women, and 1381 (77%) were White, 303 (17%) were Asian, and 47 (3%) were Black. The randomization was stratified according to clinical subgroup (mild cognitive impairment or mild dementia stage of the disease); the presence or absence of concomitant approved therapies for Alzheimer’s disease at baseline (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine); ApoE ε4 carrier status; and geographical region. The primary efficacy outcome was change from baseline at 18 months in the CDR-SB. Key secondary endpoints included change from baseline at 18 months for the following measures: amyloid Positron Emission Tomography (PET) using Centiloids, ADAS-Cog14, and Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL). LEQEMBI treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared to placebo at 18 months (-0.45 [-27%], P<0.0001). Statistically significant differences (P<0.01) between treatment groups were also seen in the results for ADAS Cog14 and ADCS MCI-ADL at 18 months, as presented in Table 8. Both ApoE ε4 carriers and ApoE ε4 noncarriers showed statistically significant treatment differences for the primary endpoint and all secondary endpoints. In an exploratory subgroup analysis of ApoE ε4 homozygotes, which represented 15% of the trial population, a treatment effect was not observed with LEQEMBI treatment on the primary endpoint, CDR-SB, compared to placebo, although treatment effects that favored LEQEMBI were observed for the secondary clinical endpoints, ADAS-Cog14 and ADCS MCI-ADL. Treatment effects on disease-relevant biomarkers (amyloid beta PET, plasma Aβ42/40 ratio, plasma p-tau 181) also favored LEQEMBI in the ApoE ε4 homozygous subgroup. Starting at six months, across all time points, LEQEMBI treatment showed statistically significant changes in the primary and all key secondary endpoints from baseline compared to placebo; see Figure 2. 17 Reference ID: 5478605 - ti) I ..... = C, 0. .0 ,.. C: J:: sh = C, ..c V = r: E "O 0 vi ;:I I. .-, "O I ■ Placebo .A. 10 mg/kg every two weeks I i ii 0 9 12 I 7 49 13 779 7 7 10 m /k 24 7 77 7 7 714 p Table 8: Results for CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in Study 2 Clinical Endpoints LEQEMBI 10 mg/kg Every Two Weeks Placebo CDR-SB N=859 N=875 Mean baseline 3.17 3.22 Adjusted mean change from baseline at 18 months (%) Difference from placebo 1.21 -0.45 (-27%) (P<0.0001) 1.66 ADAS-Cog14 N=854 N=872 Mean baseline 24.45 24.37 Adjusted mean change from baseline at 18 months (%) Difference from placebo 4.140 -1.442 (-26%) (P=0.00065) 5.581 ADCS MCI-ADL N=783 N=796 Mean baseline 41.2 40.9 Adjusted mean change from baseline at 18 months Difference from placebo -3.5 (-37%) 2.0 (P<0.0001) -5.5 Figure 2: Adjusted Mean Change from Baseline in CDR-SB in Study 2 18 Reference ID: 5478605 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied LEQEMBI (lecanemab-irmb) injection is a preservative-free, sterile, clear to opalescent, and colorless to pale yellow solution. LEQEMBI is supplied one vial per carton as follows: 500 mg/5 mL (100 mg/mL) single-dose vial (with white flip cap) – NDC 62856-215-01 200 mg/2 mL (100 mg/mL) single-dose vial (with dark grey flip cap) – NDC 62856-212-01 16.2 Storage and Handling Unopened Vial  Store in a refrigerator at 2°C to 8°C (36°F to 46°F).  Store in the original carton to protect from light.  Do not freeze or shake. Diluted Solution For storage of the diluted infusion solution, see Dosage and Administration (2.4). 17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide). Amyloid Related Imaging Abnormalities Inform patients that LEQEMBI may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as a temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms; however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients to notify their healthcare provider if these symptoms occur. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking LEQEMBI, and that the use of antithrombotic or thrombolytic medications while taking LEQEMBI may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA [see Warnings and Precautions (5.1)]. Inform patients that although ARIA can occur in any patient treated with LEQEMBI, there is an increased risk in patients who are ApoE ε4 homozygotes and that testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Inform patients that if testing is not performed, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA. Inform patients that some symptoms of ARIA-E can mimic ischemic stroke and that their healthcare providers may need to perform additional testing to determine how to treat those symptoms in patients taking LEQEMBI. Advise patients to carry information that they are being treated with LEQEMBI. 19 Reference ID: 5478605 Patient Registry Providers should encourage patients to participate in real world data collection (e.g., registries) to help further the understanding of Alzheimer’s disease and the impact of Alzheimer’s disease treatments. Providers and patients can contact Eisai at 888-274-2378 for a list of currently enrolling programs [see Warnings and Precautions (5.1)]. Hypersensitivity Reactions Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis have occurred in patients who were treated with LEQEMBI. Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions [see Warnings and Precautions (5.2)]. Infusion-Related Reactions Advise patients of the potential risk of infusion-related reactions, which can include flu-like symptoms, nausea, vomiting, and changes in blood pressure, the majority of which occur with the first infusion [see Warnings and Precautions (5.3)]. Manufactured by: Eisai Inc. Nutley, NJ 07110 U.S. License No. 1862 LEQEMBI® is a registered trademark of Eisai R&D Management Co., Ltd. © 2024 Eisai Inc. and Biogen 20 Reference ID: 5478605 MEDICATION GUIDE LEQEMBI® (leh-kem’-bee) (lecanemab-irmb) injection, for intravenous use What is the most important information I should know about LEQEMBI? LEQEMBI can cause serious side effects including:  Amyloid Related Imaging Abnormalities or “ARIA”. ARIA is a side effect that does not usually cause any symptoms but serious symptoms can occur. ARIA can be fatal. It is most commonly seen as temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain, and infrequently, larger areas of bleeding in the brain can occur. Most people who develop ARIA do not get symptoms; however, some people may have symptoms, such as: o headache o nausea o confusion o difficulty walking o dizziness o seizures o vision changes Some people have a genetic risk factor (homozygous apolipoprotein E gene carriers) that may cause an increased risk for ARIA. Talk to your healthcare provider about testing to see if you have this risk factor. You may be at a higher risk of developing bleeding in the brain if you take medicines to reduce blood clots from forming (antithrombotic medicines) while receiving LEQEMBI. Your healthcare provider will do magnetic resonance imaging (MRI) scans before and during your treatment with LEQEMBI to check you for ARIA. You should carry information that you are receiving LEQEMBI which can cause ARIA and that ARIA symptoms can look like stroke symptoms. Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above. There are registries that collect information on treatments for Alzheimer’s disease. Your healthcare provider can help you become enrolled in these registries. For more information, call Eisai at 888-274-2378. What is LEQEMBI? LEQEMBI is a prescription medicine used to treat people with Alzheimer’s disease. It is not known if LEQEMBI is safe and effective in children. Do not receive LEQEMBI if you:  have serious allergic reactions to lecanemab-irmb or to any of the ingredients in LEQEMBI. See the end of this Medication Guide for a complete list of ingredients in LEQEMBI. Before receiving LEQEMBI, tell your healthcare provider about all of your medical conditions, including if you:  are pregnant or plan to become pregnant. It is not known if LEQEMBI will harm your unborn baby. Tell your healthcare provider if you become pregnant during your treatment with LEQEMBI.  are breastfeeding or plan to breastfeed. It is not known if lecanemab-irmb (the active ingredient in LEQEMBI) passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while receiving LEQEMBI. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take medicines to reduce blood clots from forming (antithrombotic medicines, including aspirin). Ask your healthcare provider for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How will I receive LEQEMBI?  LEQEMBI is given by a healthcare provider through a needle placed in your vein (intravenous (IV) infusion) in your arm.  LEQEMBI is given every 2 weeks. Each infusion will last about 1 hour. Reference ID: 5478605  If you miss an infusion of LEQEMBI, you should receive your next dose as soon as possible. What are the possible side effects of LEQEMBI? LEQEMBI can cause serious side effects, including:  see “What is the most important information I should know about LEQEMBI?”  serious allergic reactions. Swelling of the face, lips, mouth, or tongue, hives, or difficulty breathing have happened during a LEQEMBI infusion. Tell your healthcare provider if you have any symptoms of a serious allergic reaction during or after LEQEMBI infusion.  infusion-related reactions. Infusion-related reactions are a common side effect which can be serious. Tell your healthcare provider right away if you get these symptoms during an infusion of LEQEMBI: o fever o dizziness or lightheadedness o flu-like symptoms (chills, body aches, feeling o changes in your heart rate or feel like your chest is shaky, and joint pain) pounding o nausea o difficulty breathing or shortness of breath o vomiting If you have an infusion-related reaction, your healthcare provider may give you medicines before your LEQEMBI infusions to decrease your chance of having an infusion-related reaction. These medicines may include antihistamines, anti- inflammatory medicines, or steroids. The most common side effects of LEQEMBI include:  infusion-related reactions  swelling in areas of the brain, with or without small spots of bleeding in or on the surface of the brain (ARIA)  headache These are not all the possible side effects of LEQEMBI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of LEQEMBI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about LEQEMBI that is written for healthcare professionals. What are the ingredients in LEQEMBI? Active ingredient: lecanemab-irmb. Inactive ingredients: arginine hydrochloride, histidine, histidine hydrochloride monohydrate, polysorbate 80, and water for injection. Manufactured by: Eisai Inc. Nutley, NJ 07110 U.S. License No. 1862 LEQEMBI® is a registered trademark of Eisai R&D Management Co., Ltd. © 2024 Eisai Inc. and Biogen For more information, go to www.LEQEMBI.com or call 1-888-274-2378. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5478605	custom-source	2025-02-12T15:46:40.033668	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761269s008lbl.pdf', 'application_number': 761269, 'submission_type': 'SUPPL ', 'submission_number': 8}
80,211	_________________ ______________ ______________ ______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HERZUMA safely and effectively. See full prescribing information for HERZUMA. HERZUMA® (trastuzumab-pkrb) for injection, for intravenous use Initial U.S. Approval: 2018 HERZUMA (trastuzumab-pkrb) is biosimilar* to HERCEPTIN (trastuzumab). WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete boxed warning Cardiomyopathy: Trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue HERZUMA for cardiomyopathy. (2.5, 5.1) Infusion Reactions, Pulmonary Toxicity: Discontinue HERZUMA for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. (5.2, 5.4) Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception. (5.3, 8.1, 8.3) __________________RECENT MAJOR CHANGES _________________ Dosage and Administration, Evaluation and Testing Before 11/2024 Initiating HERZUMA (2.1) __________________ INDICATIONS AND USAGE HERZUMA is a HER2/neu receptor antagonist indicated in adults for: • the treatment of HER2-overexpressing breast cancer. (1.1, 1.2) • the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. (1.3) Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product. (1, 2.2) _______________ DOSAGE AND ADMINISTRATION For intravenous (IV) infusion only. Do not administer as an IV push or bolus. HERZUMA has different dosage and administration instructions than subcutaneous trastuzumab products. (2.3) Do not substitute HERZUMA (trastuzumab-pkrb) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. (2.3) Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.2) Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.2) Administer at either: • Initial dose of 4 mg/kg over 90 minutes IV infusion, then 2 mg/kg over 30 minutes IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of HERZUMA, administer 6 mg/kg as an IV infusion over 30 to 90 minutes every three weeks to complete a total of 52 weeks of therapy, or • Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every three weeks for 52 weeks. Metastatic HER2-Overexpressing Breast Cancer (2.3) • Initial dose of 4 mg/kg as a 90 minutes IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minutes IV infusions. Metastatic HER2-Overexpressing Gastric Cancer (2.3) • Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks. DOSAGE FORMS AND STRENGTHS • For Injection: 150 mg lyophilized powder in a single-dose vial for reconstitution. (3) • For Injection: 420 mg lyophilized powder in a multiple-dose vial for reconstitution. (3) ___________________ CONTRAINDICATIONS____________________ None. (4) _______________ WARNINGS AND PRECAUTIONS _______________ Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1) ____________________ADVERSE REACTIONS____________________ Adjuvant Breast Cancer • Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and chills. (6.1) Metastatic Breast Cancer • Most common adverse reactions (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. (6.1) Metastatic Gastric Cancer • Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS _______________ Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of HERZUMA. (8.3) See 17 for PATIENT COUNSELING INFORMATION * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of HERZUMA has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY 1 INDICATIONS AND USAGE 1.1 Adjuvant Breast Cancer 1.2 Metastatic Breast Cancer 1.3 Metastatic Gastric Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Evaluation and Testing Before Initiating HERZUMA 2.2 Patient Selection 2.3 Recommended Dosage 2.4 Important Dosing Considerations 2.5 Dosage Modifications for Adverse Reactions 2.6 Preparation Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 1 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy 5.2 Infusion Reactions 5.3 Embryo-Fetal Toxicity 5.4 Pulmonary Toxicity 5.5 Exacerbation of Chemotherapy-Induced Neutropenia 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION Reference ID: 5478083 12 CLINICAL PHARMACOLOGY 14.1 Adjuvant Breast Cancer 12.1 Mechanism of Action 14.2 Metastatic Breast Cancer 12.2 Pharmacodynamics 14.3 Metastatic Gastric Cancer 12.3 12.6 Pharmacokinetics Immunogenicity 16 17 HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility *Sections or subsections omitted from the full prescribing information are not 14 CLINICAL STUDIES listed. 2 Reference ID: 5478083 FULL PRESCRIBING INFORMATION WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY Cardiomyopathy Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with HERZUMA. Discontinue HERZUMA treatment in patients receiving adjuvant therapy and withhold HERZUMA in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. Infusion Reactions; Pulmonary Toxicity Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration of trastuzumab products. Interrupt HERZUMA infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue HERZUMA for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.2, 5.4)]. Embryo-Fetal Toxicity Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. 1 INDICATIONS AND USAGE 1.1 Adjuvant Breast Cancer HERZUMA is indicated in adults for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • as part of a treatment regimen with docetaxel and carboplatin • as a single agent following multi-modality anthracycline based therapy 3 Reference ID: 5478083 Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2)]. 1.2 Metastatic Breast Cancer HERZUMA is indicated in adults: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2)]. 1.3 Metastatic Gastric Cancer HERZUMA is indicated in adults, in combination with cisplatin and capecitabine or 5 fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Evaluation and Testing Before Initiating HERZUMA Assess left ventricular ejection fraction (LVEF) prior to initiation of HERZUMA and at regular intervals during treatment. [see Boxed Warning, Dosage and Administration (2.5), Warnings and Precautions (5.1)]. Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)]. 2.2 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. 4 Reference ID: 5478083 Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.3 Recommended Dosage • HERZUMA is for intravenous infusion only. Do not administer as an intravenous push or bolus. • HERZUMA has different dosage and administration instructions than subcutaneous trastuzumab products. • Do not mix HERZUMA with other drugs. • Do not substitute HERZUMA (trastuzumab-pkrb) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. Adjuvant Treatment of Breast Cancer Administer according to one of the following doses and schedules for a total of 52 weeks of HERZUMA therapy: During and following paclitaxel, docetaxel, or docetaxel and carboplatin: • Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin). • One week following the last weekly dose of HERZUMA, administer HERZUMA at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks. As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens: • Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes • Subsequent doses at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks. • Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)]. Metastatic Breast Cancer • Administer HERZUMA, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression. Metastatic Gastric Cancer • Administer HERZUMA at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks until disease progression. 5 Reference ID: 5478083 2.4 Important Dosing Considerations Missed Dose If the patient has missed a dose of HERZUMA by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; once every three week schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent HERZUMA maintenance doses should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively. If the patient has missed a dose of HERZUMA by more than one week, a re-loading dose of HERZUMA should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; once every three week schedule: 8 mg/kg) as soon as possible. Subsequent HERZUMA maintenance doses (weekly schedule: 2 mg/kg; once every three week schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively. 2.5 Dosage Modifications for Adverse Reactions Infusion Reactions [see Boxed Warning, Warnings and Precautions (5.2)] • Decrease the rate of infusion for mild or moderate infusion reactions • Interrupt the infusion in patients with dyspnea or clinically significant hypotension • Discontinue HERZUMA for severe or life-threatening infusion reactions. Cardiomyopathy [see Boxed Warning, Warnings and Precautions (5.1)] Assess left ventricular ejection fraction (LVEF) prior to initiation of HERZUMA and at regular intervals during treatment. Withhold HERZUMA dosing for at least 4 weeks for either of the following: • ≥ 16% absolute decrease in LVEF from pre-treatment values • LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. HERZUMA may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%. Permanently discontinue HERZUMA for a persistent (> 8 weeks) LVEF decline or for suspension of HERZUMA dosing on more than 3 occasions for cardiomyopathy. 2.6 Preparation Instructions To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is HERZUMA (trastuzumab-pkrb) and not ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. 420 mg Multiple-dose vial 6 Reference ID: 5478083 Reconstitution Reconstitute each 420 mg vial of HERZUMA with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab-pkrb that delivers 20 mL (420 mg trastuzumab-pkrb). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a one-time use solution. Use appropriate aseptic technique when performing the following reconstitution steps: • Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized powder of HERZUMA, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab-pkrb. • Swirl the vial gently to aid reconstitution. DO NOT SHAKE. • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. • Store reconstituted HERZUMA in the refrigerator at 2○C to 8○C (36°F to 46°F); discard unused HERZUMA after 28 days. If HERZUMA is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze. Dilution • Determine the dose (mg) of HERZUMA [see Dosage and Administration (2.3)]. Calculate the volume of the 21 mg/mL reconstituted HERZUMA solution needed, withdraw this amount from the vial using a sterile needle and syringe and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. • Gently invert the bag to mix the solution. • The solution of HERZUMA for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze. 150 mg Single-dose vial Reconstitution Reconstitute each 150 mg vial of HERZUMA with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab-pkrb that delivers 7.15 mL (150 mg trastuzumab-pkrb). Use appropriate aseptic technique when performing the following reconstitution steps: 7 Reference ID: 5478083 • Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of HERZUMA, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution containing 21 mg/mL trastuzumab-pkrb. • Swirl the vial gently to aid reconstitution. DO NOT SHAKE. • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. • Use the HERZUMA solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for one-time use only. If not used immediately, store the reconstituted HERZUMA solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused HERZUMA after 24 hours. Do not freeze. Dilution • Determine the dose (mg) of HERZUMA [see Dosage and Administration (2.3)]. • Calculate the volume of the 21 mg/mL reconstituted HERZUMA solution needed. • Withdraw this amount from the vial using a sterile needle and syringe and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. • Gently invert the bag to mix the solution. • The solution of HERZUMA for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze. 3 DOSAGE FORMS AND STRENGTHS • For injection: 150 mg of HERZUMA as a white to pale yellow lyophilized powder in a single-dose vial • For injection: 420 mg of HERZUMA as a white to pale yellow lyophilized powder in a multiple-dose vial. 4 CONTRAINDICATIONS None. 8 Reference ID: 5478083 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4 to 6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with an anthracycline. Withhold HERZUMA for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.5)]. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Patients who receive anthracycline after stopping trastuzumab products may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement immediately prior to initiation of HERZUMA • LVEF measurements every 3 months during and upon completion of HERZUMA • Repeat LVEF measurement at 4 week intervals if HERZUMA is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.5)] • LVEF measurements every 6 months for at least 2 years following completion of HERZUMA as a component of adjuvant therapy. In NSABP B31, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In HERA (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In BCIRG006, a total of 2.9% (31/1056) of patients in the TCH (docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity. Among 64 patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF 9 Reference ID: 5478083 (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product- induced left ventricular cardiac dysfunction has not been studied. Table 1: Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of Congestive Heart Failure % (n) Study Regimen Trastuzumab Control NSABP B31 & NCCTG N9831a ACb→Paclitaxel+Trastuzumab 3.2% (64/2000)c 1.3% (21/1655) HERAd Chemotherapy → Trastuzumab 2% (30/1678) 0.3% (5/1708) BCIRG006 ACb→Docetaxel+Trastuzumab 2% (20/1068) 0.3% (3/1050) BCIRG006 Docetaxel+Carboplatin+Trastuzumab 0.4% (4/1056) 0.3% (3/1050) a Median follow-up duration for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→paclitaxel + trastuzumab arm. b Anthracycline (doxorubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology. d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year trastuzumab arm. In HERA (one-year trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%. Table 2: Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies Incidence NYHA I-IV NYHA III-IV Study Event Trastuzumab Control Trastuzumab Control H0648g (AC)b Cardiac Dysfunction 28% 7% 19% 3% H0648g (paclitaxel) Cardiac Dysfunction 11% 1% 4% 1% H0649g Cardiac Dysfunctionc 7% N/A 5% N/A a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy. In BCIRG006, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the trastuzumab containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T. 10 Reference ID: 5478083 5.2 Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)]. In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt HERZUMA infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab products after experiencing a severe infusion reaction. Prior to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre-medications. 5.3 Embryo-Fetal Toxicity Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA. Advise pregnant women and females of reproductive potential that exposure to HERZUMA during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of HERZUMA [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)]. 5.4 Pulmonary Toxicity Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. 11 Reference ID: 5478083 5.5 Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not [see Adverse Reactions (6.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions (5.1)] • Infusion Reactions [see Warnings and Precautions (5.2)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)] • Pulmonary Toxicity [see Warnings and Precautions (5.4)] • Exacerbation of Chemotherapy-induced Neutropenia [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions in patients receiving trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.5)]. In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. Adjuvant Breast Cancer The information below reflects exposure to one-year trastuzumab therapy across three randomized, open-label studies, NSABP B31, NCCTG N9831, and HERA with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer. HERA 12 Reference ID: 5478083 Table 3 reflects exposure to trastuzumab in 1678 patients in HERA; the median treatment duration was 51 weeks and median number of infusions was 18 [see Clinical Studies (14.1)]. Table 3: Adverse Reactions (>1%) in HERA (All Grades)a Adverse Reactions Trastuzumab (n = 1678) % Observation (n = 1708) % Nervous System Headache 10 3 Paresthesia 2 0.6 Musculoskeletal Arthralgia 8 6 Back Pain 5 3 Myalgia 4 1 Bone Pain 3 2 Muscle Spasm 3 0.2 Infections Nasopharyngitis 8 3 Urinary tract infection 3 0.8 Gastrointestinal Diarrhea 7 1 Nausea 6 1 Vomiting 3.5 0.6 Constipation 2 1 Dyspepsia 2 0.5 Upper abdominal pain 2 1 General Pyrexia 6 0.4 Peripheral edema 5 2 Chills 5 0 Asthenia 4.5 2 Influenza-like illness 2 0.2 Respiratory Thoracic Mediastinal Cough 5 2 13 Reference ID: 5478083 Adverse Reactions Trastuzumab (n = 1678) % Observation (n = 1708) % Influenza 4 0.5 Dyspnea 3 2 URI 3 1 Rhinitis 2 0.4 Pharyngolaryngeal Pain 2 0.5 Sinusitis 2 0.3 Epistaxis 2 0.06 Cardiac Hypertension 4 2 Dizziness 4 2 Ejection fraction decreased 3.5 0.6 Palpitations 3 0.7 Cardiac arrhythmiasb 3 1 Cardiac failure (congestive) 2 0.3 Skin & Subcutaneous Tissue Rash 4 0.6 Nail Disorders 2 0 Pruritus 2 0.6 a The incidence of Grade 3 or higher adverse reactions was < 1% in both arms for each listed term. b Higher level grouping term. Clinically relevant adverse reactions in < 1% of patients who received trastuzumab in HERA included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%), autoimmune thyroiditis (0.3%), and sudden death (0.06%). Adjuvant Treatment of Breast Cancer with Trastuzumab Beyond One Year Extending adjuvant treatment beyond one year is not recommended [see Dosage and Administration (2.3)]. In HERA, a comparison of trastuzumab administered once every 3 weeks for two years versus one year was performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab compared to the 1-year trastuzumab treatment arm (8.1% versus 4.6%, respectively). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%). 14 Reference ID: 5478083 NSABP B31 and NCCTG N9831 The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks [see Clinical Studies (14.1)]. In NSABP B31, only Grade 3-5 adverse events, treatment-related Grade 2 events, and Grade 2 to 5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity. In NCCTG N9831, data collection was limited to the following investigator-attributed treatment- related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3 to 5 non-hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1-5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The following non- cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity. BCIRG006 Safety data from BCIRG006 reflect exposure to trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and once every three week dosing in the monotherapy period [see Clinical Studies (14.1)]. In BCIRG006, the toxicity profile was similar to that reported in NSABP B31, NCCTG N9831, and HERA with the exception of a lower incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The safety of trastuzumab was evaluated in one randomized, open-label study (H0648g) of chemotherapy with (n = 235) or without (n = 234) intravenous trastuzumab in patients with metastatic breast cancer and in one single-arm study (H0649g) in patients with metastatic breast cancer (n = 222) [see Clinical Studies (14.1)]. Patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly. In H0648g, 58% of patients received trastuzumab for ≥ 6 months and 9% received trastuzumab for ≥ 12 months, respectively. In H0649g, 31% of patients received trastuzumab for ≥ 6 months and 16% received trastuzumab for ≥ 12 months, respectively. Table 4 shows the adverse reactions (≥ 5%) in patients from H0648g and H0649g. 15 Reference ID: 5478083 Table 4: Adverse Reactionsa (≥ 5%) in the Trastuzumab Arms in H0648g and H0649g Trastuzumaba n = 352 % Trastuzumab + Paclitaxel n = 91 % Paclitaxel n = 95 % Trastuzumab + ACb n = 143 % ACb n = 135 % General Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Gastrointestinal Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Anorexia 14 24 16 31 26 Nausea and vomiting 8 14 11 18 9 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 < 1 Nervous Insomnia 14 25 13 29 15 16 Reference ID: 5478083 Trastuzumaba n = 352 % Trastuzumab + Paclitaxel n = 91 % Paclitaxel n = 95 % Trastuzumab + ACb n = 143 % ACb n = 135 % Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Cardiovascular Congestive heart failure 7 11 1 28 7 Tachycardia 5 12 4 10 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Urogenital Urinary tract infection 5 18 14 13 7 Blood and Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 a Data for trastuzumab single agent were from 4 studies, including 213 patients from H0649g b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide Metastatic Gastric Cancer The safety of trastuzumab was evaluated in patients with previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma in an open label, multi-center trial (ToGA) [see Clinical Studies (14.3)]. Patients were randomized (1:1) to receive trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) (n=294) or chemotherapy alone (FC) (n=290). Patients in the trastuzumab plus chemotherapy arm received trastuzumab 8 mg/kg administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1 to 14 or 5 fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21 day cycles. Median duration of trastuzumab 17 Reference ID: 5478083 treatment was 21 weeks and the median number of trastuzumab infusions administered was eight. Table 5: Adverse Reactions (All Grades ≥ 5% or Grade 3-4 ≥ 1% between Arms) in ToGA Adverse Reactions Trastuzumab + FC (N = 294) % FC (N = 290) % All Grades Grades 3-4 All Grades Grades 3-4 Investigations Neutropenia 78 34 73 29 Hypokalemia 28 10 24 6 Anemia 28 12 21 10 Thrombocytopenia 16 5 11 3 Blood and Lymphatic System Disorders Febrile Neutropenia — 5 — 3 Gastrointestinal Disorders Diarrhea 37 9 28 4 Stomatitis 24 1 15 2 Dysphagia 6 2 3 < 1 General Fatigue 35 4 28 2 Fever 18 1 12 0 Mucosal Inflammation 13 2 6 1 Chills 8 < 1 0 0 Metabolism and Nutrition Disorders Weight Decrease 23 2 14 2 Infections and Infestations Upper Respiratory Tract Infections 19 0 10 0 Nasopharyngitis 13 0 6 0 Renal and Urinary Disorders Renal Failure and Impairment 18 3 15 2 Nervous System Disorders Dysgeusia 10 0 5 0 18 Reference ID: 5478083 The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In HERA, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year trastuzumab arm); and in NSABP B31 and NCCTG N9831, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. Following initiation of trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in NSABP B31 and NCCTG N9831, and in patients receiving one-year trastuzumab monotherapy compared to observation in HERA (see Table 6, Figures 1 and 2). The incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery. Table 6: Myocardial Dysfunction (by LVEF) in NSABP B31, NCCTG N9831, HERA and BCIRG006a Study and Arm LVEF < 50% and Decrease from Baseline LVEF Decrease LVEF < 50% ≥ 10% decrease ≥ 16% decrease < 20% and ≥ 10% ≥ 20% NSABP B31 & NCCTG N9831b, c AC→TH (n = 1856) 23.1% (428) 18.5% (344) 11.2% (208) 37.9% (703) 8.9% (166) AC→T (n = 1170) 11.7% (137) 7.0% (82) 3.0% (35) 22.1% (259) 3.4% (40) HERAd Trastuzumab (n = 1678) 8.6% (144) 7.0% (118) 3.8% (64) 22.4% (376) 3.5% (59) Observation (n = 1708) 2.7% (46) 2.0% (35) 1.2% (20) 11.9% (204) 1.2% (21) BCIRG006e TCH (n = 1056) 8.5% (90) 5.9% (62) 3.3% (35) 34.5% (364) 6.3% (67) AC→TH (n = 1068) 17% (182) 13.3% (142) 9.8% (105) 44.3% (473) 13.2% (141) AC→T (n = 1050) 9.5% (100) 6.6% (69) 3.3% (35) 34% (357) 5.5% (58) 19 Reference ID: 5478083 0.50 0.45 0.40 0.35 ., g 0.30 ., 0.25 "O ·;:; - ..!: Q) 0.20 > "-; "3 0.15 E ~ ::, (.) 0.10 0.05 0.00 J __ _,_,.,--- ___ r-- _,,----------- ,...,........, _ ,........, ,.. Number at Risk 1959 1870 951 ◄92 481 221 139 AC->T•H 1316 1156 1a. 257 256 159 98 AC->T 0 2 3 4 5 6 7 8 Time from lnitation of Paclitaxel/Trastuzumab (Years) AC->T AC->T+H a For NSABP B31, NCCTG N9831 and HERA, events are counted from the beginning of trastuzumab treatment. For BCIRG006, events are counted from the date of randomization. b NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH). c Median duration of follow-up for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→TH arm. d Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm. e BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH). Figure 1: NSABP B31 and NCCTG N9831: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is initiation of paclitaxel or trastuzumab + paclitaxel therapy. 20 Reference ID: 5478083 0.50 0.45 0.40 0.35 Q) 0 C Q) 0.30 u ·o 0.25 .s -~ 0.20 ;;; 0.15 s E 0.10 :::, (.) 0.05 0.00 0.50 - 0.45 - 0.40 - 0 35 - 0.30 - 0.25 - 0.20 - 0.15 - 0 10 - 0.05 - 0.00 - 0 Number at risk AC->T 1050 AC->TH 1068 TCH 1056 ~ ------------ Numbe at Risk 1678 1142 873 538 263 Trastuzumab 1-Year 1708 1154 831 498 245 Observation Only 0 6 12 18 24 Time from Randomization (Months) Observation Only Trastuzumab 1-Year - AC->T (doxorubid n + cyclophosphamide -> docetaxel) --- AC->TH (doxorubicin + cyclophosphamlde -> docetaxel + trastuzumab -- TCH ( docetaxel + carboplatin + trastuzumab) .---------·-------------------- ... -----···~· -~-- ....... II - - --- - -- d::- _.,_,. _ _ 4JOi""" - 6 947 975 975 12 836 839 877 18 Time (Months) 523 474 535 24 359 315 350 36 259 248 271 Figure 2: HERA: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. Figure 3: BCIRG006: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. 21 Reference ID: 5478083 The incidence of congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I to IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received trastuzumab concurrently with anthracyclines. In ToGA, 5% of patients in the trastuzumab plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with trastuzumab, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of trastuzumab infusion); permanent discontinuation of trastuzumab for infusion reactions was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9% of patients, on second or subsequent trastuzumab infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [H0648g]), of selected NCI-CTC Grade 2-5 anemia (12.3% vs. 6.7% [NSABP B31]), and of anemia requiring transfusions (0.1% vs. 0 patients [NCCTG N9831]) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of trastuzumab as a single agent (H0649g), the incidence of NCI CTC Grade 3 anemia was < 1%. In ToGA (metastatic gastric cancer), on the trastuzumab containing arm as compared to the chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI-CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4 to 5 neutropenia (1.7% vs. 0.8% [NCCTG N9831]) and of selected Grade 2 to 5 neutropenia (6.4% vs. 4.3% [NSABP B31]) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic gastric cancer) on the trastuzumab containing arm as compared to the chemotherapy alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection 22 Reference ID: 5478083 The overall incidences of infection (46% vs. 30% [H0648g]), of selected NCI-CTC Grade 2 to 5 infection/febrile neutropenia (24.3% vs. 13.4% [NSABP B31]) and of selected Grade 3 to 5 infection/febrile neutropenia (2.9% vs. 1.4% [NCCTG N9831]) were higher in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In BCIRG006, the overall incidence of infection was higher with the addition of trastuzumab to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3 to 4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2 to 5 pulmonary toxicity (14.3% vs. 5.4% [NSABP B31]) and of selected NCI-CTC Grade 3 to 5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [NCCTG N9831]) was higher in patients receiving trastuzumab and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2 to 5: 11.8% vs. 4.6% [NSABP B31]; NCI-CTC Grade 2 to 5: 2.4% vs. 0.2% [NCCTG N9831]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving trastuzumab, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In HERA, there were 4 cases of interstitial pneumonitis in the one-year trastuzumab treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months. Metastatic Breast Cancer Among women receiving trastuzumab for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions (5.4). Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [NSABP B31], 2.5% and 3.7% vs. 2.2% [BCIRG006] and 2.1% vs. 0% [H0648g]). 23 Reference ID: 5478083 Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2 5 diarrhea (6.7% vs. 5.4% [NSABP B31]) and of NCI-CTC Grade 3 to 5 diarrhea (2.2% vs. 0% [NCCTG N9831]), and of Grade 1 to 4 diarrhea (7% vs. 1% [HERA; one-year trastuzumab treatment at 12.6 months median duration of follow-up]) were higher in patients receiving trastuzumab as compared to controls. In BCIRG006, the incidence of Grade 3 to 4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1 to 4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab. Of patients receiving trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In ToGA (metastatic gastric cancer) on the trastuzumab-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the trastuzumab-containing arm and 0.3% on the chemotherapy only arm. In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of trastuzumab therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of trastuzumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Infusion reaction [see Warnings and Precautions (5.2)] • Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions (5.3)] • Glomerulopathy [see Adverse Reactions (6.1)] • Immune thrombocytopenia • Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with trastuzumab products. Patients with significant tumor burden (e.g. bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated. 24 Reference ID: 5478083 7 DRUG INTERACTIONS Anthracyclines Patients who receive anthracycline after stopping trastuzumab products may be at increased risk of cardiac dysfunction because of trastuzumab products' estimated long washout period [see Clinical Pharmacology (12.3)]. If possible, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab products. If anthracyclines are used, closely monitor the patient's cardiac function. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post- marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Data]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if a trastuzumab product is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of a trastuzumab product [see Clinical Considerations]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received HERZUMA during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal/neonatal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data In post-marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence. Fetal manifestations included pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In most reported cases, amniotic fluid index increased after trastuzumab was stopped. In reported cases where trastuzumab therapy was resumed after amniotic index improved, oligohydramnios recurred. Animal Data In studies where trastuzumab was administered to pregnant Cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the 25 Reference ID: 5478083 recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects. 8.2 Lactation Risk Summary There is no information regarding the presence of trastuzumab products in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated with neonatal toxicity [see Data]. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for HERZUMA treatment and any potential adverse effects on the breastfed child from HERZUMA or from the underlying maternal condition. This consideration should also take into account the trastuzumab product wash out period of 7 months [see Clinical Pharmacology (12.3)]. Data In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of trastuzumab products). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA. Contraception Females Trastuzumab products can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with HERZUMA and for 7 months following the last dose of HERZUMA [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of HERZUMA in pediatric patients have not been established. 26 Reference ID: 5478083 8.5 Geriatric Use Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in H0648g and H0649g, or adjuvant therapy in NSABP B31 and NCCTG N9831. Limitations in data collection and differences in study design of the 4 studies of trastuzumab in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of trastuzumab in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of trastuzumab treatment in older patients is different from that observed in patients < 65 years of age for metastatic disease and adjuvant treatment. In ToGA (metastatic gastric cancer), of the 294 patients treated with trastuzumab, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed. 11 DESCRIPTION Trastuzumab-pkrb is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab-pkrb is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. HERZUMA (trastuzumab-pkrb) for injection is a sterile, white to pale yellow, preservative-free lyophilized powder with a cake-like appearance, for intravenous administration. Each multiple-dose vial of HERZUMA delivers 420 mg trastuzumab-pkrb, 839 mg α,α-trehalose dihydrate, 9.5 mg L-histidine HCl, 6.1 mg L-histidine, and 1.7 mg polysorbate 20. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab-pkrb that delivers 20 mL (420 mg trastuzumab-pkrb), at a pH of approximately 6. If HERZUMA is reconstituted with SWFI without preservative, the reconstituted solution is considered single-dose. Each single-dose vial of HERZUMA delivers 150 mg trastuzumab-pkrb, 299.6 mg α,α-trehalose dihydrate, 3.4 mg L-histidine HCl, 2.2 mg L-histidine, and 0.6 mg polysorbate 20. Reconstitution with 7.4 mL of sterile water for injection (SWFI) yields a solution containing 21 mg/mL trastuzumab-pkrb that delivers 7.15 mL (150 mg trastuzumab-pkrb), at a pH of approximately 6. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. 27 Reference ID: 5478083 Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. 12.2 Pharmacodynamics Trastuzumab product exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized. Cardiac Electrophysiology The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors. 12.3 Pharmacokinetics The pharmacokinetics of trastuzumab were evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways. Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the once every three week schedule compared to the weekly schedule of trastuzumab, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first trastuzumab cycle and at steady state exposure are described in Tables 7 and 8, respectively. Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations in at least 95% of breast cancer patients and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Table 7: Population Predicted Cycle 1 PK Exposures (Median with 5th to 95th Percentiles) in Breast Cancer and MGC Patients Schedule Primary tumor type N Cmin (mcg/mL) Cmax (mcg/mL) AUC0-21 days (mcg.day/mL) 8 mg/kg + 6 mg/kg q3w Breast cancer 1195 29.4 (5.8 to 59.5) 178 (117 to 291) 1373 (736 to 2245) MGC 274 23.1 (6.1 to 50.3) 132 (84.2 to 225) 1109 (588 to 1938) 28 Reference ID: 5478083 Schedule Primary tumor type N Cmin (mcg/mL) Cmax (mcg/mL) AUC0-21 days (mcg.day/mL) 4 mg/kg + 2 mg/kg qw Breast cancer 1195 37.7 (12.3 to 70.9) 88.3 (58 to 144) 1066 (586 to 1754) Table 8: Population Predicted Steady State PK Exposures (Median with 5th to 95th Percentiles) in Breast Cancer and MGC Patients Schedule Primary tumor type N a Cmin,ss (mcg/mL) b Cmax,ss (mcg/mL) AUCss, 0-21 days (mcg.day/mL) Time to steady- state (week) Total CL range at steady- state (L/day) 8 mg/kg + 6 Breast cancer 1195 47.4 (5 to 115) 179 (107 to 309) 1794 (673 to 3618) 12 0.173 to 0.283 mg/kg q3w MGC 274 32.9 (6.1 to 88.9) 131 (72.5 to 251) 1338 (557 to 2875) 9 0.189 to 0.337 4 mg/kg + 2 mg/kg qw Breast cancer 1195 66.1 (14.9 to 142) 109 (51.0 to 209) 1765 (647 to 3578) 12 0.201 to 0.244 a Steady-state trough serum concentration of trastuzumab b Maximum steady-state serum concentration of trastuzumab Specific Populations Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (< 65 (n=1294); ≥ 65 (n=288)), race (Asian (n=264); non-Asian (n=1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n=636) or moderate (CLcr 30 to 60 mL/min) (n=133)). The pharmacokinetics of trastuzumab products in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown. Drug Interaction Studies There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinically significant interactions between trastuzumab and concomitant medications used in clinical trials have not been observed. Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy. 29 Reference ID: 5478083 Docetaxel and carboplatin: When trastuzumab was administered in combination with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered. Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in ToGA, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with trastuzumab. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of trastuzumab or of other trastuzumab products. Among 903 women with metastatic breast cancer, human anti human antibody (HAHA) to trastuzumab was detected in one patient using an enzyme linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The clinical relevance of the development of anti-trastuzumab antibodies after treatment with trastuzumab is not known. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Trastuzumab products have not been tested for carcinogenic potential. No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab. A fertility study was conducted in female Cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. 14 CLINICAL STUDIES 14.1 Adjuvant Breast Cancer The safety and efficacy of trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer were evaluated in an integrated analysis of two randomized, open-label, clinical trials (NSABP B31 and NCCTG N9831) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (HERA) with a total of 3386 women at definitive Disease-Free Survival analysis for one-year 30 Reference ID: 5478083 trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (BCIRG006). NSABP B31 and NCCTG N9831 In NSABP B31 and NCCTG N9831, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (NCCTG N9831) or was required to be performed at a reference laboratory (NSABP B31). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible. Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC→paclitaxel) alone or paclitaxel plus trastuzumab (AC→paclitaxel + trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks in NSABP B31; paclitaxel was administered only by the weekly schedule in NCCTG N9831. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline [see Dosage and Administration (2.5)]. Radiation therapy, if administered, was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The major efficacy outcome measure of the combined efficacy analysis was Disease-Free Survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. An additional efficacy outcome measure was overall survival (OS). A total of 3752 patients were included in the joint efficacy analysis of DFS following a median follow-up of 2.0 years in the AC→paclitaxel + trastuzumab arm. The pre-planned final OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel + trastuzumab arm. The data from both arms in NSABP B31 and two of the three study arms in NCCTG N9831 were pooled for efficacy analyses. The patients included in the DFS analysis had a median age of 49 years (range, 22 to 80 years; 6% > 65 years), 84% were White, 7% Black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+ tumors. HERA In HERA, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory. Patients with node-negative disease were required to have ≥ T1c primary tumor. Patients with a history of congestive heart failure or LVEF < 55%, uncontrolled arrhythmias, angina requiring medication, clinically significant valvular heart disease, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic > 180 mm Hg or diastolic > 100 mm Hg) were not eligible. 31 Reference ID: 5478083 Patients were randomized (1:1:1) upon completion of definitive surgery, and at least four cycles of chemotherapy to receive no additional treatment, or one year of trastuzumab treatment or two years of trastuzumab treatment. Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The major efficacy outcome measure was Disease-Free Survival (DFS), defined as in NSABP B31 and NCCTG N9831. HERA was designed to compare one and two years of once every three week trastuzumab treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). A protocol specified interim efficacy analysis comparing one-year trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the trastuzumab arm. Among the 3386 patients randomized to the observation (n = 1693) and trastuzumab one year (n = 1693) treatment arms, the median age was 49 years (range 21 to 80), 83% were White, and 13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node positive, 32% node negative, and in 11% of patients, nodal status was not assessable due to prior neo-adjuvant chemotherapy. Ninety-six percent (1055/1098) of patients with node-negative disease had high-risk features: among the 1098 patients with node-negative disease, 49% (543) were ER- and PgR-, and 47% (512) were ER and/or PgR + and had at least one of the following high-risk features: pathological tumor size greater than 2 cm, Grade 2 to 3, or age < 35 years. Prior to randomization, 94% of patients had received anthracycline-based chemotherapy regimens. After the DFS results comparing observation to one-year trastuzumab treatment were disclosed, a prospectively planned analysis that included comparison of one year versus two years of trastuzumab treatment at a median follow-up duration of 8 years was performed. Based on this analysis, extending trastuzumab treatment for a duration of two years did not show additional benefit over treatment for one year [Hazard Ratios of two-years trastuzumab versus one-year trastuzumab treatment in the intent to treat (ITT) population for Disease-Free Survival (DFS) = 0.99 (95% CI: 0.87, 1.13), p-value = 0.90 and Overall Survival (OS) = 0.98 (0.83, 1.15); p-value = 0.78]. BCIRG006 In BCIRG006, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one of the following high-risk features: ER/PR negative, tumor size > 2 cm, age < 35 years, or histologic and/or nuclear Grade 2 or 3. Patients with a history of CHF, myocardial infarction, Grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic > 100 mm Hg), any T4 or N2, or known N3 or M1 breast cancer were not eligible. Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab (AC-TH), or docetaxel and carboplatin plus trastuzumab (TCH). In both the AC-T and AC-TH arms, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were administered every 3 weeks for four cycles; docetaxel 100 mg/m2 was administered every 3 weeks for four cycles. In 32 Reference ID: 5478083 the TCH arm, docetaxel 75 mg/m2 and carboplatin (at a target AUC of 6 mg/mL/min as a 30- to 60-minute infusion) were administered every 3 weeks for six cycles. Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg) concurrently with either T or TC, and then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. Disease-Free Survival (DFS) was the major efficacy outcome measure. Among 3222 patients, the median age was 49 (range 22 to 74 years; 6% ≥ 65 years). Disease characteristics included 54% ER+ and/or PR+ and 71% node positive. Prior to randomization, all patients underwent primary surgery for breast cancer. The results for DFS for the integrated analysis of NSABP B31 and NCCTG N9831, HERA, and BCIRG006 and OS results for the integrated analysis of NSABP B31 and NCCTG N9831, and HERA are presented in Table 9. For NSABP B31 and NCCTG N9831, the duration of DFS following a median follow-up of 2.0 years in the AC→TH arm is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm is presented in Figure 5. The duration of DFS for BCIRG006 is presented in Figure 6. For NSABP B31 and NCCTG N9831, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3 years of median follow up [AC→TH], the survival rate was estimated to be 86.9% in the AC→TH arm and 79.4% in the AC→T arm. The final OS analysis results from NSABP B31 and NCCTG N9831 indicate that OS benefit by age, hormone receptor status, number of positive lymph nodes, tumor size and grade, and surgery/radiation therapy was consistent with the treatment effect in the overall population. In patients ≤ 50 years of age (n = 2197), the OS hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in patients > 50 years of age (n = 1866), the OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-positive disease (ER-positive and/or PR-positive) (n = 2223), the hazard ratio for OS was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-negative disease (ER-negative and PR-negative) (n = 1830), the hazard ratio for OS was 0.64 (95% CI: 0.52, 0.80). In the subgroup of patients with tumor size ≤ 2 cm (n = 1604), the hazard ratio for OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size > 2 cm (n = 2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80). 33 Reference ID: 5478083 Table 9: Efficacy Results from Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831, HERA, and BCIRG006) DFS events DFS Hazard ratio (95% CI) p-value Deaths (OS events) OS Hazard ratio p-value NSABP B31 and NCCTG N9831a AC→TH (n = 1872)b (n = 2031)c 133b 0.48b, d (0.39, 0.59) p< 0.0001e 289c 0.64c, d (0.55, 0.74) p< 0.0001e AC→T (n = 1880)b (n = 2032)c 261b 418c HERAf Chemo→ Trastuzumab (n = 1693) 127 0.54 (0.44, 0.67) p< 0.0001g 31 0.75 p = NSh Chemo→ Observation (n = 1693) 219 40 BCIRG006i TCH (n = 1075) 134 0.67 (0.54 to 0.84) p = 0.0006e, j 56 AC→TH (n = 1074) 121 0.60 (0.48 to 0.76) p< 0.0001e, i 49 AC→T (n = 1073) 180 80 CI = confidence interval a NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH). b Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC→TH arm. c Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the AC→TH arm). d Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes, and hormone receptor status. e stratified log-rank test. f At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm. g log-rank test. h NS = non-significant. i BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH). j A two-sided alpha level of 0.025 for each comparison. 34 Reference ID: 5478083 1.0 0.8 .. ~ u.. 0.6 ..!. C .. Iii C 0 "t: 0 0. 0.4 e a.. 0.2 0.0 Number at risk Ac-' T Ac-' T + H --.. ---------------~--- - - - - AC-> TH (doxorubicin + cyclophosphamide -> paclitaxel + trastuzumab) 1---- AC-> T (doxorubicin + cyclophosphamide -> paclitaxel) --, --1 1 0.0 0.5 1.0 1.5 20 Disease-Free Survival (years) 1880 1490 1159 926 68.9 1872 1529 1240 997 764 1---, --1 25 3.0 3.5 534 375 195 575 426 239 Figure 4: Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831) 35 Reference ID: 5478083 1.0 0.8 -~ 0.6 <( C .2 5 C. e 0. 0.4 0.2 0.0 0 Numbor :1t nsk AC->T 2032 AC->T • H 2031 1.0 - ---- AC-> T (doxorubicin + cyclophosphamide -> paclitaxel) ---- AC-> T +H (doxorubicin + cyclophosphamide -> paclitaxel + trastuzumab) 2 3 4 5 6 7 8 9 10 Overall Survival (years) 19151 18113 180& 1732 1643 1538 1377 979 830 399 1992 1957 1897 1843 1787 1714 1~ 1127 787 485 - .. - -... ..... ~ ... -=:..a..- --- 0.8 - ........ -:.. ... ..::.:":..o-...._ ____ - - - =~--=-=-=----.. --: ., ~ u, c 0.6 ~ w C ,Q t: 0.4 0 Q. e Q. 0.2 0.0 Number at risk AC->T AC->TH TCH - - - --- AC-> TH (doxorubicin + cydophosphamide •> docetaxel + trastuzumab - - TCH ( docetaxel + carboplatin + trastuzumab) - AC->T (doxorubicin + cydophosphamide •> docetaxel) - I 0 1073 1074 1075 I 1 971 1023 1018 I 2 I 3 Disease-Free Survival (years) 802 417 885 457 877 447 I 4 103 126 126 AC=doxorubicin and cyclophosphamide; T=docetaxel; TCH=docetaxel, platinum salt, and trastuzumab; TH=docetaxel and trastuzumab. Kaplan-Meier estimates are shown 11 1~1 1~9 I 5 Figure 5: Overall Survival in Patients with Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831) Figure 6: Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (BCIRG006) 36 Reference ID: 5478083 Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were conducted for patients in NCCTG N9831 and HERA, where central laboratory testing data were available. The results are shown in Table 10. The number of events in NCCTG N9831 was small with the exception of the IHC 3+/FISH+ subgroup, which constituted 81% of those with data. Definitive conclusions cannot be drawn regarding efficacy within other subgroups due to the small number of events. The number of events in HERA was adequate to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and the FISH+/IHC unknown subgroups. Table 10: DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or Amplification NCCTG N9831 HERAc HER2 Assay Resulta Number of Patients Hazard Ratio DFS (95% CI) Number of Patients Hazard Ratio DFS (95% CI) IHC 3+ FISH (+) 1170 0.42 (0.27, 0.64) 91 0.56 (0.13, 2.50) FISH (−) 51 0.71 (0.04, 11.79) 8 — FISH Unknown 51 0.69 (0.09, 5.14) 2258 0.53 (0.41, 0.69) IHC < 3+ / FISH (+) 174 1.01 (0.18, 5.65) 299b 0.53 (0.20, 1.42) IHC unknown / FISH (+) — — 724 0.59 (0.38, 0.93) a IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory. b All cases in this category in HERA were IHC 2+. c Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm. 14.2 Metastatic Breast Cancer The safety and efficacy of trastuzumab in treatment of women with metastatic breast cancer were studied in a randomized, controlled clinical trial in combination with chemotherapy (H0648g, n = 469 patients) and an open-label, single agent clinical trial (H0649g, n = 222 patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2 or 3 levels of overexpression (based on a 0 to 3 scale) by immunohistochemical assessment of tumor tissue performed by a central testing lab. Previously Untreated Metastatic Breast Cancer (H0648g) H0648g was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastatic breast cancer who had not been previously treated with chemotherapy for metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened). Patients were randomized to receive chemotherapy alone or in combination with trastuzumab given intravenously as a 4 mg/kg loading dose 37 Reference ID: 5478083 followed by weekly doses of trastuzumab at 2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles). Sixty-five percent of patients randomized to receive chemotherapy alone in this study received trastuzumab at the time of disease progression as part of a separate extension study. Based upon the determination by an independent Response Evaluation Committee, the patients randomized to trastuzumab and chemotherapy experienced a significantly longer median time to disease progression (TTP), a higher overall response rate (ORR), and a longer median duration of response (DoR), as compared with patients randomized to chemotherapy alone. Patients randomized to trastuzumab and chemotherapy also had a longer median overall survival (OS) (see Table 11). These treatment effects were observed both in patients who received trastuzumab plus paclitaxel and in those who received trastuzumab plus AC; however, the magnitude of the effects was greater in the paclitaxel subgroup. Table 11: H0648g: Efficacy Results in First-Line Treatment for Metastatic Breast Cancer Combined Results Paclitaxel Subgroup ACa Subgroup Trastuzumab + All Chemotherapy (n = 235) All Chemotherapy (n = 234) Trastuzumab + Paclitaxel (n = 92) Paclitaxel (n = 96) Trastuzumab + ACa (n = 143) ACa (n = 138) Time to Disease Progression (TTP) Median (months)b, c 7.2 4.5 6.7 2.5 7.6 5.7 95% CI 7, 8 4, 5 5, 10 2, 4 7, 9 5, 7 p-valued < 0.0001 < 0.0001 0.002 Overall Response Rate (ORR)b Events (n) 45 29 38 15 50 38 95% CI 39, 51 23, 35 28, 48 8, 22 42, 58 30, 46 p-valuee < 0.001 < 0.001 0.10 Duration of Response (DoR) Median (months)b, c 8.3 5.8 8.3 4.3 8.4 6.4 25%, 75% Quartile 6, 15 4, 8 5, 11 4, 7 6, 15 4, 8 Overall Survival (OS) Median (months)c 25.1 20.3 22.1 18.4 26.8 21.4 38 Reference ID: 5478083 Combined Results Paclitaxel Subgroup ACa Subgroup Trastuzumab + All Chemotherapy (n = 235) All Chemotherapy (n = 234) Trastuzumab + Paclitaxel (n = 92) Paclitaxel (n = 96) Trastuzumab + ACa (n = 143) ACa (n = 138) 95% CI 22, 30 17, 24 17, 29 13, 24 23, 33 18, 27 p-valued 0.05 0.17 0.16 a AC = Anthracycline (doxorubicin or epirubicin) and cyclophosphamide b Assessed by an independent Response Evaluation Committee c Kaplan-Meier Estimate d log-rank test e χ2-test Data from H0648g suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+) (see Table 12). Table 12: Treatment Effects in H0648g as a Function of HER2 Overexpression or Amplification HER2 Assay Result Number of Patients (N) Relative Riskb for Time to Disease Progression (95% CI) Relative Riskb for Mortality (95% CI) CTA 2+ or 3+ 469 0.49 (0.40, 0.61) 0.80 (0.64, 1.00) FISH (+)a 325 0.44 (0.34, 0.57) 0.70 (0.53, 0.91) FISH (−)a 126 0.62 (0.42, 0.94) 1.06 (0.70, 1.63) CTA 2+ 120 0.76 (0.50, 1.15) 1.26 (0.82, 1.94) FISH (+) 32 0.54 (0.21, 1.35) 1.31 (0.53, 3.27) FISH (–) 83 0.77 (0.48, 1.25) 1.11 (0.68, 1.82) CTA 3+ 349 0.42 (0.33, 0.54) 0.70 (0.51, 0.90) FISH (+) 293 0.42 (0.32, 0.55) 0.67 (0.51, 0.89) FISH (–) 43 0.43 (0.20, 0.94) 0.88 (0.39, 1.98) a FISH testing results were available for 451 of the 469 patients enrolled on study. b The relative risk represents the risk of progression or death in the trastuzumab plus chemotherapy arm versus the chemotherapy arm. Previously Treated Metastatic Breast Cancer (H0649g) Trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical trial (H0649g) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of trastuzumab at 2 mg/kg IV. 39 Reference ID: 5478083 The ORR (complete response + partial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate. Complete responses were observed only in patients with disease limited to skin and lymph nodes. The overall response rate in patients whose tumors tested as CTA 3+ was 18% while in those that tested as CTA 2+, it was 6%. 14.3 Metastatic Gastric Cancer The safety and efficacy of trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma (ToGA). In this open-label, multi-center trial, 594 patients were randomized 1:1 to trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastric vs. gastroesophageal junction), tumor measurability (yes vs. no), ECOG performance status (0, 1 vs. 2), and fluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene amplified (FISH+) or HER2 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function (e.g., LVEF > 50%). On the trastuzumab-containing arm, trastuzumab was administered as an IV infusion at an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both study arms, cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. On both study arms, capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively, continuous intravenous infusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day from Day 1 through Day 5 every three weeks for 6 cycles. The median age of the study population was 60 years (range: 21 to 83); 76% were male; 53% were Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 82% had primary gastric cancer and 18% had primary gastroesophageal adenocarcinoma. Of these patients, 23% had undergone prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant therapy, and 2% had received prior radiotherapy. The main outcome measure of ToGA was overall survival (OS), analyzed by the unstratified log- rank test. The final OS analysis based on 351 deaths was statistically significant (nominal significance level of 0.0193). An updated OS analysis was conducted at one year after the final analysis. The efficacy results of both the final and the updated analyses are summarized in Table 13 and Figure 7. Table 13: Overall Survival in ToGA (ITT Population) FCa + Trastuzumab Arm N = 298 FCa Arm N = 296 Overall Survival (interim analysis) N (%) 167 (56.0%) 184 (62.2%) Median (months) 13.5 11.0 95% CI (11.7, 15.7) (9.4, 12.5) 40 Reference ID: 5478083 1.0 0.8 -~ ~ 0.6 ta ~ 0 ... Q. ta -~ 0.4 = VI 0.2 0.0 1 2Q6 2 2Q8 0 207 232 10 130 158 Product-Limit Survival Estimates With Number of Subjects at Risk 60 86 20 34 48 14 24 30 Duration of Survival (months) 3 11 40 2 5 I + Censored I 0 0 50 Fluoropyrimidine + Cisplatin - - - Fluoropyrimidine + Cisplatin + Trastuzumab FCa + Trastuzumab Arm N = 298 FCa Arm N = 296 Hazard Ratio 0.73 95% CI (0.60, 0.91) p valueb 0.0038 Overall Survival (updated) N (%) 221 (74.2%) 227 (76.7%) Median (months) 13.1 11.7 95% CI (11.9, 15.1) (10.3, 13.0) Hazard Ratio 0.80 95% CI (0.67, 0.97) a FC = capecitabine vs. 5-fluorouracil b Two sided p-value comparing with the nominal significance level of 0.0193 Figure 7: Updated Overall Survival in Patients with Metastatic Gastric Cancer (ToGA) 41 Reference ID: 5478083 An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression (IHC) testing is summarized in Table 14. Table 14: Exploratory Analyses by HER2 Status Using Updated Overall Survival Results FC (N = 296)a FC + H (N = 298)b FISH+ / IHC 0, 1+ subgroup (N=133) No. Deaths / n (%) 57/71 (80%) 56/62 (90%) Median OS Duration (mos.) 8.8 8.3 95% CI (mos.) (6.4, 11.7) (6.2, 10.7) Hazard ratio (95% CI) 1.33 (0.92, 1.92) FISH+ / IHC2+ subgroup (N=160) No. Deaths / n (%) 65/80 (81%) 64/80 (80%) Median OS Duration (mos.) 10.8 12.3 95% CI (mos.) (6.8, 12.8) (9.5, 15.7) Hazard ratio (95% CI) 0.78 (0.55, 1.10) FISH+ or FISH- / IHC3+c subgroup (N=294) No. Deaths / n (%) 104/143 (73%) 96/151 (64%) Median OS Duration (mos.) 13.2 18.0 95% CI (mos.) (11.5, 15.2) (15.5, 21.2) Hazard ratio (95% CI) 0.66 (0.50, 0.87) a Two patients on the FC arm who were FISH+ but IHC status unknown were excluded from the exploratory subgroup analyses. b Five patients on the trastuzumab-containing arm who were FISH+, but IHC status unknown were excluded from the exploratory subgroup analyses. c Includes 6 patients on chemotherapy arm, 10 patients on trastuzumab arm with FISH–, IHC3+ and 8 patients on chemotherapy arm, 8 patients on trastuzumab arm with FISH status unknown, IHC 3+. 16 HOW SUPPLIED/STORAGE AND HANDLING 420 mg Multiple-dose vial NDC 63459-305-47 HERZUMA (trastuzumab-pkrb) for Injection 420 mg/vial is supplied in a multiple-dose vial as a white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial (420 mg/vial) of HERZUMA and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative. 150 mg Single-dose vial NDC 63459-303-43 42 Reference ID: 5478083 HERZUMA (trastuzumab-pkrb) for Injection 150 mg/vial is supplied in a single-dose vial as a white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one single- dose vial (150 mg/vial) of HERZUMA. Store HERZUMA vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution. 17 PATIENT COUNSELING INFORMATION Cardiomyopathy • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential that HERZUMA exposure during pregnancy or within 7 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of HERZUMA [see Use in Specific Populations (8.3)]. Manufactured by: CELLTRION, Inc. 23, Academy-ro, Yeonsu-gu, Incheon 22014, Republic of Korea U.S. License No. 1996 HERZUMA® is a registered trademark of CELLTRION, Inc. Marketed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 43 Reference ID: 5478083	custom-source	2025-02-12T15:46:40.225925	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761091s033lbl.pdf', 'application_number': 761091, 'submission_type': 'SUPPL ', 'submission_number': 33}
80,225	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use REVUFORJ safely and effectively. See full prescribing information for REVUFORJ. REVUFORJ (revumenib) tablets, for oral use Initial U.S. Approval: 2024 WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Differentiation syndrome, which can be fatal, has occurred with REVUFORJ. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution (5.1) -----------------------------INDICATIONS AND USAGE-------------------------- REVUFORJ is a menin inhibitor indicated for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older. (1). ------------------------DOSAGE AND ADMINISTRATION---------------------- • Select patients for treatment with REVUFORJ based on the presence of a KMT2A translocation. (2.1) • Administer REVUFORJ orally twice daily fasted or with a low-fat meal at approximately the same time each day. (2.2) • See Full Prescribing Information for recommended REVUFORJ dosage regimen, dosage modifications, and administration instructions. (2.2, 2.3) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- • Tablets: 25 mg, 110 mg, 160 mg (3) -------------------------------CONTRAINDICATIONS------------------------------ • None. (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. Correct hypokalemia and hypomagnesemia prior to and during treatment. If QTc interval prolongation occurs, interrupt, reduce, or permanently discontinue REVUFORJ. (2.3, 5.2). • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. (5.3, 8.1, 8.3) -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions (≥ 20%) including laboratory abnormalities, are hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals, Inc., at 1-888-539-3REV or FDA at 1-800-FDA 1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- • Strong CYP3A4 Inhibitors: Reduce the REVUFORJ dose. (2.2, 7.1) • Strong or moderate CYP3A4 Inducers: Avoid concomitant use with REVUFORJ. (7.1) • QTc Prolonging Drugs: Avoid concomitant use with REVUFORJ. If concomitant use is unavoidable, monitor patients more frequently for QTc interval prolongation. (5.2, 7.1) --------------------------USE IN SPECIFIC POPULATIONS-------------------- • Lactation: Advise not to breastfeed (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DIFFERENTIATION SYNDROME 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Dosage Modifications for Adverse Reactions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Differentiation Syndrome 5.2 QTc Interval Prolongation 5.3 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on REVUFORJ 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Relapsed or Refractory Acute Leukemia with a KMT2A Translocation 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5479801 FULL PRESCRIBING INFORMATION WARNING: DIFFERENTIATION SYNDROME Differentiation syndrome, which can be fatal, has occurred with REVUFORJ. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution. [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 1 INDICATIONS AND USAGE Relapsed or Refractory Acute Leukemia REVUFORJ is indicated for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of acute leukemia with REVUFORJ based on the presence of a KMT2A translocation in bone marrow cells [see Clinical Studies (14.1)]. An FDA-approved companion diagnostic for the detection of a KMT2A translocation is not currently available. 2.2 Recommended Dosage The recommended dosage of REVUFORJ varies by patient weight and concomitant use of strong CYP3A4 inhibitors. See Table 1 for the recommended dosage for patients 1 year and older. Do not start REVUFORJ until the WBC is reduced to less than 25 Gi/L. Continue REVUFORJ until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Table 1. REVUFORJ Recommended Dosage for Patients 1 Year and Older Patient Weight Without Strong CYP3A4 Inhibitors With Strong CYP3A4 Inhibitors 40 kg or more 270 mg orally twice daily 160 mg orally twice daily Less than 40 kg 160 mg/m2 orally twice daily* 95 mg/m2 orally twice daily* See Table 2 for the total tablet dosage by BSA (body surface area) for patients weighing less than 40 kg. Reference ID: 5479801 Table 2: Recommended Dosage using Tablets for Patients Weighing Less than 40 kg BSA (m2) REVUFORJ Dosage for 160 mg/m2 REVUFORJ Dosage for 95 mg/m2 1.4 220 mg twice daily 135 mg twice daily 1.3 220 mg twice daily 135 mg twice daily 1.2 185 mg twice daily 110 mg twice daily 1.1 185 mg twice daily 110 mg twice daily 1 160 mg twice daily 100 mg twice daily 0.9 135 mg twice daily 75 mg twice daily 0.8 135 mg twice daily 75 mg twice daily 0.7 110 mg twice daily 50 mg twice daily 0.6 100 mg twice daily 50 mg twice daily 0.5 75 mg twice daily 50 mg twice daily 0.4 50 mg twice daily 25 mg twice daily * If needed, attain the desired dose by combining different strengths of REVUFORJ tablets. • If the strong CYP3A4 inhibitor is discontinued, increase the REVUFORJ dose after at least 5 half- lives of the strong CYP3A4 inhibitor to the recommended dosage without strong CYP3A4 inhibitors (Table 1). • Concurrent use of standard intrathecal chemotherapy prophylaxis is recommended for patients with risk of central nervous system relapse. Administration: • Administer REVUFORJ twice daily fasted or with a low-fat meal (e.g., meals with approximately 400 calories, 25% or less fat). • Administer REVUFORJ orally around the same time each day. • Advise patients to swallow tablets whole and to not cut or chew tablets. If patients are unable to swallow tablets, they may be crushed and dispersed in water and taken within 2 hours of preparation [see Instructions for Use]. • If a dose of REVUFORJ is missed or not taken at the usual time, administer the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours. 2.3 Dosage Modifications for Adverse Reactions Assess blood counts, electrolytes, and liver enzymes prior to the initiation of REVUFORJ and monthly thereafter. Perform an electrocardiogram (ECG) prior to the initiation of REVUFORJ, at least once a week for the first 4 weeks, and at least monthly thereafter. Monitor for QTc interval prolongation and Reference ID: 5479801 manage any abnormalities promptly [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Interrupt dosing or reduce dose for adverse reactions as per Table 3. Dose levels for dose reductions are listed in Table 4, Table 5, and Table 6. Table 3. Recommended Management and Dosage Modifications for Adverse Reactions Adverse reaction Recommended action Differentiation Syndrome [see • If differentiation syndrome is suspected, administer systemic Warnings and Precautions corticosteroids and initiate hemodynamic monitoring until symptom (5.1)] resolution and for a minimum of 3 days. [see Warnings and Precautions (5.1)]. • Interrupt REVUFORJ if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier for life-threatening symptoms such as pulmonary symptoms requiring ventilator support [see Warnings and Precautions (5.1)]. Resume REVUFORJ at the same dose when signs and symptoms improve to Grade 1* or lower. Noninfectious leukocytosis • Initiate treatment with hydroxyurea in patients with an elevated or rapidly rising leukocyte count. Add leukapheresis if clinically indicated. • Taper hydroxyurea only after leukocytosis improves or resolves. QTc interval greater than 480 msec to 500 msec [see Warnings and Precautions (5.2)] • Interrupt REVUFORJ. • Check electrolyte levels. Correct hypokalemia and hypomagnesemia [see Warnings and Precautions (5.2)]. • Restart REVUFORJ at the same dose level after the QTc interval returns to less than or equal to 480 msec. QTc interval greater than 500 msec (Grade 3) [see Warnings and Precautions (5.2)] • Interrupt REVUFORJ. • Check electrolyte levels. Correct hypokalemia and hypomagnesemia [see Warnings and Precautions (5.2)]. • Restart REVUFORJ at the reduced dose level* after the QTc interval returns to less than or equal to 480 msec. QTc interval prolongation with • Permanently discontinue REVUFORJ. signs/symptoms of life- threatening arrhythmia, Torsades de pointes, polymorphic ventricular tachycardia, signs/ symptoms of life-threatening arrhythmia (Grade 4) [see Warnings and Precautions (5.2)]. Reference ID: 5479801 Adverse reaction Recommended action Potassium 3.6-3.9 mEq/L, and/or Magnesium 1.7-1.9 mg/dL or 0.66-0.81 mmol/L • Supplement potassium and/or magnesium. • Continue REVUFORJ. Potassium ≤ 3.5 mEq/L, • Supplement potassium and/or magnesium, and recheck levels and/or within 24 hours. Magnesium ≤ 1.6 mg/dL or • On recheck of potassium and magnesium labs within 24 hours, if ≤ 0.65 mmol/L potassium is greater than 3.5 mEq/Land/or magnesium is greater than 1.6 mg/dL, continue REVUFORJ. If potassium is less than 3.5 mEq/L and/or magnesium is less than 1.6 mg/dL, hold REVUFORJ and continue supplementation; resume REVUFORJ at the same dose level when the correction is complete. Other nonhematological • Interrupt REVUFORJ until recovery to Grade 1 or baseline. adverse reactions Grade ≥ 3* [see Adverse Reactions (6.1)] • If recovered in ≤ 7 days, restart REVUFORJ at the same dose level. If the same Grade ≥ 3* toxicity recurs, interrupt REVUFORJ until recovery to Grade 1* or baseline. Restart REVUFORJ at the reduced dose level. If recovered in > 7 days, restart REVUFORJ at the reduced dose level. If the same Grade ≥ 3* toxicity recurs, discontinue REVUFORJ. Grade 4* neutropenia or • Interrupt REVUFORJ until recovery to Grade ≤ 2* or baseline. thrombocytopenia [see Adverse Reactions (6.1)] • Restart REVUFORJ at the same dose level. • If Grade 4* neutropenia or thrombocytopenia recurs without attributable cause, interrupt REVUFORJ until recovery to Grade ≤ 3. Restart REVUFORJ at the reduced dose level.* Grade 3* or higher allergic reactions [see Adverse Reactions (6.1)] • Permanently discontinue REVUFORJ. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0). See Tables 4, 5 and 6 for the reduced dose levels. Reference ID: 5479801 Table 4. REVUFORJ Dosage Reduction for Adverse Reactions in Patients NOT on Strong CYP3A4 Inhibitors Patients Weighing 40 kg or Greater at Starting Dose 270 mg orally twice daily Patients Weighing Less Than 40 kg at Starting Dose 160 mg/m2 orally twice daily Reduced Dose 160 mg orally twice daily 95 mg/m2 orally twice daily *See Table 6 for BSA-based dosage recommendations for the reduced dosage of 95 mg/m2 twice daily. Table 5. REVUFORJ Dosage Reduction for Adverse Reactions in Patients on Strong CYP3A4 Inhibitors Patients Weighing 40 kg or Greater at Starting Dose 160 mg orally twice daily Patients Weighing Less Than 40 kg at Starting Dose 95 mg/m2 orally twice daily Reduced Dose 110 mg orally twice daily 65 mg/m2 orally twice daily See Table 6 for BSA-based dosage recommendations for the reduced dosage of 65 mg/m2 twice daily. Table 6: Recommended Reduced Dosage Using Tablets for Patients Weighing Less than 40 kg BSA (m2) REVUFORJ Dosage for 95 mg/m2 REVUFORJ Dosage for 65 mg/m2 1.4 135 mg twice daily 100 mg twice daily 1.3 135 mg twice daily 75 mg twice daily 1.2 110 mg twice daily 75 mg twice daily 1.1 110 mg twice daily 75 mg twice daily 1 100 mg twice daily 50 mg twice daily 0.9 75 mg twice daily 50 mg twice daily 0.8 75 mg twice daily 50 mg twice daily 0.7 50 mg twice daily 50 mg twice daily 0.6 50 mg twice daily 25 mg twice daily 0.5 50 mg twice daily 25 mg twice daily 0.4 25 mg twice daily 25 mg twice daily * If needed, attain the desired dose by combining different strengths of REVUFORJ tablets. 3 DOSAGE FORMS AND STRENGTHS Tablets: • 25 mg of revumenib: Pink modified oval film-coated tablet debossed with “S” on one side and “25” on the other side. • 110 mg of revumenib: Beige modified oval film-coated tablet debossed with “S” on one side and “110” on the other side. • 160 mg of revumenib: Purple modified oval film-coated tablet debossed with “S” on one side and “160” on the other side. Reference ID: 5479801 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Differentiation Syndrome REVUFORJ can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of differentiation syndrome, including those seen in patients treated with REVUFORJ, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension. In clinical trials, DS occurred in 39 (29%) of 135 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation, including 32% of patients with acute myeloid leukemia (AML), 25% of patients with mixed-phenotype acute leukemia (MPAL), and 14% of patients with acute lymphoblastic leukemia (ALL). DS was Grade 3 or 4 in 13% and fatal in one patient. The median time to onset was 10 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1% [see Adverse Reactions (6.1)]. Reduce the white blood cell count (WBC) to less than 25 Gi/L prior to starting REVUFORJ. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10 mg intravenously every 12 hours in adults or dexamethasone 0.25 mg/kg/dose intravenously every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt REVUFORJ if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids [see Dosage and Administration (2.3)]. 5.2 QTc Interval Prolongation REVUFORJ can cause QT (QTc) interval prolongation [see Clinical Pharmacology (12.2)]. In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation; QTc interval prolongation was Grade 3 in 12%. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. REVUFORJ dose reduction was required for 5% due to QTc interval prolongation [see Adverse Reactions (6.1)]. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older. Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with REVUFORJ. Perform an ECG prior to initiation of treatment with REVUFORJ, and do not initiate REVUFORJ in patients with QTcF > 450 msec. Perform an ECG at least once a week for the first 4 weeks on treatment, and at least monthly thereafter [see Dosage and Administration (2.3)]. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use of REVUFORJ with drugs known to prolong the QTc interval Reference ID: 5479801 may increase the risk of QTc interval prolongation [see Drug Interactions (7.1), Clinical Pharmacology (12.2)]. Interrupt REVUFORJ if QTcF increases to greater than 480 msec and less than 500 msec, and restart REVUFORJ at the same dose twice daily after the QTcF interval returns to less than or equal to 480 msec. Interrupt REVUFORJ if QTcF increases to greater than 500 msec or by > 60 msec from baseline, and restart REVUFORJ twice daily at the lower dose level after the QTcF interval returns to less than or equal to 480 msec. Permanently discontinue REVUFORJ in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life- threatening arrhythmia [see Dosage and Administration (2.3)]. 5.3 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, REVUFORJ can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of revumenib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, malformations, and altered fetal growth at maternal exposures approximately 0.5 times the human exposure (AUC) at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Differentiation Syndrome [see Warnings and Precautions (5.1)] • QTc Interval Prolongation [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Acute Leukemia with KMT2A translocation The safety of REVUFORJ reflects exposure in 135 patients (104 adult and 31 pediatric patients) with relapsed or refractory (R/R) acute leukemia with KMT2A translocation treated with REVUFORJ at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor [see Clinical Studies (14.1)]. The median duration of exposure to REVUFORJ was 2.3 months (range < 1 to 23 months), and 3% of patients were exposed for more than 6 months. Fatal adverse reactions occurred in 4 (3%) patients who received REVUFORJ, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death. Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥ 5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%). Reference ID: 5479801 Adverse reactions leading to dose interruption occurred in 42% of patients. The most common adverse reactions (≥ 5%) leading to dose interruption were electrocardiogram QT prolonged, febrile neutropenia, differentiation syndrome, infection, hypokalemia, and nausea. Adverse reactions leading to dose reduction occurred in 10% of patients who received REVUFORJ. Adverse reactions leading to a dose reduction (> 1%) included electrocardiogram QT prolonged. Adverse reactions leading to permanent discontinuation occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation (> 1%) included infection and respiratory failure. The most common (≥ 20%) adverse reactions were hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased. The common adverse reactions are summarised in Table 7. Table 7. Adverse Reactions Reported in ≥ 20% (Any Grade) or ≥ 5% (Grade 3 or 4) in Patients with R/R Acute Leukemia with KMT2A Translocation REVUFORJ N = 135 Adverse Reaction All Grades % Grade 3 or 4 % Vascular disorders Hemorrhagea# 53 9 Thrombosisb 10 5 Gastrointestinal disorders Nauseac 51 4 Diarrhead 30 4 Constipation 23 1 Musculoskeletal and connective tissue disorders Musculoskeletal paine 42 6 Infections and infestations Infectionf 41 29 Bacterial infectiong 31 20 Viral infectionh 23 4 Blood and lymphatic system disorders Febrile neutropenia 35 33 Leukocytosis 8 5 Neoplasms benign, malignant and unspecified (including cysts and polyps) Differentiation syndrome# 29 13 Investigations Electrocardiogram QT prolonged 29 12 Metabolism and nutrition disorders Decreased appetite 24 8 General disorders and administration site conditions Edemai 23 1 Fatiguej 22 5 Reference ID: 5479801 # Includes the following fatal adverse reactions: DS (n=2); hemorrhage (n=1) a – Includes epistaxis, contusion, petechiae, gingival bleeding, haematuria, mouth hemorrhage, hematoma, hemoptysis, hemorrhoidal hemorrhage, subdural hematoma, vaginal hemorrhage, catheter site hemorrhage, conjunctival hemorrhage, ecchymosis, hemorrhage intracranial, anal hemorrhage, brain stem hemorrhage, eye hematoma, gastrointestinal hemorrhage, genital contusion, hematochezia, injection site hematoma, lower gastrointestinal hemorrhage, melena, mucosal hemorrhage, oral contusion, pulmonary, upper gastrointestinal hemorrhage, vitreous hemorrhage. b – Includes disseminated intravascular coagulation, pulmonary embolism, cerebrovascular accident, deep vein thrombosis, embolism, hemorrhoids thrombosed, medical device site thrombosis, renal infarct, superficial vein thrombosis, thrombosis, transient ischemic attack. c – Includes nausea, and vomiting. d – Includes diarrhea, colitis, neutropenic colitis. e – Includes back pain, arthralgia, pain in extremity, neck pain, myalgia, musculoskeletal chest pain, myositis, flank pain, musculoskeletal discomfort, musculoskeletal pain. f – Includes sepsis, pneumonia, urinary tract infection, septic shock, sinusitis, upper respiratory tract infection, device related infection, skin infection, acute sinusitis, enterocolitis infectious, perirectal abscess, rectal abscess, rhinitis, abscess limb, appendicitis, bronchitis, conjunctivitis, endocarditis, epididymitis, eye infection, gastroenteritis, neutropenic sepsis, osteomyelitis, rash pustular, retinitis, shock, sialadenitis, tooth abscess, tooth infection, vascular device infection. g – Includes bacteremia, cellulitis, clostridium difficile infection, staphylococcal bacteremia, paronychia, clostridium test positive, enterobacter infection, enterobacter sepsis, escherichia bacteremia, alpha haemolytic streptococcal infection, bacteriuria, cellulitis staphylococcal, enterobacter bacteremia, enterococcal bacteremia, enterococcal infection, escherichia urinary tract infection, folliculitis, klebsiella infection, klebsiella sepsis, lactobacillus bacteremia, pseudomonal bacteremia. h – Includes COVID-19, rhinovirus infection, respiratory syncytial virus infection, cytomegalovirus infection reactivation, herpes simplex, herpes simplex reactivation, herpes zoster, COVID-19 pneumonia, coronavirus infection, cytomegalovirus infection, cytomegalovirus test positive, enterovirus infection, enterovirus test positive, Epstein-Barr virus infection, herpes simplex pharyngitis, herpes virus infection, norovirus infection, oral herpes, pneumonia cytomegaloviral. i – Includes edema peripheral, generalised edema, edema, localized edema, peripheral swelling. j – Includes fatigue and malaise. Clinically relevant adverse reactions in less than 20% of patients who received REVUFORJ include: Cardiac disorders: Cardiac failure, pericardial effusion, ventricular tachycardia, cardiac arrest Endocrine disorders: Hyperparathyroidism Eye disorders: Cataract Gastrointestinal disorders: Abdominal pain General disorders and administration site conditions: Sudden death Immune system disorders: Drug hypersensitivity Metabolism and nutrition disorders: Hyponatremia, hyperkalemia Nervous system disorders: Taste disorder, syncope, headache, paresthesia Renal disorders: Renal impairment Skin and subcutaneous disorders: Rash Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory acute leukemia with KMT2A translocation are shown in Table 8. Reference ID: 5479801 Table 8. Selected New or Worsening Laboratory Abnormalities in Patients with R/R Acute Leukemia with KMT2A translocation REVUFORJ Laboratory Abnormality Grades 1-4* % Grades 3-4 % Phosphate increased 50 - Aspartate aminotransferase increased 37 1 Alanine aminotransferase increased 33 3 Parathyroid hormone, intact increased 33 - Phosphate decreased 25 - Triglycerides increased 25 3 Potassium decreased 24 5 Alkaline phosphatase increased 21 0 Cholesterol increased 19 0 Creatinine increased 19 0 Calcium corrected increased 15 0 *The denominator used to calculate the rate varied from 73 to 135 based on the number of patients with a baseline value and at least one post baseline value. 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on REVUFORJ Strong CYP3A4 Inhibitors If concomitant use of strong CYP3A4 inhibitors is required, reduce the REVUFORJ dosage [see Recommended Dosage (2.2)]. Revumenib is primarily metabolized by CYP3A4 [see Clinical Pharmacology (12.3)]. Concomitant use with a strong CYP3A4 inhibitor increases revumenib systemic exposure [see Clinical Pharmacology (12.3)], which may increase the risk of REVUFORJ adverse reactions. Strong or Moderate CYP3A4 Inducers Avoid concomitant use with strong or moderate CYP3A4 inducers. Revumenib is primarily metabolized by CYP3A4 [see Clinical Pharmacology (12.3)]. Concomitant use with a strong or moderate CYP3A4 inducer may decrease revumenib and increase M1 systemic exposure [see Clinical Pharmacology (12.3)], which may reduce REVUFORJ efficacy or increase the risk of QT prolongation associated with the M1 metabolite. Drugs that Prolong QTc Interval Avoid concomitant use of REVUFORJ with other drugs with a known potential to prolong QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.2)]. Withhold REVUFORJ if the QTc interval is greater than 480 msec. Restart REVUFORJ after the QTc interval returns to less than or equal to 480 msec [see Dosage and Administration (2.3)]. REVUFORJ causes QTc interval prolongation [see Clinical Pharmacology (12.2)]. Concomitant use of REVUFORJ with other drugs that prolong QTc interval may result in an increase in the QTc interval and adverse reactions associated with QTc interval prolongation [see Warnings and Precautions (5.2)]. Reference ID: 5479801 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], REVUFORJ can cause fetal harm when administered to a pregnant woman. There are no available data on REVUFORJ use in pregnant women to evaluate for a drug-associated risk. In an animal reproduction study, oral administration of revumenib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, malformations, and altered fetal growth at maternal exposures approximately 0.5 times the human exposure (AUC) at the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In an embryo-fetal development study, revumenib was administered once daily via oral gavage at doses of 30, 100, and 300 mg/kg/day to pregnant rats during the period of organogenesis (gestation days 6-17). Decreased maternal body weight gain and adverse embryo-fetal findings including decreases in the number of live fetuses, increases in resorptions and post-implantation loss, and decreases in fetal body weight were observed at all doses. At 300 mg/kg/day, total litter resorption and eye malformations were observed. At the dose of 30 mg/kg/day in rats, the maternal exposures (AUC) were approximately 0.5 times the human exposure at the recommended dose. 8.2 Lactation Risk Summary There are no data on the presence of revumenib or its metabolites in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with REVUFORJ and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on findings in animals and its mechanism of action, REVUFORJ can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential within 7 days prior to initiating REVUFORJ. Contraception Females Reference ID: 5479801 Advise females of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Males Advise males of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Infertility Females and Males Based on findings in animals, REVUFORJ may impair fertility. The effects on fertility were reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of REVUFORJ have been established in pediatric patients 1 year and older with relapsed or refractory acute leukemia with a KMT2A translocation. Use of REVUFORJ for this indication is supported by evidence from adequate and well-controlled trials in adults and pediatric patients [see Clinical Studies (14.1)] and additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. The patients included 13 infants (age < 2 years), 41 children (age 2 to < 12 years) and 16 adolescents (age 12 to < 17 years). The recommended dosage in patients weighing less than 40 kg is BSA-based. The safety and efficacy of REVUFORJ in pediatric patients less than 1 year old have not been established. Animal Data In a repeat dose toxicity study in 6-7 week-old rats treated with revumenib at 75, 150, or 300 mg/kg/day for 13 weeks, an irreversible increase in femur growth plate closure was observed at revumenib exposures approximately 2 times the human exposure (AUC) at the recommended dose. Based on the findings in animals, monitor bone growth and development in pediatric patients. 8.5 Geriatric Use Of the 135 patients with relapsed or refractory acute leukemia with a KMT2A translocation in clinical studies of REVUFORJ, 16 (12%) patients were 65 years of age and older and 3 (2%) patients were 75 years of age and older [see Clinical Studies (14.1)]. No overall differences were observed in the effectiveness of REVUFORJ between patients who were 65 years and older and younger patients [see Clinical Studies (14.1) and Clinical Pharmacology (12.3)]. Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older [see Warnings and Precautions (5.2)]. 11 DESCRIPTION REVUFORJ contains revumenib, a menin inhibitor. Revumenib is present as revumenib citrate hydrate with a chemical name of benzamide, N-ethyl-2-[[4-[7-[[trans-4 [(ethylsulfonyl)amino]cyclohexyl]methyl]-2,7-diazaspiro[3.5]non-2-yl]-5-pyrimidinyl]oxy]-5-fluoro-N-[1 Reference ID: 5479801 methylethyl]-, 2-hydroxypropane-1,2,3-tricarboxylic acid, hydrate (1:1:1). The molecular formula is C32H47FN6O4S●C6H8O7●H2O with a molecular weight 840.96 g/mol. Revumenib citrate hydrate is a white to faint pink solid. Revumenib citrate hydrate is soluble at pH 1.2 and 6.8, and sparingly soluble at pH 4.5. The chemical structure is shown in Figure 1. Figure 1: Chemical structure of Revumenib Citrate hydrate N N N F O N O N NHSO2Et HOOC COOH OH COOH · · H2O REVUFORJ is available as tablets for oral use. Each 25 mg strength tablet contains 25 mg revumenib, equivalent to 33.4 mg revumenib citrate, and the following inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide. Each 110 mg strength tablet contains 110 mg revumenib, equivalent to 146.5 mg revumenib citrate, and the following inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide, and yellow iron oxide. Each 160 mg strength tablet contains 160 mg revumenib equivalent to 213.2 mg revumenib citrate, and the following inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide, and FD&C blue #2/indigo carmine aluminum lake. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Revumenib is a menin inhibitor and blocks the interaction of both wild-type lysine methyltransferase 2A (KMT2A) and KMT2A fusion proteins with menin. The binding of KMT2A fusion proteins with menin is involved in KMT2A-rearranged (KMT2Ar) acute leukemias through activation of a leukemogenic transcriptional pathway. In nonclinical studies using cells that express KMT2A fusions, inhibition of the menin-KMT2A interaction with revumenib altered the transcription of multiple genes including differentiation markers. In nonclinical in vitro and in vivo studies, revumenib demonstrated antiproliferative and antitumor activity in leukemia cells harboring KMT2A fusion proteins. Reference ID: 5479801 12.2 Pharmacodynamics Revumenib exposure-response relationships have not been fully characterized and the time course of pharmacodynamic response is unknown. Cardiac Electrophysiology The effect of REVUFORJ on the QTc interval was evaluated across a dose range of 113 mg to 339 mg twice daily (1.2 times the highest adult approved recommended dosage) with and without strong CYP3A4 inhibitors in patients with relapsed or refractory acute leukemia with KMT2Ar. The increase in QTc interval was concentration dependent with an increase in QTc predicted to be 27 msec (upper bound of 90% confidence interval: 30 msec) at the mean steady-state maximum concentration (Cmax) observed in patients at the highest approved recommended dosage without CYP3A4 inhibitors. The increase in QTc interval was predicted to be 19 msec (upper bound of 90% confidence interval: 22 msec) at steady-state Cmax after administration of 163 mg twice daily with strong CYP3A4 inhibitors [see Warnings and Precautions (5.2)]. 12.3 Pharmacokinetics The pharmacokinetics of revumenib were characterized in patients with relapsed or refractory acute leukemia following single and multiple oral administration of revumenib with or without strong CYP3A4 inhibitors. Steady-state pharmacokinetic parameters are presented as geometric mean [coefficient of variation (%CV)] unless otherwise specified. Table 9. Revumenib Pharmacokinetics in Patients with Relapsed or Refractory Acute Leukemia Parameter Dosage 163 mg twice daily (with strong CYP3A4 inhibitors)a 276 mg twice daily (without strong CYP3A4 inhibitors)a General Information Exposureb Cmax (ng/mL) 3220 (34%) 2052 (79%) AUC0-12h (ng•h/mL) 22,610 (50%) 10,150 (69%) Dose Proportionalityc Dose proportional increases in Cmax and AUC0-12h Time to Steady-State 2-3 days Accumulationb 2-fold Absorption Tmax Median (range) hours 2 (0-6) 1 (0.5-4) Effect of Food Low fat meald No clinically significant differences in revumenib pharmacokinetics observed (Cmax and AUC decreased by 27% and 12% respectively) Distribution Apparent Volume of Distributionb (L) 78 (50%) Protein Bindinge 90% Blood to plasma ratio 0.8 Elimination Reference ID: 5479801 Half-Lifeb (hours) 7.5 (57%) 3.6 (36%) Apparent Clearanceb (L/h) 7 (51%) 27 (69%) Metabolism Primary Pathway CYP3A4 Active Metabolite M1f Excretiong Feces Approximately 49% (7% unchanged) Urine Approximately 27% (7% unchanged) Abbreviations: Cmax = maximum plasma concentration; AUC = area under the time concentration curve; Tmax = time to peak concentration a - 1.02 times the highest adult approved recommended dosages b - Steady-state c - Dosage range of 113 mg to 339 mg (1.26 times the highest adult approved recommended dosage) d - Approximately 400-500 calories, 25% of calories from fat e - Independent of concentration f - M1 contributes to revumenib’s clinically significant effects on QTc [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)] but does not contribute to its efficacy at the approved recommended dosage g - A single dose of radiolabeled revumenib 276 mg (1.02 times the highest adult approved recommended dosage) to adult patients with relapsed/refractory acute leukemia Specific Populations No clinically significant differences in the pharmacokinetics of revumenib were observed based on age (1 to 82 years), race (71% White, 8% Asian, 8% Black), sex, mild to moderate (CLcr 30 to 89 mL/min) renal impairment, and mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr less than 30 mL/min), end- stage renal disease (CLcr less than 15 mL/min), or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment is unknown. Body weight (8-146 kg) has a significant effect on the pharmacokinetics of revumenib, with higher revumenib exposures in patients with lower body weight (less than 40 kg). This supports the use of BSA-based dosage in patients weighing less than 40 kg. Pediatric Patients Revumenib geometric mean (CV%) steady-state Cmax was 3137 (39%) ng/mL and AUC0-tau was 14,630 (55%) ng·hr/mL following 95 mg/m2 twice daily (approximately 1.02 times the highest approved recommended adult dosage) with strong CYP3A4 inhibitors. Revumenib predicted geometric mean (%CV) steady-state Cmax was 1597 (70%) ng/mL and AUC0 tau was 12,570 (56%) ng·hr/mL following 160 mg/m2 twice daily (approximately 1.02 times the highest approved recommended adult dosage) without strong CYP3A4 inhibitors. Drug Interaction Studies Clinical Studies Strong CYP3A4 Inhibitors: Revumenib AUC and Cmax is increased by 2-fold following concomitant use of multiple doses of revumenib with certain azole antifungals that are strong CYP3A4 inhibitors (i.e., posaconazole, itraconazole, and voriconazole). Similarly, revumenib AUC and Cmax is increased Reference ID: 5479801 by 2.5-fold following concomitant use of multiple doses of revumenib with cobicistat (strong CYP3A4 inhibitor). Strong and Moderate CYP3A4 Inducers: Revumenib exposure is expected to decrease and M1 exposure is expected to increase with strong and moderate CYP3A4 inducers. Other Drugs: No clinically significant differences in revumenib pharmacokinetics were observed when used concomitantly with fluconazole (moderate CYP3A4 inhibitor), isavuconazole (moderate CYP3A4 inhibitor). In Vitro Studies Cytochrome P450 (CYP) Enzymes: Revumenib inhibits CYP3A4, but does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Revumenib does not induce CYP1A2, CYP2B6, and CYP3A4. Transporter Systems: Revumenib is a substrate of OCT1, OCT2, OAT1, OAT3, and MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, MATE2-K, or BSEP. M1 is a substrate of OATP1B1, but is not a substrate of P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B3, MATE1, or MATE2-K. Revumenib inhibits MATE1, but does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MATE2-K. M1 inhibits MATE1, but does not inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs in one animal. Revumenib was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, or an in vivo rat peripheral blood reticulocyte micronucleus assay. Fertility studies in animals have not been conducted with revumenib. In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25 or 40 mg/kg/day for 13 weeks, microscopic findings in the testes and epididymis consisted of depletion of germ cells and decreased sperm at ≥12.5 mg/kg/day. In females, microscopic changes of atrophy in the mammary glands, uterus, and vagina and decreased number of corpora lutea in the ovaries were observed at ≥12.5 mg/kg/day. At the end of the 13-week recovery period, the findings in the female reproductive organs were reversed at all doses, and the testicular and epididymal effects were reversed at 12.5 mg/kg/day. At the dose of 12.5 mg/kg/day in dogs, exposures (AUC) were approximately 1.3 times the human exposure (AUC) at the recommended dose. 13.2 Animal Toxicology and/or Pharmacology In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25, or 40 mg/kg/day for 13 weeks, microscopic findings of nerve fiber degeneration in the brain, sciatic nerves, and spinal cord segments were observed at ≥ 12.5 mg/kg/day and were not reversed at the end of a 13-week recovery period. Reference ID: 5479801 In a repeat dose toxicity study in rats treated with revumenib at 75, 150, 300 mg/kg/day for 13 weeks, dose dependent ocular findings of lens opacities were observed at ≥ 75 mg/kg/day; the findings progressed during the dosing and recovery periods and were not reversed. Hyperplasia was observed in multiple organs including the testes, mammary gland, uterus, pancreas, and kidney in rats treated at ≥ 75 mg/kg/day for up to 13 weeks. The findings were irreversible in the testes, mammary gland, and pancreas. Revumenib exposures at 75 mg/kg/day in rats are approximately 2 times the human exposure (AUC) at the recommended dose. 14 CLINICAL STUDIES 14.1 Relapsed or Refractory Acute Leukemia with a KMT2A Translocation SNDX-5613-0700 The efficacy of REVUFORJ was evaluated in a single-arm cohort of an open-label, multicenter trial (SNDX-5613-0700, NCT04065399; AUGMENT-101) in adult and pediatric patients at least 30 days old with relapsed or refractory (R/R) acute leukemia with a KMT2A translocation. Patients with an 11q23 partial tandem duplication were excluded. Eligibility required a QTcF < 450 msec at study baseline. Treatment consisted of REVUFORJ at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor until disease progression, unacceptable toxicity, failure to achieve morphological leukemia-free state by 4 cycles of treatment, or hematopoietic stem cell transplantation (HSCT). The baseline demographic and disease characteristics of the 104 treated patients are shown in Table 10. Twenty-four (23%) patients underwent HSCT following treatment with REVUFORJ. Table 10. Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory Acute Leukemia with KMT2A translocation (Study SNDX-5613-0700) Demographic and Disease Characteristics REVUFORJ N = 104 Demographics Median Age (years) (Range) 37 (1, 79) Age, n (%) < 17 years old 25 (24) ≥ 17 years old 79 (76) Sex, n (%) Male 37 (36) Female 67 (64) Race, n (%) Black or African American 8 (8) Asian 10 (10) White 75 (72) Multiple 1 (1) Reference ID: 5479801 Demographic and Disease Characteristics REVUFORJ N = 104 Unknown 10 (10) Ethnicity, n (%) Hispanic or Latino 23 (22) Not Hispanic or Latino 76 (73) Unknown 5 (5) Disease Characteristics Leukemia morphological type, n (%) Acute myeloid leukemia (AML) 86 (83) Acute lymphoblastic leukemia (ALL) 16 (15) Mixed phenotype acute leukemia (MPAL) 2 (2) Translocations1, n (%) t(9;11) 23 (22) t(11;19) 20 (19) t(6;11) 10 (10) t(10;11) 10 (10) t(4;11) 7 (7) t(1;11) 3 (3) t(11;17) 2 (2) t(11;22) 2 (2) t(11;16) 1(1) KMT2A fusion partner unknown 26 (25) Disease status, n (%) Primary refractory 22 (21) Untreated relapse 21 (20) Refractory relapse 61 (59) Prior treatment Number of prior regimens, median (range) 2 (1, 11) Prior stem cell transplantation, n (%) 46 (44) Number of prior relapses, n (%) 0 22 (21) 1 55 (53) 2 20 (19) ≥3 7 (7) 1. One patient did not have a translocation type reported. Efficacy was established on the basis of the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 5.73 months (range, 0.3 to 28.9 Reference ID: 5479801 months). The efficacy results are shown in Table 11. On subgroup analysis, CR+CRh was achieved by 18/86 (21%) of patients with AML, 3/16 (19%) of patients with ALL, and 1/2 (50%) of patients with MPAL. Table 11. Efficacy Results in Patients with Relapsed or Refractory Acute Leukemia with KMT2A translocation (Study SNDX-5613-0700) Endpoint REVUFORJ N = 104 CR1+CRh2 n (%) 95% CI Median DOCR+CRh3 (months) 95% CI 22 (21.2) (13.8, 30.3)6 6.46 (2.7, NE) CR n (%) 95% CI Median DOCR4 (months) 95% CI 13 (12.5) (6.8, 20.4)6 4.36 (1.0, NE) CRh n (%) 95% CI Median DOCRh5 (months) 95% CI 9 (8.7) (4.0, 15.8)6 6.46 (1.9, NE) CI: confidence interval; NE = not estimable; DOCR = duration of CR; DOCRh = duration of CRh. 1. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L and platelet count ≥100 × 109/L. 2. CRh is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; residual neutropenia (>0.5 × 109/L) and thrombocytopenia (>50 × 109/L), but the count recovery criteria for CR are not met. 3. Duration of CR+CRh is defined as the time from first CR or CRh to the first documented relapse or death, whichever occurs first. 4. Duration of CR is defined as the time from first CR to the first documented relapse or death, whichever occurs first. 5. Duration of CRh is defined as the time from first CRh to the first documented relapse or death, whichever occurs first. 6. The 95% CI of the response rate is derived using the exact method based on binomial distribution. The median of the response duration is derived using Kaplan-Meier method. Of the 22 patients who achieved a CR or CRh, the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months). Among the 83 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 12 (14%) became independent of RBC and platelet transfusions during any 56-day post- baseline period. Of the 21 patients who were independent of both RBC and platelet transfusions at baseline, 10 (48%) remained transfusion independent during any 56-day post-baseline period. 16 HOW SUPPLIED/STORAGE AND HANDLING 25 mg: Pink modified oval film-coated tablet debossed with “S” on one side and “25” on the other side. • 30-count bottles with a desiccant and child resistant closure (NDC 73555-500-00) 110 mg: Beige modified oval film-coated tablet debossed with “S” on one side and “110” on the other side. • 30-count bottles with a desiccant and child resistant closure (NDC 73555-501-00) Reference ID: 5479801 160 mg: Purple modified oval film-coated tablet debossed with “S” on one side and “160” on the other side. • 30-count bottles with a desiccant and child resistant closure (NDC 73555-502-00) Store tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep in original container until dispensed. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) and Instructions for Use. Differentiation Syndrome Advise patients of the risks of developing differentiation syndrome as early as 1 day after the start of therapy and during treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, low blood pressure, rapid weight gain, swelling of their arms or legs, or decreased urinary output, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)]. Prolonged QT Interval Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes [see Warnings and Precautions (5.2)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with REVUFORJ and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise females and males of reproductive potential of the potential for impaired fertility from REVUFORJ [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Drug Interactions Advise patients to inform their healthcare providers of all concomitant products, including over-the counter products and supplements [see Drug Interactions (7.1)]. Reference ID: 5479801 Dosing Instructions Advise patients to swallow tablets whole with a cup of water and not to cut or chew tablets. If patients are unable to swallow the tablets, they may be crushed and dispersed in water [see Instructions for Use]. Instruct patients that, if they miss a dose of REVUFORJ, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day [see Dosage and Administration (2.2)]. Manufactured for Syndax Pharmaceuticals, Inc., Waltham, MA 02451 REVUFORJ ® is a registered trademark of Syndax Pharmaceuticals, Inc. © 2024 Syndax Pharmaceuticals, Inc. 218944-SYND-USPI-001 Reference ID: 5479801 Medication Guide REVUFORJ (REV-you-forge) (revumenib) tablets, for oral use What is the most important information I should know about REVUFORJ? REVUFORJ may cause serious side effects including: • differentiation syndrome. Differentiation syndrome is a serious, but common condition that affects your blood cells which may be life threatening or lead to death if not treated. Differentiation syndrome has happened as early as 3 days and up to 41 days after starting REVUFORJ. Tell any healthcare provider caring for you that you are taking a medicine that can cause differentiation syndrome. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome during treatment with REVUFORJ: o fever o dizziness or lightheadedness o cough o fast weight gain o shortness of breath o swelling of arms, legs, neck, groin, or underarm area o severe headache o decreased urination o confusion If you develop any of these symptoms of differentiation syndrome, your healthcare provider may start you on a medicine given through a vein (intravenous) called corticosteroids and may monitor you in the hospital. See “What are the possible side effects of REVUFORJ?” for more information about side effects. What is REVUFORJ? REVUFORJ is a prescription medicine used to treat adults and children 1 year and older with acute leukemia with a lysine methyltransferase 2A gene translocation (KMT2A) whose disease has come back or has not improved after previous treatment(s). Your healthcare provider will perform a test to make sure that REVUFORJ is right for you. It is not known if REVUFORJ is safe and effective in children less than 1 year of age. Before taking REVUFORJ, tell your healthcare provider about all of your medical conditions, including if you: • have any heart problems, including a condition called long QT syndrome. • have been told you have low blood levels of potassium or magnesium. • are pregnant or plan to become pregnant. REVUFORJ can harm your unborn baby. o Your healthcare provider will perform a pregnancy test within 7 days before you start treatment with REVUFORJ. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with REVUFORJ. o Females who are able to become pregnant should use effective birth control (contraception) during treatment with REVUFORJ and for 4 months after the last dose of REVUFORJ. o Males who have female partners who are able to become pregnant should use effective birth control during treatment with REVUFORJ and for 4 months after the last dose of REVUFORJ. o Talk to your healthcare provider about birth control methods you can use during this time. • are breastfeeding or plan to breastfeed. It is not known if REVUFORJ passes into your breast milk. Do not breastfeed during your treatment with REVUFORJ or for 1 week after your last dose of REVUFORJ. Tell your healthcare provider about any other medications you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. REVUFORJ and other medicines may affect each other causing side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take REVUFORJ? • Take REVUFORJ exactly as your healthcare provider tells you to. Do not change your dose or stop taking REVUFORJ unless your healthcare provider tells you to. • REVUFORJ tablets come in different strengths. Each strength is a different color. Your healthcare provider may prescribe more than 1 strength of REVUFORJ tablets for you, so it is important that you understand how to take your medicine the right way. Be sure that you understand exactly how many tablets you need to take, and what strengths to take. • Take REVUFORJ 2 times a day at about the same time each day about 12 hours apart. Reference ID: 5479801 • REVUFORJ can be taken fasted or with a low-fat meal. • Swallow REVUFORJ tablets whole with a cup of water. If you are unable to swallow tablets, crush the tablets and break them apart in water. See the Instructions for Use for detailed instructions on how to prepare and give REVUFORJ tablets. Do not cut or chew tablets. • If you miss a dose of REVUFORJ or did not take it at the usual time, take your dose as soon as possible and at least 12 hours before your next dose. Do not take 2 doses within 12 hours. Return to your normal scheduled dose the following day. What are the possible side effects of REVUFORJ? REVUFORJ may cause serious side effects including: • see “What is the most important information I should know about REVUFORJ?” • changes in electrical activity of your heart called QT prolongation. QT prolongation is a serious, but common side effect that can cause irregular heartbeats that can be life-threatening or lead to death. Your healthcare provider will check the electrical activity of your heart with a test called an electrocardiogram (ECG) and will also do blood tests to check your potassium and magnesium levels before and during treatment with REVUFORJ. Tell your healthcare provider right away if you feel faint, lightheaded, dizzy, or if you feel your heart beating irregularly or fast during treatment with REVUFORJ. The most common side effects of REVUFORJ include: • bleeding (hemorrhage) • changes in liver function tests • nausea and vomiting • swelling in the arms and legs • muscle pain • decreased appetite • infections, including bacterial and viral infections • constipation • low white blood cell counts with fever • tiredness • diarrhea Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with REVUFORJ if you develop certain side effects. REVUFORJ may cause fertility problems in females and males. Talk to your healthcare provider if this is a concern for you. These are not all possible side effects of REVUFORJ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store REVUFORJ? • Store REVUFORJ at room temperature between 68°F to 77°F (20°C to 25°C). • Keep the tablets in the bottle that it comes in until you are ready to take it. • The REVUFORJ bottle has a drying agent (desiccant) and child resistant closure. Keep REVUFORJ and all medicines out of reach of children. General information about the safe and effective use of REVUFORJ. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REVUFORJ for a condition for which it is not prescribed. Do not give REVUFORJ to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or health professionals for information about REVUFORJ that is written for healthcare professionals. What are the ingredients in REVUFORJ? Active ingredient: revumenib Inactive ingredients: microcrystalline cellulose, dicalcium phosphate, crospovidone, hypromellose, sodium bicarbonate, hydrophobic colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide. The 110 mg tablet also includes yellow iron oxide. The 160 mg tablet also includes FD&C blue #2/indigo carmine aluminum lake. Manufactured for: Syndax Pharmaceuticals, Inc., Waltham, MA 02451 REVUFORJ ® is a registered trademark of Syndax Pharmaceuticals, Inc. Copyright © 2024 Syndax Pharmaceuticals, Inc. For more information, go to www.revuforj.com or call Syndax at 1-888-539-3REV. 218944-SYND-MG-001 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5479801 ® -cap banel- e _ bottom ==.=r,==-plunger ~ INSTRUCTIONS FOR USE REVUFORJ (REV-you-forge) revumenib tablets, for oral use Read these Instructions for Use to prepare and take or give a dose of REVUFORJ tablets broken apart (dispersed) in water and each time you or your child get a prescription refill. There may be new information. This information does not take the place of talking with your healthcare provider about you or your child’s medical condition or your treatment. Important information you need to know before preparing to break apart the REVUFORJ tablets in water: • For more information about REVUFORJ tablets, see the Medication Guide. • REVUFORJ tablets broken apart in water should be prepared for people who are unable to swallow whole REVUFORJ tablets. People who can swallow the tablets whole should not cut, chew, or break the tablets apart in water. • Take or give REVUFORJ tablets exactly as your healthcare provider tells you to. Do not change your dose or stop taking REVUFORJ unless your provider tells you to. • REVUFORJ tablets come in different strengths. Each strength is a different color. Your healthcare provider may prescribe more than 1 strength of REVUFORJ tablets for you or your child, so it is important that you understand how to take or give the medicine the right way. Be sure that you understand exactly how many tablets you need to take, and what strengths to take. • Check the expiration date on the REVUFORJ tablet bottles. Do not use REVUFORJ if the expiration date on the bottles have passed. Contact your healthcare provider or pharmacist. • The REVUFORJ tablets should be crushed in a clean and dry pill crusher. • Use room temperature water to dissolve the REVUFORJ tablets. • Use a teaspoon to measure the room temperature water. Use a 20 mL oral syringe to administer the medicine. o Oral syringes can look different. Talk to your pharmacist if you are not sure if you have the correct oral syringe size. o Replace the oral syringe if there are signs of damage. See Step 15. Supplies needed to prepare and break apart the REVUFORJ tablets in water. You will need to get the 20 mL oral syringe and pill crusher, which are available from your pharmacy. Figure A 20 mL Oral Syringe Pill Crusher Room Temperature Water 1 Teaspoon Small Plastic or Glass Cup Reference ID: 5479801 8_ Preparing to dissolve the REVUFORJ tablets Step 1: Gather and place the REVUFORJ bottles and supplies on a clean, flat surface. Check your prescribed dose. Count out the strengths and number of REVUFORJ tablets needed for the prescribed dose. Add all the REVUFORJ tablets to a clean and dry pill crusher. Screw the top of the pill crusher down until it touches the REVUFORJ tablets. Turn the pill crusher cap back and forth to crush the REVUFORJ tablets. Continue turning the pill crusher cap back and forth, increasing the crushing pressure on the REVUFORJ tablets each time. Repeat until all large REVUFORJ tablet pieces are broken up. The crushed REVUFORJ tablets should be like the consistency of flour. Figure B Step 2: Use two teaspoons to measure 10 mL of room temperature water. Add the 10 mL of water to the small cup. Add water to the cup first and then add the crushed REVUFORJ tablets. Do not add the crushed REVUFORJ tablets first followed by the room temperature water. Figure C Step 3: Tip the crushed REVUFORJ tablets from the pill crusher into the small cup that contains 10 mL of water. Carefully add all of the crushed REVUFORJ tablets to the small cup. Hold the pill crusher upside down over the small cup. Tap the pill crusher to make sure no more crushed REVUFORJ tablet pieces are left in the pill crusher. Figure D Reference ID: 5479801 ~ plunger Step 4: Carefully swirl the cup right after adding the crushed REVUFORJ tablets to the small cup with water. Swirl the small cup every 30 seconds to 1 minute for a total of 5 minutes. The crushed REVUFORJ tablets in water will look cloudy. Figure E Step 5: Draw up the medicine into the 20 mL oral syringe right away. Push the plunger of the oral syringe all the way up towards the tip. Place the tip of the oral syringe in the small cup. Pull the oral syringe plunger to draw up all of the medicine in the small cup. The medicine must be taken within 2 hours of preparation. Turn the oral syringe upside down and back several times before taking or giving the medicine. Figure F Step 6: The adult or child should sit up straight or stand before taking the medicine. Place the tip of the oral syringe into the mouth against the inside of the cheek. Slowly and gently press down on the plunger to gently squirt the medicine into the mouth. Allow the adult or child to swallow the medicine. Make sure that no medicine is left in the mouth. The adult or child should remain sitting up straight or standing for 2 to 3 minutes right after receiving a dose of the medicine. If the medicine is vomited or all of the medicine is not swallowed, do not give another dose. Wait until the next scheduled dose. Figure G Reference ID: 5479801 Step 7: The small cup must be rinsed to make sure the adult or child receives the full dose of REVUFORJ tablets. Place two teaspoons (10 mL) of room temperature water in the cup rinsing down the sides (Figure H) Swirl the water around the sides of the small cup to make sure any remaining crushed REVUFORJ tablets is mixed with the water (Figure I). Figure H Figure I Step 8: Repeat Step 5 and Step 6 until no more medicine is left in the cup. Reference ID: 5479801 barrel plunger G) ® Cleaning the oral syringe after use Follow the instructions below for cleaning and storing the oral syringe (Step 9 through Step 15). Throw away the oral syringe in your household trash if it is damaged (See Step 15), and use a new 20 mL oral syringe. Step 9: Remove the plunger from the barrel of the oral syringe. Figure J Step 10: Rinse the barrel and plunger in warm running water to help make sure all of the medicine has been removed from the oral syringe. Do not boil the oral syringe. Figure K Step 11: Put the plunger into the barrel of the oral syringe. Figure L Reference ID: 5479801 () () () \) () Step 12: Hold the oral syringe tip under water and draw warm water several times into the oral syringe and squirt out again until all of the medicine has been removed from the oral syringe. Repeat this Step until the oral syringe is clean. Figure M Step 13: Remove the plunger from the barrel of the oral syringe. Rinse the barrel and plunger again with warm water. Figure N Step 14: Shake off excess water or wipe off the outside of the plunger and barrel. Place the barrel and plunger on a clean, dry paper towel to dry. Figure O Reference ID: 5479801 Step 15: Make sure the oral syringe parts are fully dry before putting the plunger back into the barrel of the oral syringe. Store the oral syringe in a clean place until the next use. Replace the oral syringe if: • there is any damage to the barrel, plunger, or tip. • you cannot see the dosage markings or it becomes difficult to move the plunger. Cleaning the pill crusher after use Step 16: Rinse both parts of the pill crusher with water after use. Shake off excess water or wipe both parts of the pill crusher. Place both parts of the pill crusher on a clean, dry paper towel to dry. Storing REVUFORJ • Store REVUFORJ at room temperature between 68°F to 77°F (20°C to 25°C). • Keep the tablets in the bottle that it comes in until you are ready to take it. • The REVUFORJ bottle has a drying agent (desiccant) and child resistant closure. Keep REVUFORJ and all medicines out of reach of children. Manufactured for: Syndax Pharmaceuticals, Inc., Waltham, MA 02451 REVUFORJ ® is a registered trademark of Syndax Pharmaceuticals, Inc. Copyright © 2024 Syndax Pharmaceuticals, Inc. For more information, go to www.revuforj.com or call Syndax at 1-888-539-3REV. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5479801	custom-source	2025-02-12T15:46:42.480813	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218944s000lbl.pdf', 'application_number': 218944, 'submission_type': 'ORIG ', 'submission_number': 1}
80,226	1 KENALOG-40 INJECTION KENALOG-80 INJECTION (triamcinolone acetonide injectable suspension, USP) NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL For Intramuscular or Intra-articular Use Only NOT FOR INTRAVENOUS, INTRADERMAL, INTRAOCULAR, EPIDURAL, OR INTRATHECAL USE DESCRIPTION KENALOG-40 Injection and KENALOG-80 Injection (triamcinolone acetonide injectable suspension, USP) are a synthetic glucocorticoid corticosteroid with anti- inflammatory action. THESE FORMULATION ARE SUITABLE FOR INTRAMUSCULAR AND INTRA-ARTICULAR USE ONLY. THESE FORMULATION ARE NOT FOR INTRADERMAL INJECTION. KENALOG-40 Injection: Each mL of the sterile aqueous suspension provides 40 mg triamcinolone acetonide, with 0.66% sodium chloride for isotonicity, 0.99% (w/v) benzyl alcohol as a preservative, 0.63% carboxymethylcellulose sodium, and 0.04% polysorbate 80. Sodium hydroxide or hydrochloric acid may be present to adjust pH to 5.0 to 7.5. At the time of manufacture, the air in the container is replaced by nitrogen. KENALOG-80 Injection: Each mL of the sterile aqueous suspension provides 80 mg triamcinolone acetonide, with 0.66% sodium chloride for isotonicity, 0.99% (w/v) benzyl alcohol as a preservative, 0.63% carboxymethylcellulose sodium, and 0.04% polysorbate 80. Sodium hydroxide or hydrochloric acid may be present to adjust pH to 5.0 to 7.5. At the time of manufacture, the air in the container is replaced by nitrogen. The chemical name for triamcinolone acetonide is 9-Fluoro-11,16,17,21- tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is: Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 MW 434.50 Triamcinolone acetonide occurs as a white to cream-colored, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems. KENALOG-40 Injection and KENALOG-80 Injection have an extended duration of effect which may be sustained over a period of several weeks. Studies indicate that following a single intramuscular dose of 60 mg to 100 mg of triamcinolone acetonide, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. This finding correlates closely with the extended duration of therapeutic action achieved with the drug. INDICATIONS AND USAGE Intramuscular Where oral therapy is not feasible, injectable corticosteroid therapy, including KENALOG-40 Injection and KENALOG-80 Injection (triamcinolone acetonide injectable suspension, USP) is indicated for intramuscular use as follows: Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous system: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. Intra-Articular The intra-articular or soft tissue administration of KENALOG-40 Injection and KENALOG-80 Injection are indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. CONTRAINDICATIONS KENALOG-40 Injection and KENALOG-80 Injection are contraindicated in patients who are hypersensitive to any components of this product (see WARNINGS: General). Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids (see WARNINGS: Neurologic). Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. General Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Cases of serious anaphylaxis, including death, have been reported in individuals receiving triamcinolone acetonide injection, regardless of the route of administration. Because KENALOG-40 Injection and KENALOG-80 Injection (triamcinolone acetonide injectable suspension, USP) are suspensions, they should not be administered intravenously. Unless a deep intramuscular injection is given, local atrophy is likely to occur. (For recommendations on injection techniques, see DOSAGE AND ADMINISTRATION.) Due to the significantly higher incidence of local atrophy when the material is injected into the deltoid area, this injection site should be avoided in favor of the gluteal area. Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. KENALOG-40 Injection and KENALOG-80 Injection are long-acting preparations, and are not suitable for use in acute stress situations. To avoid drug-induced adrenal insufficiency, supportive dosage may be required in times of stress (such as trauma, surgery, or severe illness) both during treatment with KENALOG-40 Injection and KENALOG-80 Injection and for a year afterwards. Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an intravenous corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including KENALOG-40 Injection and KENALOG-80 Injection, should not be used for the treatment of traumatic brain injury. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Cardio-Renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when they are used in large doses. Dietary salt restriction and potassium supplementation may be necessary (see PRECAUTIONS). All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B injection and potassium- depleting agents). Endocrine Corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Immunosuppression and Increased Risk of Infection Corticosteroids, including KENALOG-40 and KENALOG-80, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:  Reduce resistance to new infections  Exacerbate existing infections  Increase the risk of disseminated infections  Increase the risk of reactivation or exacerbation of latent infections  Mask some signs of infection Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages. Monitor for the development of infection and consider KENALOG-40 or KENALOG-80 withdrawal or dosage reduction as needed. Do not administer KENALOG-40 and KENALOG-80 by an intraarticular, intrabursal, or intratendinous route in the presence of acute local infection. Tuberculosis If KENALOG-40 or KENALOG-80 is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of the disease may occur. Closely monitor such patients for reactivation. During prolonged KENALOG-40 or KENALOG-80 therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicella and measles can have a serious or even fatal course in non-immune patients receiving corticosteroids, including KENALOG-40 or KENALOG-80. In corticosteroid- treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:  If a KENALOG-40- or KENALOG-80- treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If varicella develops, treatment with antiviral agents may be considered.  If a KENALOG-40- or KENALOG-80-treated patient is exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including KENALOG-40 and KENALOG-80. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with KENALOG-40 and KENALOG-80. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Fungal Infections Corticosteroids, including KENALOG-40 and KENALOG-80, may exacerbate systemic fungal infections; therefore, avoid KENALOG-40 and KENALOG-80 use in the presence of such infections unless KENALOG-40 or KENALOG-80 is needed to control drug reactions. For patients on chronic KENALOG-40 or KENALOG-80 therapy who develop systemic fungal infections, KENALOG-40 or KENALOG-80 withdrawal or dosage reduction is recommended. Amebiasis Corticosteroids, including KENALOG-40 and KENALOG-80, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating KENALOG-40 or KENALOG-80 in patients who have spent time in the tropics or patients with unexplained diarrhea. Strongyloides Infestation Corticosteroids, including KENALOG-40 and KENALOG-80, should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Cerebral Malaria Avoid corticosteroids, including KENALOG-40 and KENALOG-80, in patients with cerebral malaria. Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Neurologic Epidural and intrathecal administration of this product is not recommended. Reports of serious medical events, including death, have been associated with epidural and intrathecal routes of corticosteroid administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. Adequate studies to demonstrate the safety of KENALOG-40 Injection and KENALOG- 80 Injection use by intraturbinal, subconjunctival, sub-Tenons, retrobulbar, and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure, and visual disturbances including vision loss have been reported with intravitreal administration. Administration of KENALOG-40 Injection and KENALOG-80 Injection intraocularly or into the nasal turbinates is not recommended. Intraocular injection of corticosteroid formulations containing benzyl alcohol, such as KENALOG-40 Injection, is not recommended because of potential toxicity from the benzyl alcohol. Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Cardio-Renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Neuro-Psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION). An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychiatric derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. CYP3A4 inhibitors: Triamcinolone acetonide is a substrate of CYP3A4. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Co-administration of other strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin, cobicistat-containing products) with KENALOG-40 Injection may cause increased plasma concentration of triamcinolone leading to adverse reactions. (See ADVERSE REACTIONS.) During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving triamcinolone acetonide and strong CYP3A4 inhibitors (e.g., ritonavir). (See WARNINGS, Endocrine and PRECAUTIONS, Endocrine.) Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic enzyme inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory drugs) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Immunosuppression and Increased Risk of Infection, Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids in the pediatric population are based on the well- established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well- controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Geriatric Use No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS (listed alphabetically under each subsection) The following adverse reactions may be associated with corticosteroid therapy: Allergic reactions: Anaphylaxis including death, and angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypo- pigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, postmenopausal vaginal hemorrhage, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration [see WARNINGS: Neurologic]), elevation in serum liver enzyme levels Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids (see WARNINGS: Serious Neurologic Adverse Reactions with Epidural Administration and WARNINGS: Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 DOSAGE AND ADMINISTRATION General NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS). The initial dose of KENALOG-40 Injection and KENALOG-80 Injection may vary from 2.5 mg to 100 mg per day depending on the specific disease entity being treated (see Dosage section below). However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. Dosage SYSTEMIC The suggested initial dose is 60 mg, injected deeply into the gluteal muscle. Atrophy of subcutaneous fat may occur if the injection is not properly given. Dosage is usually adjusted within the range of 40 mg to 80 mg, depending upon patient response and duration of relief. However, some patients may be well controlled on doses as low as 20 mg or less. Hay fever or pollen asthma: Patients with hay fever or pollen asthma who are not responding to pollen administration and other conventional therapy may obtain a remission of symptoms lasting throughout the pollen season after a single injection of Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 40 mg to 100 mg. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of triamcinolone for a week followed by 64 mg every other day for one month are recommended (see PRECAUTIONS: Neuro-Psychiatric). In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 mg/kg/day to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 mg/m2bsa/day to 48 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. LOCAL Intra-articular administration: A single local injection of triamcinolone acetonide is frequently sufficient, but several injections may be needed for adequate relief of symptoms. Initial dose: 2.5 mg to 5 mg for smaller joints and from 5 mg to 15 mg for larger joints, depending on the specific disease entity being treated. For adults, doses up to 10 mg for smaller areas and up to 40 mg for larger areas have usually been sufficient. Single injections into several joints, up to a total of 80 mg, have been given. Administration GENERAL STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniformsuspension. Prior to withdrawal, the suspension should be inspected Approved 1.0 v ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 for clumping or granular appearance (agglomeration). Agglomeration occurs when the drug substance separates from the solution and appears as a white precipitate in the vial. An agglomerated product should be discarded and should not be used. After withdrawal, KENALOG-40 Injection and KENALOG-80 Injection should be injected without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing infection. SYSTEMIC For systemic therapy, injection should be made deeply into the gluteal muscle (see WARNINGS). For adults, a minimum needle length of 1½ inches is recommended. In obese patients, a longer needle may be required. Use alternative sites for subsequent injections. LOCAL For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid. With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy. In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of the corticosteroid is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness. HOW SUPPLIED KENALOG-40 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in vials providing 40 mg triamcinolone acetonide per mL. 40 mg/mL, 1 mL single-dose vial NDC 0003-0293-05 40 mg/mL, 5 mL multiple-dose vial NDC 0003-0293-20 40 mg/mL, 10 mL multiple-dose vial NDC 0003-0293-28 Approved 1.0 v This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 KENALOG-80 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in vials providing 80 mg triamcinolone acetonide per mL. 80 mg/mL, 1 mL single-dose vial NDC 0003-0315-05 80 mg/mL, 5 mL multiple-dose vial NDC 0003-0315-20 Storage Store at controlled room temperature, 20C to 25C (68°F to 77°F); protect from temperatures below 20°C (68°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Store vial in carton to protect from light. Do not refrigerate. Store vial upright. Once in use: Chemical and physical in-use stability has been demonstrated for 28 days below 25°C (77°F). From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days at 15°C to 25°C (59°F to 77°F). Other in-use storage times and conditions are the responsibility of the user. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Revised: XXX 20XX Approved 1.0 v ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:42.574302	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/014901Orig1s055lbl.pdf', 'application_number': 14901, 'submission_type': 'SUPPL ', 'submission_number': 55}
80,230	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EPYSQLI safely and effectively. See full prescribing information for EPYSQLI. EPYSQLI® (eculizumab-aagh) injection, for intravenous use Initial U.S. Approval: 2024 EPYSQLI (eculizumab-aagh) is biosimilar* to SOLIRIS (eculizumab). WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning. Eculizumab products increase the risk of serious and life- threatening infections caused by Neisseria meningitidis. • Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. (5.1) • Patients receiving eculizumab products are at increased risk for invasive disease caused by N. meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections, and evaluate immediately if infection is suspected. (5.1) EPYSQLI is available only through a restricted program called the EPYSQLI REMS. (5.2) ----------------------------RECENT MAJOR CHANGES------------------------ Indications and Usage (1.3) 11/2024 Dosage and Administration (2.4, 2.5) 11/2024 -----------------------------INDICATIONS AND USAGE-------------------------- EPYSQLI is a complement inhibitor indicated for: • the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. (1.1) • the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. (1.2) Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). • the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. (1.3) ------------------------DOSAGE AND ADMINISTRATION---------------------- For intravenous infusion only PNH Dosage Regimen: (2.2) aHUS Dosage Regimen: (2.3) gMG Dosage Regimen: (2.4) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Injection: 300 mg/30 mL (10 mg/mL) in a single-dose vial. (3) -------------------------------CONTRAINDICATIONS------------------------------ EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Use caution when administering EPYSQLI to patients with any other systemic infection. (5.3) • Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures. (5.6) -------------------------------ADVERSE REACTIONS----------------------------- The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. (6.1) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. (6.1) The most frequently reported adverse reaction in the gMG placebo- controlled clinical trial (≥10%) is: musculoskeletal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Samsung Bioepis Co., Ltd. at 1-800-806-0716 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of EPYSQLI has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS MENINGOCOCCAL INFECTIONS 1 INDICATIONS AND USAGE 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) 1.3 Generalized Myasthenia Gravis (gMG) 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection 2.2 Recommended Dosage Regimen – PNH 2.3 Recommended Dosage Regimen – aHUS 2.4 Recommended Dosage Regimen – gMG 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion 2.6 Preparation 2.7 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Meningococcal Infections 5.2 EPYSQLI REMS 5.3 Other Infections 5.4 Monitoring Disease Manifestations after EPYSQLI Discontinuation 5.5 Thrombosis Prevention and Management 5.6 Infusion-Related Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion 7.2 Neonatal Fc Receptor Blockers 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use Reference ID: 5479711 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) 14.3 Generalized Myasthenia Gravis (gMG) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5479711 FULL PRESCRIBING INFORMATION WARNING: SERIOUS MENINGOCOCCAL INFECTIONS Eculizumab products, complement inhibitors, increase the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. • Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying therapy with EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. • Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, EPYSQLI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called EPYSQLI REMS [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) EPYSQLI is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) EPYSQLI is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Reference ID: 5479711 1.3 Generalized Myasthenia Gravis (gMG) EPYSQLI is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y, and B) according to current ACIP recommendations at least 2 weeks prior to initiation of EPYSQLI [see Warnings and Precautions (5.1)]. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe EPYSQLI must enroll in the EPYSQLI REMS [see Warnings and Precautions (5.2)]. 2.2 Recommended Dosage Regimen – PNH For patients 18 years of age and older, EPYSQLI therapy consists of: • 600 mg weekly for the first 4 weeks, followed by • 900 mg for the fifth dose 1 week later, then • 900 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points [see Warnings and Precautions (5.4)]. 2.3 Recommended Dosage Regimen – aHUS For patients 18 years of age and older, EPYSQLI therapy consists of: • 900 mg weekly for the first 4 weeks, followed by • 1,200 mg for the fifth dose 1 week later, then • 1,200 mg every 2 weeks thereafter. For patients less than 18 years of age, administer EPYSQLI based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in aHUS Patients Less Than 18 Years of Age Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly x 4 doses 1,200 mg at week 5; then 1,200 mg every 2 weeks 30 kg to less than 40 kg 600 mg weekly x 2 doses 900 mg at week 3; then 900 mg every 2 weeks Reference ID: 5479711 20 kg to less than 30 kg 600 mg weekly x 2 doses 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg weekly x 1 dose 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg weekly x 1 dose 300 mg at week 2; then 300 mg every 3 weeks Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. 2.4 Recommended Dosage Regimen – gMG For adult patients with generalized myasthenia gravis, EPYSQLI therapy consists of: • 900 mg weekly for the first 4 weeks, followed by • 1,200 mg for the fifth dose 1 week later, then • 1,200 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of EPYSQLI is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2). Table 2: Supplemental Dose of EPYSQLI after PE/PI Type of Plasma Intervention Most Recent EPYSQLI Dose Supplemental EPYSQLI Dose with Each Plasma Intervention Timing of Supplemental EPYSQLI Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange ≥600 mg 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion ≥300 mg 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma 2.6 Preparation Dilute EPYSQLI to a final admixture concentration of 5 mg/mL using the following steps: • Withdraw the required amount of EPYSQLI from the vial into a sterile syringe. • Transfer the recommended dose to an infusion bag. Reference ID: 5479711 • Dilute EPYSQLI to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; or 5% Dextrose in Water Injection, USP to the infusion bag. The final admixed EPYSQLI 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses (Table 3). Table 3: Preparation and Reconstitution of EPYSQLI EPYSQLI Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1,200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted EPYSQLI solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the EPYSQLI admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of EPYSQLI are stable for 24 hours refrigerated at 2°C to 8°C (36°F to 46°F) and at room temperature. If an adverse reaction occurs during the administration of EPYSQLI, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction. 3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/30 mL (10 mg/mL) as a clear to slightly opalescent, and colorless solution in a single-dose vial. 4 CONTRAINDICATIONS EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1)]. Reference ID: 5479711 5 WARNINGS AND PRECAUTIONS 5.1 Serious Meningococcal Infections Eculizumab products, complement inhibitors, increase a patient's susceptibility to serious, life- threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. .The initiation of EPYSQLI treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of EPYSQLI, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy with EPYSQLI. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including eculizumab products. The benefits and risks of treatment with EPYSQLI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis. Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life- threatening or fatal if not recognized and treated early. Consider interruption of EPYSQLI in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. EPYSQLI is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)]. 5.2 EPYSQLI REMS EPYSQLI is available only through a restricted program under a REMS called EPYSQLI REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1)]. Notable requirements of the EPYSQLI REMS include the following: • Prescribers must enroll in the REMS. • Prescribers must counsel patients about the risk of serious meningococcal infection. • Prescribers must provide the patients with the REMS educational materials. Reference ID: 5479711 • Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EPYSQLI. • Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of EPYSQLI. • Healthcare settings and pharmacies that dispense EPYSQLI must be certified in the REMS and must verify prescribers are certified. • Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. • Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI. Further information is available at www.EPYSQLIREMS.com or 1-866-318-8144. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported. Eculizumab products block terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab products may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving eculizumab products are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after EPYSQLI Discontinuation Treatment Discontinuation for PNH Monitor patients after discontinuing EPYSQLI for at least 8 weeks to detect hemolysis. Treatment Discontinuation for aHUS After discontinuing EPYSQLI, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during EPYSQLI Reference ID: 5479711 --- treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during EPYSQLI treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during EPYSQLI treatment. If TMA complications occur after EPYSQLI discontinuation, consider reinstitution of EPYSQLI treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. 5.5 Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during eculizumab products treatment has not been established. Therefore, treatment with eculizumab products should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of eculizumab products may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of eculizumab. Interrupt EPYSQLI infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Serious Meningococcal Infections [see Warnings and Precautions (5.1)] • Other Infections [see Warnings and Precautions (5.3)] • Monitoring Disease Manifestations after EPYSQLI Discontinuation [see Warnings and Precautions (5.4)] • Thrombosis Prevention and Management [see Warnings and Precautions (5.5)] • Infusion-Related Reactions [see Warnings and Precautions (5.6)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [see Warnings and Precautions (5.1)]. PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Eculizumab was Reference ID: 5479711 studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received eculizumab and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05 001). 182 patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. Table 4 summarizes the adverse reactions that occurred at a numerically higher rate in the eculizumab group than the placebo group and at a rate of 5% or more among patients treated with eculizumab. Table 4: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction Eculizumab Placebo (N=43) (N=44) N (%) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Reference ID: 5479711 Table 5: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Vascular Disorders C08-002A/B (N=17) Number (%) of Patients C08-003A/B C10-004 (N=20) (N=41) Total (N=78) Hypertensiona 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea Abdominal pain Nervous System Disorders Headache Blood and Lymphatic System Disorders 5 (29) 3 (18) 7 (41) 8 (40) 6 (30) 10 (50) 5 (12) 6 (15) 15 (37) 18 (23) 15 (19) 32 (41) Anemia Leukopenia Psychiatric Disorders Insomnia Renal and Urinary Disorders Renal Impairment Proteinuria Respiratory, Thoracic and Mediastinal Disorders 6 (35) 4 (24) 4 (24) 5 (29) 2 (12) 7 (35) 3 (15) 2 (10) 3 (15) 1 (5) 7 (17) 5 (12) 5 (12) 6 (15) 5 (12) 20 (26) 12 (15) 11 (14) 14 (18) 8 (10) Cough General Disorders and 4 (24) 6 (30) 8 (20) 18 (23) Administration Site Conditions Fatigue Peripheral edema Pyrexia Asthenia Eye Disorder Metabolism and Nutrition Disorders 3 (18) 5 (29) 4 (24) 3 (18) 5 (29) 4 (20) 4 (20) 5 (25) 4 (20) 2 (10) 3 (7) 9 (22) 7 (17) 6 (15) 8 (20) 10 (13) 18 (23) 16 (21) 13 (17) 15 (19) Hypokalemia Neoplasms benign, malignant, and unspecified (including cysts and polyps) 3 (18) 1 (6) 2 (10) 6 (30) 4 (10) 1 (20) 9 (12) 8 (10) Skin and Subcutaneous Tissue Disorders Rash Pruritus Musculoskeletal and Connective 2 (12) 1 (6) 3 (15) 3 (15) 6 (15) 4 (10) 11 (14) 8 (10) Tissue Disorders Arthralgia Back pain 1 (6) 3 (18) 2 (10) 3 (15) 7 (17) 2 (5) 10 (13) 8 (10) Reference ID: 5479711 a. includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 6 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10 003. Table 6: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs Total (N=18) (N=22) Eye Disorders Gastrointestinal Disorders 3 (17) 3 (14) Abdominal pain Diarrhea Vomiting Dyspepsia General Disorders and Administration Site Conditions 6 (33) 5 (28) 4 (22) 0 7 (32) 7 (32) 6 (27) 3 (14) Pyrexia Infections and Infestations 9 (50) 11 (50) Upper respiratory tract infection Nasopharyngitis Rhinitis Urinary Tract infection Catheter site infection 5 (28) 3 (17) 4 (22) 3 (17) 3 (17) 7 (32) 6 (27) 4 (18) 4 (18) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms Nervous System Disorders Headache Renal and Urinary Disorders Respiratory, Thoracic and Mediastinal Disorders 2 (11) 3 (17) 3 (17) 3 (14) 4 (18) 4 (18) Cough Oropharyngeal pain 7 (39) 1 (6) 8 (36) 3 (14) Skin and Subcutaneous Tissue Disorders Rash Vascular Disorders 4 (22) 4 (18) Hypertension 4 (22) 4 (18) Reference ID: 5479711 In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 7. Table 7: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients < 2 yrs 2 to < 12 yrs 12 to < 18 yrs Total (N=5) (N=10) (N=4) (N=19) General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infectiona 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) a. includes the preferred terms upper respiratory tract infection and nasopharyngitis. Generalized Myasthenia Gravis (gMG) In a 26-week placebo-controlled trial evaluating the effect of eculizumab for the treatment of gMG (gMG Study 1), 62 patients received eculizumab at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies (14.3)]. Patients were 19 to 79 years of age, and 66% were female. Table 8 displays the most common adverse reactions from gMG Study 1 that occurred in ≥5% of eculizumab-treated patients and at a greater frequency than on placebo. Table 8: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in gMG Study 1 and at a Greater Frequency than in Placebo-Treated Patients Eculizumab Placebo (N=62) (N=63) N (%) N (%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) Reference ID: 5479711 Eculizumab Placebo (N=62) (N=63) N (%) N (%) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus 5 (8) 1 (2) infections Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥10%) that occurred in eculizumab-treated patients in the long-term extension to gMG Study 1, Study ECU-MG-302, and that are not included in Table 8 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to eculizumab products exposure. Adverse Reactions from Postmarketing Spontaneous Reports • Fatal or serious infections: Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified. • Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with eculizumab products. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks. 7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion Concomitant use of eculizumab products with plasma exchange (PE), plasmapheresis (PP) or fresh frozen plasma infusion (PE/PI) treatment can reduce serum eculizumab product concentrations and requires a supplemental dose of EPYSQLI [see Dosage and Administration (2.5)]. Reference ID: 5479711 7.2 Neonatal Fc Receptor Blockers Concomitant use of eculizumab products with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab products. Closely monitor for reduced effectiveness of EPYSQLI. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy (see Clinical Considerations). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 Reference ID: 5479711 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. 8.2 Lactation Risk Summary Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab products on the breastfed infant. There are no data on the effects of eculizumab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EPYSQLI and any potential adverse effects on the breastfed child from EPYSQLI or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of EPYSQLI for the treatment of PNH or gMG in pediatric patients have not been established. The safety and effectiveness of EPYSQLI for the treatment of aHUS have been established in pediatric patients. Use of EPYSQLI in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1), and Clinical Studies (14.2)]. Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [see Warnings and Precautions (5.1, 5.3)]. 8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. 11 DESCRIPTION Eculizumab-aagh, a complement inhibitor, is a recombinant humanized monoclonal IgG2/4κ antibody produced in a Chinese Hamster Ovary cell line expression system and purified by standard bioprocess technology . Eculizumab-aagh contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab-aagh is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. EPYSQLI (eculizumab-aagh) injection is a sterile, preservative-free, clear to slightly opalescent and colorless solution for intravenous infusion and is supplied in a 30 mL single-dose vial. Each mL Reference ID: 5479711 contains 10 mg of eculizumab-aagh, dibasic sodium phosphate (0.77 mg), monobasic sodium phosphate (0.55 mg), polysorbate 80 (0.22 mg) (vegetable origin), trehalose (86 mg), and Water for Injection, USP. The pH is 7. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eculizumab-aagh, the active ingredient in EPYSQLI, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. 12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [see Clinical Studies (14)]. In patients with PNH, aHUS, and gMG, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity. 12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (Cmax) was 194 ± 76 mcg/mL and the trough concentration (Ctrough) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD Ctrough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with gMG, the week 26 observed mean ± SD Cmax was 783 ± 288 mcg/mL and the Ctrough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab was approximately 270 h to 414 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 250-fold and reduced the half-life to 1.26 h. Supplemental dosing is recommended when EPYSQLI is administered to patients receiving plasma exchange or infusion [see Dosage and Administration (2.5)]. Specific Populations Reference ID: 5479711 Age, Sex, and Race: The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment: Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m2 to105 mL/min/1.73 m2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula). 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti- drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of eculizumab or of other eculizumab products. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro- chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS and gMG indications, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to eculizumab were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period. None of the 62 patients with gMG had antibodies to eculizumab detected following the 26-week active treatment. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH and the 3 patients with aHUS with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility. 14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (PNH Study 1, NCT00122330); PNH Reference ID: 5479711 patients were also treated with eculizumab in a single arm 52 week study (PNH Study 2, NCT00122304) and in a long- term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH Study 1: PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the "set-point") which would define each patient’s hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 9). Table 9: PNH Study 1 Patient Baseline Characteristics Study 1 Parameter Placebo (N=44) Eculizumab (N=43) Mean age (SD) 38 (13) 42 (16) Gender - female (%) 29 (66) 23 (54) History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19) Patients with history of thrombosis (events) 8 (11) 9 (16) Concomitant anticoagulants (%) 20 (46) 24 (56) Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33) Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3)) 17 (14, 25) 18 (12, 24) Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1) Pre-treatment LDH levels (median, U/L) 2,234 2,032 Free hemoglobin at baseline (median, mg/dL) 46 41 Patients treated with eculizumab had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 10). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health- Reference ID: 5479711 related quality of life. Because of the study sample size and duration, the effects of eculizumab products on thrombotic events could not be determined. Table 10: PNH Study 1 Results Placebo Eculizumab (N=44) (N=43) Percentage of patients with stabilized hemoglobin levels 0 49 Packed RBC units transfused per patient (median) 10 0 (range) (2 - 21) (0 - 16) Transfusion avoidance (%) 0 51 LDH levels at end of study (median, U/L) 2,167 239 Free hemoglobin at end of study (median, mg/dL) 62 5 PNH Study 2 and Extension Study: PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti- thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 eculizumab- treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab products therapy was not studied [see Warnings and Precautions (5.5)]. 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08 003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09 001r and Study C10-003 was based on body weight [see Dosage and Administration (2.3)]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: • platelet count change from baseline • hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks) Reference ID: 5479711 • complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks) • TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) • Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day). aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in Study C08- 002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 11 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B. Table 11: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N=17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0.26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 109/L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08 002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m2 at baseline to 56 ± 40 mL/min/1.73m2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m2). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08- 002A/B, mean platelet count (± SD) increased from 109 ± 32 x109/L at baseline to 169 ± 72 x109/L by one week; this effect was maintained through 26 weeks (210 ± 68 x109/L), and 2 years (205 ± 46 x109/L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Reference ID: 5479711 Table 12 summarizes the efficacy results for Study C08-002A/B. Table 12: Efficacy Results for Study C08-002A/B Efficacy Parameter Study C08-002A/B at 26 wks1 (N=17) Study C08-002A/B at 2 yrs2 (N=17) Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range) 11 (65) 38 (25, 56) 13 (77) 99 (25, 139) eGFR improvement ≥15 mL/min/1.73 m2, n (%) Median duration of eGFR improvement, days (range) 9 (53) 251 (70, 392) 10 (59) ND Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range) 13 (76) 37 (25, 62) 15 (88) 99 (25, 145) TMA event-free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.82 (0.04, 1.52) 0 (0, 0.31) 0.82 (0.04, 1.52) 0 (0, 0.36) 1.At data cut-off (September 8, 2010). 2.At data cut-off (April 20, 2012). aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08 003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08- 003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-003A/B. Table 13: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N=20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0.66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 109/L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks. In Study C08 003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m2) and 2 years (40 ± 18 mL/min/1.73m2). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an Reference ID: 5479711 increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 x 109/L at baseline, 233 ± 69 x 109/L at week 26, and 224 ± 52 x 109/L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In Study C08-003A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 14 summarizes the efficacy results for Study C08-003A/B. Table 14: Efficacy Results for Study C08-003A/B Efficacy Parameter Study C08-003A/B at 26 wks1 (N=20) Study C08-003A/B at 2 yrs2 (N=20) Complete TMA response, n (%) Median duration of complete TMA response, weeks (range) 5 (25) 32 (12, 38) 11 (55) 68 (38, 109) eGFR improvement ≥15 mL/min/1.73 m2, n (%) 1 (5) 8 (40) TMA Event-free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.23 (0.05, 1.07) 0 0.23 (0.05, 1.07) 0 (0, 0.01) Hematologic normalization4, n (%) Median duration of hematologic normalization, weeks (range)3 18 (90) 38 (22, 52) 18 (90) 114 (33, 125) 1. At data cut-off (September 8, 2010). 2. At data cut-off (April 20, 2012). 3. Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model. 4. In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI. Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 x109/L at baseline to 233 ±109 x109/L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 x109/L). A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B (Table 15). No pediatric patient required new dialysis during treatment with eculizumab. Table 15: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r Efficacy Parameter <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Reference ID: 5479711 Patients with eGFR improvement ≥ 15 mL/min/1.73 m2, n (%)2 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%)1 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 1 (0, 2) <1 (0, <1) <1 (0.07, 1.46) 0 (0, <1) <1 (0, 1) 0 (0, <1) 0.31 (0.00, 2.38) 0.00 (0.00 , 0.08) 1. Platelet count normalization was defined as a platelet count of at least 150,000 X 109/L on at least two consecutive measurements spanning a period of at least 4 weeks. 2. Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m2, one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation. Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 16 summarizes the key baseline clinical and disease- related characteristics of patients enrolled in Study C10-004. Table 16: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N=41) Time from aHUS diagnosis until start of study drug in months, median (range) 0.79 (0.03 – 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.52 (0.03-19) Baseline platelet count (× 109/L), median (range) 125 (16 – 332) Baseline LDH (U/L), median (range) 375 (131 – 3318) Patients in Study C10-004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m2 at baseline to 47 ± 24 mL/min/1.73m2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C10- 004, mean platelet count (± SD) increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 x109/L). In Study C10-004, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto- antibodies to factor H. Table 17 summarizes the efficacy results for Study C10-004. Reference ID: 5479711 Table 17: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N=41) Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range) 23 (56) 40,72 42 (6, 75) Patients with eGFR improvement ≥ 15 mL/min/1.73m2, n (%) 22 (54) Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range) 36 (88) 46 (10, 75) TMA Event-free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Before eculizumab On eculizumab treatment 0.63 (0, 1.38) 0 (0, 0.58) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38% 121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto- antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 18 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003. Table 18: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Time from aHUS diagnosis until start of study drug in months, median (range) 0.51 (0.03 – 58) 0.56 (0.03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.23 (0.03 – 4) 0.2 (0.03-4) Baseline platelet count (x 109/L), median (range) 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m2 at baseline to 98 ± 44 mL/min/1.73m2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Responses were observed across all ages from 5 months to 17 years of age. Reference ID: 5479711 Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 x109/L at baseline to 281 ± 123 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x109/L). In Study C10-003, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 19 summarizes the efficacy results for Study C10-003. Table 19: Efficacy Results for Study C10-003 Efficacy Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range)1 11 (61) 36, 83 40 (14, 77) 14 (64) 41, 83 37 (14, 77) eGFR improvement ≥15 mL/min/ 1.73 m2•n (%) 16 (89) 19 (86) Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range) 14 (78) 38 (14, 77) 18 (82) 38 (14, 77) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment 0.2 (0, 1.7) 0 (0, 0.01) 0.4 (0, 1.7) 0 (0, 0.01) 1. Through data cutoff (October 12, 2012). 14.3 Generalized Myasthenia Gravis (gMG) The efficacy of eculizumab for the treatment of gMG was established in gMG Study 1 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi- center trial that enrolled patients who met the following criteria at screening: 1. Positive serologic test for anti-AChR antibodies, 2. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, 3. MG-Activities of Daily Living (MG-ADL) total score ≥6, 4. Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9.9 (eculizumab) versus 9.2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)]. The primary efficacy endpoint for gMG Study 1 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MGADL) Reference ID: 5479711 total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the eculizumab treated group compared with -2.3 points in the placebo-treated group (p=0.006)]. A key secondary endpoint in gMG Study 1 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the eculizumab-treated group compared with -1.6 points in the placebo- treated group (p=0.001)]. The results of the analysis of the MG-ADL and QMG from gMG Study 1 are shown in Table 20. Table 20: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in gMG Study 1 Efficacy Endpoints Eculizumab-LS Mean (N=62) (SEM) Placebo-LS Mean (N=63) (SEM) Eculizumab change relative to placebo – LS Mean Difference (95% CI) p-values MG-ADL -4.2 (0.49) -2.3 (0.48) -1.9 (-3.3, -0.6) (0.006a; 0.014b) QMG -4.6 (0.60) -1.6 (0.59) -3.0 (-4.6, -1.3) (0.001a; 0.005b) SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms a: in least square means at Week 26 using a repeated measure analysis; b: in ranks at Week 26 using a worst rank analysis). In gMG Study 1, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment. 16 HOW SUPPLIED/STORAGE AND HANDLING EPYSQLI (eculizumab-aagh) injection is a sterile, preservative-free, clear to slightly opalescent and colorless solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton (NDC 71202-010-01). • Store EPYSQLI vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. DO NOT FREEZE. DO NOT SHAKE. • Prior to administration, if needed, unopened vials of EPYSQLI may be stored in the original carton at controlled room temperature [not more than 30°C (86°F)] for a single 1 month period and then returned to refrigeration for 3 days. • Do not use beyond the expiration date shown on the carton. Reference ID: 5479711 Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of EPYSQLI. 17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide). Serious Meningococcal Infections Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of EPYSQLI or receive antibacterial drug prophylaxis if EPYSQLI treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on EPYSQLI therapy [see Warnings and Precautions (5.1)]. Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1)]: • fever • fever and a rash • fever with high heart rate • headache with nausea or vomiting • headache and a fever • headache with a stiff neck or stiff back • confusion • muscle aches with flu-like symptoms • eyes sensitive to light Inform patients that they will be given a Patient Safety Card for EPYSQLI that they should carry with them at all times during and for 3 months following treatment with EPYSQLI. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. EPYSQLI REMS EPYSQLI is available only through a restricted program called EPYSQLI REMS [see Warnings and Precautions (5.2)]. Inform the patient of the following notable requirements: • Patients must receive counseling about the risk of serious meningococcal infections. • Patients must receive written educational materials about this risk. • Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI. • Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with EPYSQLI. • Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start EPYSQLI right away. Reference ID: 5479711 Other Infections Counsel patients about gonorrhea prevention and advise regular testing for patients at-risk. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving EPYSQLI for the treatment of Ahus that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Infusion-Related Reactions Advise patients that administration of EPYSQLI may result in infusion-related reactions. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH when EPYSQLI is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following EPYSQLI discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when EPYSQLI is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following EPYSQLI discontinuation. Inform patients who discontinue EPYSQLI to keep the Patient Safety Card with them for three months after the last EPYSQLI dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of EPYSQLI. Manufacured by: Samsung Bioepis Co., Ltd. 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987 Republic of Korea US License Number 2046 Reference ID: 5479711 MEDICATION GUIDE EPYSQLI® (eh-pis’-klee) (eculizumab-aagh) injection, for intravenous use What is the most important information I should know about EPYSQLI? EPYSQLI is a medicine that affects your immune system. EPYSQLI may lower the ability of your immune system to fight infections. • EPYSQLI increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. o You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of EPYSQLI. o If you have not completed your meningococcal vaccines and EPYSQLI must be started right away, you should receive the required vaccine(s) as soon as possible. o If you have not been vaccinated and EPYSQLI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. o If you had a meningococcal vaccine in the past, you might need additional vaccines before starting EPYSQLI. Your healthcare provider will decide if you need additional meningococcal vaccines. o Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection: • fever • fever and a rash • fever with high heart rate • headache with nausea or vomiting • headache and fever • headache with a stiff neck or stiff back • confusion • eyes sensitive to light • muscle aches with flu-like symptoms Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of EPYSQLI. Your risk of meningococcal infection may continue for several weeks after your last dose of EPYSQLI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EPYSQLI is only available through a program called the EPYSQLI Risk Evaluation and Mitigation Strategy (REMS). Before you can receive EPYSQLI, your healthcare provider must: • enroll in the EPYSQLI REMS program • counsel you about the risk of serious meningococcal infections • give you information about the signs and symptoms of serious meningococcal infection • make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start EPYSQLI right away and you are not up to date on your vaccines • give you a Patient Safety Card about your risk of meningococcal infection, as discussed above EPYSQLI may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. • If your child is treated with EPYSQLI, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). • Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing. • Certain fungal infections (aspergillus) may also happen if you take EPYSQLI and have a weak immune system or a low white blood cell count. For more information about side effects, see “What are the possible side effects of EPYSQLI?” What is EPYSQLI? EPYSQLI is a prescription medicine used to treat: • people with paroxysmal nocturnal hemoglobinuria (PNH). • people with atypical hemolytic uremic syndrome (aHUS). EPYSQLI is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC- HUS). • adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive. It is not known if EPYSQLI is safe and effective in children with PNH or gMG. Who should not receive EPYSQLI? Do not receive EPYSQLI if you have a serious meningococcal infection when you are starting EPYSQLI treatment. Before you receive EPYSQLI, tell your healthcare provider about all of your medical conditions, including if you: Reference ID: 5479711 • have an infection or fever. • are pregnant or plan to become pregnant. It is not known if EPYSQLI will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if EPYSQLI passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. EPYSQLI and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive EPYSQLI? • Your healthcare provider will give you EPYSQLI into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children. • Adults will usually receive an EPYSQLI infusion: o weekly for 5 weeks, then o every 2 weeks. • Children less than 18 years of age, your healthcare provider will decide how often you will receive EPYSQLI depending on your age and body weight. • After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See “What are the possible side effects of EPYSQLI?” If you have an infusion-related reaction during your EPYSQLI infusion, your healthcare provider may decide to give EPYSQLI more slowly or stop your infusion. • If you miss an EPYSQLI infusion, call your healthcare provider right away. • If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EPYSQLI. Stopping treatment with EPYSQLI may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: o drop in the number of your red o drop in your platelet o confusion blood cell count counts o difficulty breathing o kidney problems o blood clots o chest pain • If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping EPYSQLI for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include: o stroke o confusion o seizure o chest pain (angina) o difficulty breathing o kidney problems o swelling in arms or legs o a drop in your platelet count What are the possible side effects of EPYSQLI? EPYSQLI can cause serious side effects including: • See “What is the most important information I should know about EPYSQLI?” • Serious infusion-related reactions. Serious infusion-related reactions can happen during your EPYSQLI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your EPYSQLI infusion: o chest pain o trouble breathing or shortness of breath o swelling of your face, tongue, or throat o feel faint or pass out If you have an infusion-related reaction to EPYSQLI, your healthcare provider may need to infuse EPYSQLI more slowly, or stop EPYSQLI. See “How will I receive EPYSQLI?” The most common side effects in people with PNH treated with EPYSQLI include: • headache • back pain • pain or swelling of your nose or throat (nasopharyngitis) • nausea The most common side effects in people with aHUS treated with EPYSQLI include: • headache • stomach-area • low red blood cell • nausea • diarrhea (abdominal) pain (anemia) • urinary tract infections • high blood pressure • vomiting • cough • fever (hypertension) • pain or swelling of your • swelling of legs or feet • common cold (upper nose or throat (peripheral edema) respiratory infection) (nasopharyngitis) The most common side effects in people with gMG treated with EPYSQLI include: • muscle and joint (musculoskeletal) pain Reference ID: 5479711 Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of EPYSQLI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of EPYSQLI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about EPYSQLI that is written for health professionals. What are the ingredients in EPYSQLI? Active ingredient: eculizumab-aagh Inactive ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80 (vegetable origin), trehalose, and Water for Injection. Manufactured by Samsung Bioepis Co., Ltd., 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon 21987 Republic of Korea. US License Number 2046 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5479711	custom-source	2025-02-12T15:46:46.250600	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761340s003lbl.pdf', 'application_number': 761340, 'submission_type': 'SUPPL ', 'submission_number': 3}
80,223	NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 2 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 209935: KISQALI FEMARA CO-PACK is indicated for the adjuvant treatment of adults with hormone receptor (HR)- positive, human epidermal growth factor receptor 2 (HER2)- negative stage II and III early breast cancer at high risk of recurrence. Recommendation on Regulatory Action Regular Approval NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 3 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 9 1. Executive Summary ............................................................................................................... 12 1.1 Product Introduction ........................................................................................................... 12 1.2 Conclusions on the Substantial Evidence of Effectiveness ................................................ 12 1.3 Benefit-Risk Assessment (BRA) ........................................................................................ 16 1.4 Patient Experience Data ...................................................................................................... 19 2. Therapeutic Context .............................................................................................................. 20 2.1 Analysis of Condition ......................................................................................................... 20 2.2 Analysis of Current Treatment Options .............................................................................. 20 3. Regulatory Background ......................................................................................................... 26 3.1 U.S. Regulatory Actions and Marketing History ................................................................ 26 3.2 Summary of Presubmission/Submission Regulatory Activity ............................................ 26 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................................................... 30 4.1 Office of Scientific Investigations (OSI) ............................................................................ 30 4.2 Product Quality ................................................................................................................... 32 4.3 Clinical Microbiology ......................................................................................................... 32 4.4 Devices and Companion Diagnostic Issues ........................................................................ 32 5. Nonclinical Pharmacology/Toxicology ................................................................................. 33 5.1 Executive Summary ............................................................................................................ 33 6. Clinical Pharmacology .......................................................................................................... 36 6.1 Executive Summary ............................................................................................................ 36 6.2 Summary of Clinical Pharmacology Assessment .......................................................... 38 6.2.1 Pharmacology and Clinical Pharmacokinetics........................................................ 38 6.2.2 General Dosing and Therapeutic Individualization ................................................ 39 6.2.2.1 General Dosing ............................................................................................... 39 6.2.2.2 Therapeutic Individualization ......................................................................... 39 6.2.2.3 Outstanding Issues .......................................................................................... 40 6.3 Comprehensive Clinical Pharmacology Review ............................................................ 41 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 4 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 41 6.3.2 Clinical Pharmacology Questions ........................................................................... 41 7 Sources of Clinical Data ........................................................................................................ 46 7.1 Table of Clinical Studies ..................................................................................................... 46 8 Statistical and Clinical Evaluation ......................................................................................... 49 8.1 Review of Relevant Individual Trials Used to Support Efficacy ....................................... 49 8.1.1 Study CLEE011O12301C ........................................................................................ 49 8.1.2 Study Results ........................................................................................................... 60 8.1.3 Integrated Review of Effectiveness ......................................................................... 91 8.1.4 Assessment of Efficacy Across Trials ..................................................................... 91 8.1.5 Integrated Assessment of Effectiveness ................................................................... 92 8.2 Review of Safety ................................................................................................................ 95 8.2.1 Safety Review Approach ......................................................................................... 95 8.2.2 Review of the Safety Database ................................................................................ 96 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ......................................... 101 8.2.4 Results ................................................................................................................... 103 8.2.5 Analysis of Submission-Specific Safety Issues ..................................................... 126 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ... 143 8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 143 8.2.8 Specific Safety Studies/Clinical Trials .................................................................. 146 8.2.9 Additional Safety Explorations .............................................................................. 146 8.2.10 Safety in the Postmarket Setting .......................................................................... 151 8.2.11 Integrated Assessment of Safety .......................................................................... 153 8.3 Statistical Issues ................................................................................................................ 160 8.4 Conclusions and Recommendations ................................................................................. 160 8.4.1 Approach to Substantial Evidence of Effectiveness ............................................. 161 9 Advisory Committee Meeting and Other External Consultations ....................................... 163 10 Pediatrics ............................................................................................................................. 164 11 Labeling Recommendations ................................................................................................ 165 12 Risk Evaluation and Mitigation Strategies (REMS) ............................................................ 171 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 5 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 13 Postmarketing Requirements and Commitment .................................................................. 172 14 Division Director (DHOT) (NME ONLY) .......................................................................... 174 15 Division Director (OCP) ...................................................................................................... 175 16 Division Director (OB) ........................................................................................................ 176 17 Division Director (Clinical) ................................................................................................. 177 18 Office Director (or designated signatory authority) ............................................................ 178 19 Appendices .......................................................................................................................... 179 19.1 References ....................................................................................................................... 179 19.2 Financial Disclosure ........................................................................................................ 180 19.3 Nonclinical Pharmacology/Toxicology........................................................................ 181 19.4 OCP Appendices (Technical documents supporting OCP recommendations) ............ 182 19.4.1 Population PK Analysis ....................................................................................... 182 19.4.1.1 Executive Summary .......................................................................................... 182 19.4.1.2 PPK Assessment Summary ........................................................................... 182 19.4.1.3 PPK Review Issues ........................................................................................... 190 19.4.1.4 Reviewer’s Independent Analysis..................................................................... 190 19.4.2 Exposure-Response Analysis ............................................................................... 190 19.4.2.1 ER (efficacy) Executive Summary ................................................................... 190 19.4.2.2 ER (efficacy) Assessment Summary ................................................................ 190 19.4.2.3 ER (safety) Executive Summary ....................................................................... 192 19.4.2.4 ER (safety) Assessment Summary .................................................................... 192 19.4.2.5 ER Review Issues ............................................................................................. 200 19.4.2.6 Reviewer’s Independent Analysis..................................................................... 200 19.4.2.7 Overall benefit-risk evaluation based on E-R analyses .................................... 200 19.5 Additional Safety Analyses Conducted by FDA ......................................................... 216 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 6 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table of Tables Table 1: Summary of treatment armamentarium relevant to proposed indication other than chemotherapy ................................................................................................................................ 21 Table 2: -Induced Increase in MF in Duodenum of Male MutaTMMice ........................ 33 Table 3: -Induced Increase in MF in Duodenum of Female MutaTMMice ..................... 34 Table 4: -Induced Increase in MF in Livers of Male MutaTMMice ................................ 34 Table 5: Equivocal Increase in MF in Livers of Female MutaTMMice ......................................... 35 Table 6: Key Clinical Pharmacology Review Issues .................................................................... 36 Table 7: Listing of Clinical Trials Relevant to this NDA/BLA .................................................... 46 Table 8: Patient disposition (final iDFS analysis, 21-Jul-2023 data cut-off) by treatment arm (FAS)............................................................................................................................................. 61 Table 9: Protocol deviations (FAS) .............................................................................................. 63 Table 10: Demographic Characteristics ........................................................................................ 64 Table 11: Disease characteristics (FAS) ....................................................................................... 67 Table 12: Randomization by stratification factor (Full analysis set) ............................................ 72 Table 13: Log-rank test results for iDFS (FAS) ........................................................................... 74 Table 14: FDA – iDFS Censoring Reasons (final iDFS analysis) ................................................ 77 Table 15: FDA – Timing of Censoring for Patients Censored for Withdrawal of Consent ......... 77 Table 16: FDA – iDFS Sensitivity Analyses to Account for Imbalance in Patients Censored at Randomization for Withdrawal of Consent .................................................................................. 78 Table 17: Secondary efficacy results (Study O12301C) - final iDFS analysis (21-Jul-2023 data cut-off) .......................................................................................................................................... 78 Table 18: Applicant's OS Simulation ............................................................................................ 85 Table 19: FDA – Clinical Site Inspections ................................................................................... 86 Table 20: FDA – Final iDFS by Anatomic Stage and Nodal Status ............................................. 91 Table 21: Duration of exposure to study treatment by group in Study O12301C (Safety set) ..... 96 Table 22: Overview of clinical studies with safety data ............................................................... 98 Table 23: On-treatment deaths in Study O12301C (Safety set) ................................................. 103 Table 24: FDA – Analysis of Deaths by Study Period and Cause of Death ............................... 104 Table 25: Serious adverse events by preferred term and worst toxicity grade, irrespective of causality, with incidence at least 0.2% / either group in Study O12301C (Safety set) .............. 110 Table 26: Adverse events leading to discontinuation by preferred term and worst toxicity grade, irrespective of causality, with at least 0.2% / either group in Study O12301C (Safety set) ....... 113 (b) (4) (b) (4) (b) (4) NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 7 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 27: Adverse events leading to study drug interruption by preferred term and worst toxicity grade, irrespective of causality, with incidence at least 2% / either group in Study O12301C (Safety set) .................................................................................................................................. 115 Table 28: Adverse events leading to study drug dose reduction by preferred term and worst toxicity grade, irrespective of causality with incidence at least 0.2% / either group in Study O12301C (Safety set) .................................................................................................................. 116 Table 29: Common adverse events with grade ≥ 3 events at incidence ≥ 1.0% in either group, by preferred term in Study O12301C (Safety set) ........................................................................... 119 Table 30: New or worsening postbaseline hematology and clinical chemistry abnormalities, with incidence at least 10% / either group in Study O12301C (Safety set) ........................................ 120 Table 31: Clinically notable ECG values by treatment group in Study O12301C (Safety set) .. 124 Table 32: Summary of deaths and adverse event categories in Study O12301C (Safety set) .... 153 Table 33: FDA – PMC/PMR Checklist for Trial Diversity and U.S. Population Representativeness ...................................................................................................................... 173 Table 34: Summary of disclosable financial arrangements and interests ................................... 180 Table 35: Distribution of intrinsic factors in popPK dataset ...................................................... 186 Table 36: Summary of steady-state ribociclib PK parameters across populations and studies .. 187 Table 37: Simulated C1D1 and steady-state ribociclib PK parameters at the dose of 400 mg QD in HR-positive, HER2-negative eBC patients in Study O12301C ............................................. 187 Table 38: Estimated mean QTcF change from baseline from QTcF–ribociclib concentration model (PK-ECG set) ................................................................................................................... 198 Table 39: Input parameters for ribociclib PBPK model ............................................................. 204 Table 40: Predicted and observed DDI effect of ribociclib as a CYP3A perpetrator or CYP3A victim .......................................................................................................................................... 206 Table 41: PBPK predicted and observed PK parameters or plasma concentrations of ribociclib ..................................................................................................................................................... 206 Table 42: Comparison of ribociclib CL/F reported in clinical studies, estimated by Population PK analysis and predicted by PBPK analysis ................................................................................... 209 Table 43: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inhibitors ..................................................................................................................................... 213 Table 44: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inducers ....................................................................................................................................... 214 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 8 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table of Figures Figure 1: Study design .................................................................................................................. 50 Figure 2: Kaplan-Meier plot for iDFS (FAS) - final iDFS analysis (21-Jul-2023 data cut-off) ... 75 Figure 3: Forest plot of iDFS by stratum (final iDFS analysis, 21-Jul-2023 data cut-off (FAS) . 80 Figure 4: Forest plot of iDFS – subgroup analysis (final iDFS analysis, 21-Jul-2023 data cut-off (FAS)............................................................................................................................................. 80 Figure 5: Prediction-corrected visual predictive check (VPC) of the updated popPK model compared with observed PK concentrations in Study O12301C ................................................ 189 Figure 6: Kaplan-Meier plot of iDFS by quartiles of geometric mean of popPK-predicted Ctrough (ng/mL) on non-zero dosing days (PK-iDFS set) ......................................................... 192 Figure 7: Boxplot of evaluable ribociclib SS Ctrough (ng/mL) collected on C1D15 by occurrence of newly occurring grade 3 or worse neutropenia (PK-Neutropenia set) ................................... 195 Figure 8: Scatter plot of QTcF change from baseline versus ribociclib concentration with PK-QT model and 90% CI (PK-ECG set) ............................................................................................... 199 Figure 9: Predicted and observed plasma concentration-time profiles of ribociclib in healthy subjects and patients with late cancer ......................................................................................... 207 Figure 10: Predicted and observed plasma concentration-time profiles of ribociclib in patients with early breast cancer .............................................................................................................. 208 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 9 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reviewers of Multi-Disciplinary Review and Evaluation OPQ Team Qi (Charles) Liu, Rohit Kolhatkar, Ramesh Raghavachari RBPM Utkarsh Desai OPDP Courtney Leach, Rachael Conklin PLT Susan Redwood, Barbara Fuller OSI Suyoung Tina Chang, Phillip Kronstein OSE/DMEPA Tingting Gao, Alice Tu OSE/RPM Frances Fahnbulleh QT/IRT Consult Devi Kozeli, Yanyan Ji, Anantha Ram Nookala, Eliford N. Kitabi, Ferdouse Begum, Dalong Huang, Michael Y. Li, Christina E. Garnett Safety Team Stacie Woods, Oladimeji (Ladi) Akinboro, Abhilasha Nair OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion PLT=Patient Labeling Team OSI=Office of Scientific Investigations OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DRISK=Division of Risk Management RPBM = Regulatory Business Process Manager Regulatory Project Manager Sherry Hou Pharmacology/Toxicology Reviewer George Ching-Jey Chang Pharmacology/Toxicology Team Leader Tiffany Ricks Office of Clinical Pharmacology Reviewer Francis Green Office of Clinical Pharmacology Team Leader Hong Zhao Pharmacometrics Reviewer Huali Wu Pharmacometrics Team Leader Jingyu (Jerry) Yu PBPK Reviewer Manuela Grimstein PBPK Team Leader Yuching Yang Clinical Reviewers Tatiana Prowell (Safety) Jennifer Gao (Efficacy) Clinical Team Leader Jennifer Gao Safety Analyst Ilynn Bulatao Statistical Reviewer Haley Gittleman Statistical Team Leader Joyce Cheng Associate Director for Patient Outcomes Vishal Bhatnagar Associate Director for Labeling (ADL) William Pierce Cross-Disciplinary Team Leader Jennifer Gao Division Director (OCP) Nam Atiqur Rahman Supervisory Mathematical Statistician (OB) Mallorie Fiero Division Director (OOD) Laleh Amiri-Kordestani NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 10 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Glossary aBC advanced breast cancer ADR adverse drug reaction AE adverse event AI aromatase inhibitor ANC absolute neutrophil count BC breast cancer BCRP Breast cancer resistance protein (transporter) BSEP Bile salt export pump (transporter) CDK4/6 Cyclin-dependent kinase 4/6 CRF case report form CRO contract research organization CSR clinical study report DCO data cut-off DDFS distant disease-free survival DFS disease-free survival DRFS distant recurrence-free survival ECG electrocardiogram ECOG Eastern Cooperative Oncology Group eCRS electronic case retrieval strategy eCTD electronic common technical document EORTC European Organisation for Research and Treatment of Cancer ER estrogen receptor ET endocrine therapy ET only arm/group letrozole or anastrozole, plus goserelin (if applicable) FDA Food and Drug Administration GCP good clinical practice HER2 Human epidermal growth factor receptor 2 HR hormone receptor iDFS invasive disease-free survival ILD interstitial lung disease IRT interactive response technology IND Investigational New Drug MATE1 Multidrug and toxin extrusion protein 1 (transporter) MedDRA Medical Dictionary for Regulatory Activities NDA new drug application NSAI nonsteroidal aromatase inhibitor OCT2 Organic cation transporter 2 OS overall survival PARP Poly (ADP-ribose) polymerase PBPK physiologically-based pharmacokinetic (model) PD pharmacodynamics PFS progression-free survival NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 11 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. PgR progesterone receptor PI prescribing information popPK population pharmacokinetics PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PPS per protocol set PRO patient reported outcome PSUR periodic safety update report RFS recurrence-free survival RDI relative dose intensity SAE serious adverse event SAP statistical analysis plan SC Steering Committee SCE summary of clinical efficacy SCP summary of clinical pharmacology SCS summary of clinical safety SEER Surveillance, Epidemiology, and End Results SOC system organ class SPM second primary malignancies STEEP Standardized Definitions for Efficacy End Points (in Adjuvant Breast Cancer Trials) TTR time to response TEAE treatment emergent adverse event VPC visual predictive checks NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 13 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. disease recurrence or unacceptable toxicity occurred. Endocrine therapy was given per standard of care for a total duration of at least 60 months (5 years). The primary endpoint of NATALEE was invasive disease-free survival (iDFS) by investigator in the intent to treat (ITT) population. Final iDFS analysis was planned at 500 events with 93% power to detect a hazard ratio of 0.73 at a one-sided alpha of 0.025 using a stratified log-rank test. Three interim analyses (IA) for iDFS were planned: • IA1: for futility at 40% iDFS events • IA2: for efficacy superiority at 70% iDFS events • IA3: for efficacy superiority at 85% iDFS events Secondary endpoints included overall survival (OS), although the trial was not powered for OS, and OS was not formally tested. OS analysis was planned at iDFS IA2 and IA3 if the efficacy boundary were crossed, and at the final analysis of iDFS. A total of 2549 patients were randomized to the ribociclib + ET arm and 2552 patients were randomized to the ET only arm. The trial met its primary endpoint of iDFS at IA3 demonstrating a statistically significant improvement in iDFS (hazard ratio [HR] 0.748, 95% confidence interval [CI] 0.619-0.906). The 3-year iDFS was 90.4% (88.6-91.9) on the ribociclib + ET arm compared to 87.1% (85.3-88.8) on the ET only arm, for an absolute difference of 3.3%. However, at IA3, there was a large amount of censoring for iDFS, as only 20% of patients had completed 3 years of adjuvant ribociclib. Thus, there was a concern for possible diminishing iDFS effect with longer follow-up. Additionally, OS was immature with 134 total events (OS HR 0.759, 95% CI 0.539-1.068), and there were more treatment-emergent adverse events (TEAEs) and deaths on the ribociclib + ET arm compared to the ET only arm. Due to these concerns, FDA requested the Applicant continue NATALEE until the final iDFS analysis, and to conduct an additional OS analysis at the time of final iDFS analysis. The sNDA submission for 209092/S-018 was received on December 22, 2023. The Applicant used a priority review voucher (PRV). The sNDA submission for 209935/S-027 was received on March 11, 2024, and cross-references sNDA 209092/S-018. The sNDA submissions are based on final iDFS of the NATALEE trial, with a data-cutoff date of July 21, 2023. At the final iDFS analysis, the iDFS HR was 0.749 (95% CI 0.628-0.892). While the median iDFS was not estimable on either treatment arm, the 3-year iDFS rates were 90.7% (95% CI: 89.3, 91.8) in the ribociclib + ET arm and 87.6% (95% CI: 86.1, 88.9) in the ET only arm. The interim OS analysis at the time of final iDFS remained immature with 84 deaths (3%) on the ribociclib + ET arm and 88 deaths (3%) on the ET only arm; the OS HR was 0.89 (95% CI 0.66-1.20) with median OS not estimable. The overall safety data was consistent with the known adverse event (AE) profile of ribociclib + ET, but the incidence and severity of most AEs was lower, likely due to the lower dose of ribociclib used in the adjuvant setting, as well as a generally healthier adjuvant population. As of July 21, 2023 data-cut off, 43% patients had completed ≥3 years of ribociclib + ET and 69% had completed ≥2 years of ribociclib + ET. Deaths on treatment were uncommon overall but higher on the ribociclib + ET arm, with 20 deaths (0.8%) compared to 9 deaths (0.4%) on the ET only arm. Adverse events of special interest (AESI) were analyzed, including hepatobiliary toxicity, NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 20 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 2. Therapeutic Context 2.1 Analysis of Condition The Applicant’s Position: Breast cancer (BC) is the most frequently diagnosed cancer worldwide. Approximately 2.3 million new cases of BC and 685,000 deaths attributed to this disease were estimated to occur in 2020 worldwide. Breast cancer incidence varies between individuals of different ethnicities and in different geographic locations around the world, with age-standardized world incidence rates per 100,000 ranging from 26.2 for South-Central Asia to 95.5 for Australia and New Zealand (GLOBOCAN 2020). In the United States, BC is projected to be the most common cancer diagnosed in 2023 with an estimated incidence of 297,790 new cases and 43,170 deaths (SEER 2023). Across Europe, the estimated incidence of BC in 2020 was approximately 531,000, with 142,000 deaths (GLOBOCAN 2020). Breast cancer in men is uncommon, with a reported frequency of approximately 1% of all BC (Eggemann et al 2013). Almost all newly diagnosed BC cases are early BC (eBC), localized to the breast tissue and regional lymphatics, which are potentially curable with surgical resection and a variety of treatment modalities. Based on SEER Program data collected between the years 2010 and 2019, among all HR-positive, HER2-negative breast cancer cases in females, 94.8% of cases diagnosed were eBC, with 68.9% localized to the breast tissue and 25.9% within both the breast tissue and regional lymph nodes (SEER 2022). The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of breast cancer worldwide and in the U.S. HR+, HER2-negative breast cancer is the most common subtype, and early-stage disease is treated with curative intent. 2.2 Analysis of Current Treatment OptionsThe Applicant’s Position: Besides primary surgery, systemic management of patients with HR-positive, HER2-negative eBC consists of additional antineoplastic treatment modalities including adjuvant endocrine therapy/aromatase inhibitor (ET/AI: letrozole, anastrozole or exemestane) or tamoxifen, radiotherapy, and neoadjuvant and/or adjuvant chemotherapy, typically considered for patients at risk for recurrence. The need for and selection of systemic adjuvant therapies is based on each individual’s risk of recurrence and is guided by several clinical, pathological and genomic predictive and prognostic considerations. Specifically, patients considered to be at increased risk for recurrence include anatomic stage Group II and III disease with larger tumor size and/or metastases in multiple regional lymph nodes, high tumor grade, and high recurrence genomic score, or a combination of these. Adjuvant systemic treatments, including multiagent chemotherapy and hormonal therapy in patients with eBC decrease locoregional and distant recurrences, and have been shown to improve 15-year breast cancer mortality (Clarke et al 2005). Adjuvant ET/AI or tamoxifen, independent of chemotherapy, has been shown to reduce the risk of recurrence and BC deaths (Clarke et al 2005), and has therefore been incorporated into clinical NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 21 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. guidelines as a recommended treatment for pre- and postmenopausal women with HR-positive eBC (Senkus et al 2015, NCCN 2019). Based on limited data, adjuvant AI or tamoxifen is also considered to be the treatment of choice for men with HR-positive, HER2-negative eBC (Zagouri et al 2015). While the incorporation of adjuvant ET for the treatment of patients with HR-positive eBC has been shown to reduce the risk of recurrence and BC deaths (Clarke et al 2005), recurrences are still common, affecting approximately 30-60% of patients with Stage II and III disease (Bria et al 2010, Wangchinda, Ithimakin 2016, Gomis, Gawrzak 2017 Pan et al 2017). In a meta-analysis including more than 60,000 women with ER-positive eBC who were disease-free after 5 years of adjuvant ET, the cumulative 20-year risk of distant recurrence was 31% in those with 1-3 positive nodes (N1-3), and 52% in those with 4-9 positive nodes (N4-9). Additionally, the cumulative 20-year risk of distant recurrence in patients without nodal disease (N0) was 22%, indicating that these patients are also at risk for recurrence. The corresponding cumulative 20- year risks of death from BC based on nodal status (N0, N1-3, N4-9) were 15%, 28%, and 49%, respectively (Pan et al 2017). Although the risk of recurrence in patients with HR-positive, HER-2 negative eBC is highest during the first 5 years after diagnosis, among those who recur, more than half experience late recurrences (≥ 5 years from diagnosis) (Bria et al 2010, Wangchinda, Ithimakin 2016, Gomis, Gawrzak 2017, Pan et al 2017). Disease recurrence typically presents as distant metastasis, which is generally incurable and will eventually lead to death due to BC (Pan et al 2017). Thus, prevention of both early and late recurrences are equally important considerations when making adjuvant treatment recommendations for patients with HR-positive, HER2-negative eBC. Of note, Verzenio (abemaciclib), a CDK4/6 inhibitor in combination with ET (tamoxifen or an AI) is approved for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive, eBC at high risk of recurrence. These data, including the long-term persistent risk of disease recurrence despite adjuvant ET, highlight the need for new therapeutic strategies that are well tolerated and improve clinical outcomes in patients with HR-positive, HER2-negative Stage II and III eBC. Table 1: Summary of treatment armamentarium relevant to proposed indication other than chemotherapy Products Name Relevant Indication Year of Approval And Type of Approval Dosing/ Administration Efficacy Information Important Safety and Tolerability Issues Other Comments FDA Approved Treatments Non-steroidal aromatase inhibitors NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 22 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Letrozole (Femara) Letrozole is indicated for: - Adjuvant treatment of postmenopaus al women with hormone receptor positive early breast cancer. - Extended adjuvant treatment of postmenopaus al women with early breast cancer, who have received prior standard adjuvant tamoxifen therapy. 2004 Recommended dose: 2.5.mg once daily Femara tablets are taken orally without regard to meals vs. tamoxifen DFS: HR 0.79; 95% CI (0.68, 0.92); systemic DFS: HR 0.83; 95% CI (0.70, 0.97); time to distant metastasis: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06) The most common adverse drug reactions (≥ 20%) were hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholest erolemia, sweating increased, bone pain; and musculoskel etal Initial accelerated approvals for adjuvant (2005) and extended adjuvant (2004) treatment received that was converted to full approval in 2010. Anastrozole (Arimidex) Anastrozole is indicated as monotherapy for the adjuvant treatment of postmenopaus al women with hormone receptor positive early breast cancer 2002 One 1 mg tablet taken once daily vs. tamoxifen or in combination with tamoxifen DFS: HR: 0.87, 95% CI (0.78, 0.97), HR-positive subgroup: HR 0.83, 95% CI: (0.73, 0.94). Of note, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen and is therefore not recommended to be administered The most common adverse reactions (≥10%) were hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension , depression, nausea and vomiting, rash, osteoporosis , fractures, back pain, insomnia, headache, peripheral edema and lymphedema , regardless of causality. Priority review NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 23 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. in combination. Steroidal aromatase inhibitors Exemestane (Aromasin®) Exemestane is indicated as monotherapy for the adjuvant treatment of postmenopaus al women with ER-positive early breast cancer who have received 2 to 3 years of tamoxifen and are switched to Aromasin for completion of a total of 5 consecutive years for adjuvant hormonal therapy. 2005 Recommended Dose: One 25 mg tablet once daily after a meal vs tamoxifen DFS: HR: 0.69, 95% CI: (0.58, 0.82); HR-positive subpopulation DFS: HR: 0.65, 95% CI: (0.53, 0.79) Most common adverse reactions (≥ 10%) were hot flushes, fatigue, arthralgia, headache, insomnia, and increased sweating. Selective estrogen receptor modulator Tamoxifen (Soltamox) Tamoxifen is indicated as monotherapy for the adjuvant treatment of adult patients with early- stage ER- positive breast cancer. 2005 Recommended daily dose is 20 mg daily for 5- 10 years. The 10-year outcome data were reported in 1998 for 36,689 women in 55 randomized trials of another formulation of adjuvant tamoxifen using doses of 20 to 40 mg per day for 1 to 5+ years. Most common adverse reactions: hot flashes, mood disturbance, vaginal discharge, vaginal bleeding, nausea, and fluid retention. CDK 4/6 inhibitor NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 24 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Abemaciclib (Verzenio) Abemaciclib is indicated in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR- positive, HER2- negative, node-positive, early breast cancer at high risk of recurrence. 2023 Recommended starting dose in combination with fulvestrant or an aromatase inhibitor: 150 mg twice daily. Verzenio tablets are taken orally with or without food. vs ET alone Cohort 1 population: iDFS: HR: 0.653; 95% CI: (0.567, 0.753); 2-year IDFS rates of 85.5% (abemaciclib arm) versus 78.6% (control arm). Most common adverse reactions (≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocyto penia. Priority Review PARP inhibitor Olaparib (Lynparza) Olaparib in indicated as monotherapy for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2- negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. 2022 Recommended dose: 300 mg taken orally twice daily, with or without food for up to 1 year. vs placebo iDFS: HR 0.58; 95% CI: (0.46, 0.74); OS: HR 0.68; 95% CI: (0.50, 0.91). IDFS at 3 years was 86%; 95% CI: (82.8, 88.4) for patients receiving olaparib and 77%; 95% CI: (73.7, 80.1) for those receiving placebo. Most common adverse reactions (≥10%) were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocyto penia Priority Review NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 25 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Systemic treatment options other than chemotherapy are included. Source: Femara USPI 2020, Arimidex USPI 2018, Aromasin USPI 2021, Soltamox USPI 2019, Verzenio USPI 2023, Lynparza USPI 2023 The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of the current treatment options for patients with early-stage HR+, HER2-negative breast cancer in the U.S. FDA concurs with the Applicant’s assessment that additional treatment options are needed for this patient population, where treatment is given with curative intent. As noted by the Applicant, more than half of recurrences of HR+, HER2-negative breast cancer occur ≥5 years after diagnosis. Due to the limited follow-up of the NATALEE trial, there is no information available at this time on whether addition of ribociclib to ET impacts the risk of these late recurrences. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 26 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 3. Regulatory Background 3.1 U.S. Regulatory Actions and Marketing History The Applicant’s Position: Kisqali® (ribociclib) was initially approved on 13-Mar-2017 in the US for the treatment of HR- positive/HER2-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy, based on results from Study A2301. Ribociclib was approved on 10-Dec-2021 in the US for use in men in combination with aromatase inhibitor as initial endocrine based therapy or fulvestrant as initial endocrine based therapy or following disease progression on ET in HR-positive, HER2-negative advanced or metastatic breast cancer. Kisqali was also approved for an expanded indication on 18-Jul-2018 in the US based on results from Studies E2301 and F2301. In the US, Kisqali is indicated for the treatment of adult patients with HR-positive, HER2- negative advanced or metastatic breast cancer in combination with: • an aromatase inhibitor as initial endocrine-based therapy; or • fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men Kisqali is also available in the US as part of the Kisqali® Femara® Co-Pack (ribociclib tablets co- packaged with letrozole tablets), approved on 04-May-2017. The FDA’s Assessment: FDA generally agrees with the Applicant’s summary of the U.S. marketing history of ribociclib. 3.2 Summary of Presubmission/Submission Regulatory Activity The Applicant’s Position: A summary of the key interactions with the FDA are provided below: • September 10, 2018: The protocol for Study CLEE011O12301C (Study O12301C) was submitted to FDA for the adjuvant treatment of early breast cancer on September 10, 2018 (SN 0806). • October 18, 2018: The purpose of this Type B (EOPII) meeting was to seek FDA’s advice on key aspects of the study design of Study O12301. Preliminary comments were received on November 08, 2018 and the meeting was ultimately cancelled by Novartis on November 16, 2018 as FDA agreed with Novartis questions and gave clear advice on the design of the trial. • March 31, 2023: At the request of FDA, Novartis submitted topline data from the iDFS primary analysis (IA3). NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 32 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Overall, there was no evidence of discrepancy in iDFS events reported at the five inspected trial sites. There was no other evidence of underreporting of AEs at the five inspected trial sites. No significant discrepancies or notable findings were identified at Site 5057 and 5075. OSI concluded overall that the study appears to have been conducted adequately, and the data generated by the clinical investigator sites appear acceptable in support of this sNDA. FDA concurs with OSI’s assessment. The review team concluded that the issues identified during inspection do not meaningfully alter the finding of a favorable benefit-risk assessment or preclude regulatory approval. Refer to the FDA OSI review and FDA correspondence with the Applicant for full details. 4.2 Product Quality The FDA’s Assessment: The Office of Pharmaceutical Quality (OPQ), CDER recommends approval of these applications for 209092/S-018 and 209935/S-027. Refer to FDA Product Quality’s review for full details. 4.3 Clinical Microbiology The FDA’s Assessment: Not applicable. 4.4 Devices and Companion Diagnostic Issues The FDA’s Assessment: Not applicable. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 39 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 6.2.2 General Dosing and Therapeutic Individualization 6.2.2.1 General Dosing The Applicant’s Position: The pivotal Phase III study O12301C evaluated ribociclib 400 mg for eBC patients. Selection of the ribociclib dose and regimen (400 mg daily on Days 1 to 21 of a 28-day cycle) was based on previous PK-QTcF and ANC exposure-response modeling of data in patients with advanced cancer, exposure-efficacy analysis, and exploratory progression-free survival (PFS) analysis by dose reduction in patients with aBC. Results of Study O12301C demonstrated that the 400 mg ribociclib dose is safe and efficacious for use for eBC. Thus, the recommended dose of ribociclib for the adjuvant setting for eBC is 400 mg (two 200-mg film-coated tablets) of ribociclib once daily, Days 1 to 21 of each 28-day cycle for 3 years combined with 5 years of ET. The FDA’s Assessment: FDA generally agrees with the Applicant. The proposed recommended ribociclib dosage of 400 mg daily, on Days 1 to 21 of a 28-day cycle is acceptable for the indicated eBC patient population as it is supported by the efficacy and safety demonstrated in patients with eBC enrolled in the pivotal NATALEE trial. Refer to Section 6.3 for data and analyses supporting the proposed dosing regimen. 6.2.2.2 Therapeutic Individualization The Applicant’s Position: Specific populations: The recommendation for alternative dosing regimen for subpopulations based on intrinsic patient factors has no change since the prior approvals [Studies E2301/F2301]. Patients with hepatic impairment: In Study O12301C, no apparent increase in exposure was observed in patients with mild hepatic impairment, however, the sample size is limited (n=9). A total of 3 patients with moderate hepatic impairment were treated in the ribociclib arm of Study O12301C. Based on the data in eBC patients, the previously submitted hepatic impairment data in non-cancer subjects and advanced cancer patients, as well as post-marketing experience in aBC patients, no ribociclib dose adjustment is warranted for eBC patients with hepatic impairment [SCP Study O12301C-Section 5.2.1]. Patients with renal impairment: In Study O12301C, there was no apparent effect of mild renal impairment on ribociclib PK exposure. No apparent increase in exposure was observed in patients with moderate renal impairment, however, the sample size is limited (n=8). Based on the data in eBC patients and the previously submitted renal impairment data in aBC patients and non-cancer subjects, no dose reduction is required for eBC patients with mild or moderate renal impairment, and a lower starting dose of 200 mg is recommended in eBC patients with severe renal impairment [SCP Study O12301C-Section 5.2.2]. Drug-drug interactions: NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 40 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Effect of concomitant-medications on ribociclib: PBPK model-predicted ribociclib steady- state Cmax and AUC ratios with vs without coadministration of ritonavir were 1.47 and 1.84, respectively, in patients with eBC at the dose of 400 mg. Alternate concomitant medication with a low potential to inhibit CYP3A should be considered in eBC patients. If co-administration of ribociclib with a strong CYP3A inhibitor cannot be avoided, monitor for adverse reactions and consider reducing the dose to 200 mg, if necessary. Rifampicin (a strong CYP3A4 inducer) decreased ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single oral dose of 600 mg ribociclib, compared to ribociclib alone in Study A2101 [SCP Study A2301]. Concomitant use of ribociclib with strong CYP3A4 inducers should be avoided in patients with eBC [SCP Study O12301C-Section 5.3.1]. Effect of ribociclib on concomitant medications: Ribociclib dosed at 400 mg once daily is a moderate inhibitor of CYP3A4 and increased steady-state exposure of the CYP3A4 substrate midazolam by 280% (3.8-fold). Caution is recommended when ribociclib 400 mg is administered with CYP3A substrates with a narrow therapeutic index in patients with eBC. The dose of a sensitive CYP3A substrate with a narrow therapeutic index may need to be reduced. Based on in vitro inhibition data at the dose of 400 mg dose, ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations [SCP Study O12301C- Section 5.3.2]. The FDA’s Assessment: FDA agrees with the Applicant’s position that no therapeutic individualization of ribociclib is needed based upon intrinsic factors from the popPK modeling results including age, body weight, sex, or race. The impact of renal and hepatic impairment on the PK of ribociclib in patients with eBC was similar to that in patients with aBC. No new intrinsic factors were identified for dose adjustment. Refer to Section 6.3.2.3. For patients with eBC, the FDA agrees with dose reduction from 400 mg QD to 200 mg QD when co-administration of a strong CYP3A4 inhibitor, based on PBPK predictions. Co- administration of moderate CYP3A4 inhibitor is not expected to meaningfully change the exposure of ribociclib at steady state. A moderate effect is expected with co-administration of a moderate CYP3A4 inducer. For patients with aBC, PBPK predictions, using the updated model of ribociclib, are consistent with conclusions and DDI management strategies from the original NDA submission. Refer to section 19.4.3 for details about the PBPK modeling analysis. 6.2.2.3 Outstanding Issues The Applicant’s Position: There are no PMR/PMCs currently ongoing. The FDA’s Assessment: FDA concurs with the Applicant’s position. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 41 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 6.3 Comprehensive Clinical Pharmacology Review 6.3.1 General Pharmacology and Pharmacokinetic Characteristics The Applicant’s Position: Comprehensive PK data on ribociclib were provided in the prior submissions. In Study O12301C in patients with eBC, the population mean estimate of the apparent clearance of ribociclib in eBC patients was 38.4 L/hr at a 400 mg dose, based on population PK modeling. In Study A2207 in patients with aBC, the geometric mean Cmax and AUC0-24h were approximately 28% and 43% lower for the ribociclib 400 mg arm as compared to the ribociclib 600 mg arm. The observed geometric mean apparent clearance at steady-state was 24.4 L/hr at 400 mg and 21.0 L/hr at 600 mg in patients with aBC. The steady-state PK exposure in eBC patients in Study O12301C at 400 mg was lower than those in advanced cancer patients in Study X2101 at the dose of 600 mg (56% and 48% lower for AUC and Cmax, respectively), which can be attributed to lower dose as well as faster clearance due to PK nonlinearity and population effect potentially due to no detectable disease in eBC patients [CO Study O12301-Section 3.1.2]. The FDA’s Assessment: FDA generally agrees with the Applicant on the general clinical pharmacology characteristics of ribociclib. The updated popPK model adequately characterized the PK profile of ribociclib in patients with eBC who received the proposed recommended dosage. Refer to Section 19.4.1 for data and analyses related to popPK modelling. 6.3.2 Clinical Pharmacology Questions 6.3.2.1 Does the clinical pharmacology program provide supportive evidence of effectiveness? The Applicant’s Position: Yes. Collectively, the clinical pharmacology program supports the use of ribociclib 400 mg in combination with ET (letrozole or anastrozole) in patients with HR-positive, HER2-negative eBC. Selection of the ribociclib dose and regimen (400 mg daily on Days 1 to 21 of a 28-day cycle) is discussed in Section 6.2.2.1. The evidence of effectiveness of ribociclib was demonstrated in Study O12301C in patients ≥ 18 years of age with HR-positive, HER2-negative, Stage II or Stage III eBC by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Detailed efficacy results are provided in Section 8.1.2. Due to limited sample size of patients with iDFS events, exposure-efficacy relationship cannot be characterized [CO Study O12301C-Section 3.3]. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 42 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: FDA agrees that effectiveness of the proposed recommended dosage of ribociclib 400 mg daily for Days 1 to 21 days in a 28-day cycle with ET was demonstrated via the primary endpoint of iDFS in the NATALEE trial (See Section 8.1.5). The exposure-efficacy relationship is considered exploratory and could not be adequately characterized due to the limited PK data collected in the NATALEE trial. Refer to Section 19.4.2 for data and analyses regarding the exposure-response relationship between ribociclib exposure and iDFS from the NATALEE trial. 6.3.2.2 Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought? The Applicant’s Position: Yes. Based on the observed efficacy and safety data of Study O12301C, exposure-response analysis, and the historical data in patients with aBC, 400 mg ribociclib (once daily for 3 weeks on/1 week off in a 28-day cycle) is demonstrated to be a safe and effective dose in patients with eBC. Both neutropenia and QTcF prolongation, the adverse events related to ribociclib PK exposure, are lower in eBC patients in Study O12301C at the dose of 400 mg than in aBC patients at the dose of 600 mg, supporting improved tolerability of the 400 mg dose in eBC patients. The PK- QT modeling confirmed the exposure-QTcF relationship in eBC patients, and patient population is a significant covariate where eBC patients showed less QTcF response than aBC patients. Efficacy in patients with eBC was demonstrated by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Due to limited sample size of patients with a PK collection having an iDFS event, the exposure-efficacy relationship cannot be characterized [SCP Study O12301C-Section 5.5]. The FDA’s Assessment: FDA agrees that the recommended dosage of ribociclib 400 mg daily for Days 1 to 21 of a 28-day cycle is appropriate for the general population of adults with HR+, HER2-negative stage II and III eBC based on the primary endpoint of iDFS from the NATALEE trial. The following are the Applicant’s rationales for dosage selection for the NATALEE trial: • As extended duration of treatment is critical to prolong cell cycle arrest and drive more tumor cells into senescence/death, a 3-year duration of treatment was chosen at a dose of 400 mg to improve tolerability while maintaining efficacy. • There are sufficient safety data on long-term use of ribociclib (> 60 months) in the aBC setting to support the longer treatment duration in the NATALEE trial. • The 400 mg dose was selected based on consistent efficacy in post hoc exploratory analyses from the MONALEESA program, and a potentially improved safety NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 43 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. profile in terms of dose-dependent toxicities such as QTc prolongation and neutropenia as compared to the 600 mg dosage. Therefore, this dosage and treatment duration were chosen to optimize efficacy while improving tolerability in this patient population with no detectable disease. Both neutropenia and QTcF prolongation, which have a known concentration-dependent relationship, were less common in the NATALEE trial at the dosage of 400 mg than in trials in the advanced setting at the dosage of 600 mg, supporting improved tolerability of the 400 mg dosage in patients with eBC. The median relative dose intensity for eBC patients receiving 400 mg dosage plus ET (compared to aBC patients receiving the 600 mg dosage) was 94% (vs 87.5%), while dose reductions (due to AEs) was 23.1% (vs 45%), and discontinuations was 19.7% (vs 15%). In general, the lower recommended dosage in eBC demonstrated greater tolerability compared to patients with aBC receiving 600 mg dosage plus ET as reported in the most recent USPI. 6.3.2.3 Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors (e.g. race, ethnicity, age, performance status, genetic subpopulations, etc.)? The Applicant’s Position: Yes. The recommendation for alternative dosing regimen for subpopulation based on intrinsic patient factors has no change since the prior approvals [Studies E2301/F2301]. Intrinsic factors: No clinically relevant effects of age, body weight (BW), gender, or race on the systemic exposure of ribociclib in the adult population that would require a dose adjustment were identified based on the popPK analysis previously submitted [Study A2301], [Studies E2301/F2301] [SCP Study O12301C-Section 1.1.1.2.1]. No new information is submitted in this application. Details on patients with hepatic and renal impairment are provided in Section 6.2.2.2. The FDA’s Assessment: FDA agrees that no therapeutic individualization of ribociclib is needed based upon intrinsic factors from the popPK modeling results including age, body weight, sex, or race. Additionally, no new intrinsic factors were identified for dose adjustment in this application. There are limited data for hepatic impairment in the NATALEE trial: 9 patients with mild hepatic impairment and 3 patients with moderate hepatic impairment in which no PK data were available. Patients with severe hepatic impairment were excluded from the trial. Based upon data from the most recent USPI, moderate hepatic impairment increased ribociclib exposure (GMR) by 1.4 for Cmax and 1.3 for AUCinf, while severe hepatic NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 44 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. impairment increased ribociclib exposure by 1.3 for both Cmax and AUCinf. The Applicant is proposing no dose adjustments for patients with mild and moderate hepatic impairment, which is the same recommendation for patients with aBC. There are similar limited data for moderate renal impairment. In the NATALEE trial, 42 patients had mild renal impairment and 8 patients had moderate renal impairment. Patients with severe renal impairment were excluded from the NATALEE trial. Based upon data from the most recent USPI, severe renal impairment increased ribociclib exposure (GMR) by 2.7 for Cmax and 2.1 for AUCinf. The Applicant is proposing no dose adjustment for mild or moderate renal impairment, and a dose reduction to 200 mg QD (50% dose reduction) for patients with severe renal impairment. Despite these limitations, the Applicant’s proposed dosing for eBC patients with renal and hepatic impairment are acceptable. Based on the popPK model, the impact of renal and hepatic impairment on the PK of ribociclib in patients with eBC was similar to that in patients with aBC. Because the benefit-risk profile of these subpopulations has been established in patients with aBC receiving the higher 600 mg dosage, patients with eBC who have mild to moderate hepatic impairment or severe renal impairment receiving the lower recommended dose of 400 mg are not expected to experience unacceptably high ribociclib exposures leading to additional safety concerns. 6.3.2.4 Are there clinically relevant food-drug or drug-drug interactions, and what is the appropriate management strategy? The Applicant’s Position: No new information for food-drug interactions is provided in this submission. Details on patients with drug-drug interactions and the management strategy are provided in Section 6.2.2.2. The FDA’s Assessment: FDA agrees that no new information for food-drug interactions is pertinent to this submission. Assessment about DDI results and management strategy are presented in Section 6.2.2.2. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 46 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 7 Sources of Clinical Data 7.1 Table of Clinical Studies The Applicant’s Position: Table 7: Listing of Clinical Trials Relevant to this NDA/BLA Trial Identity NCT no. Trial Design Regimen/ schedule/ route Study Endpoints Treatment Duration/ Follow Up No. of patients enrolled Study Population No. of Centers and Countries Controlled Study to Support Efficacy and Safety CLEE011O 12301C NCT03 701334 A global, Phase III, multicenter, randomized, open- label trial to evaluate efficacy and safety of ribociclib with ET (investigational arm: ribociclib + ET) versus ET alone (control arm: ET only) as adjuvant treatment in patients with HR-positive, HER2-negative, eBC. Ribociclib 400 mg once daily on Days 1 to 21 of each 28- day cycle (up to 36 months of treatment) ET: letrozole 2.5 mg by mouth, once daily, given continuously or anastrozole 1 mg by mouth, once daily, given continuously (for premenopausal women and men, plus goserelin 3.6 mg subcutaneously, on Day 1 ±3 of each 28-day cycle (up to 60 months of treatment) Primary endpoint: - iDFS using STEEP criteria, as assessed by Investigator. Secondary endpoints: - RFS using STEEP criteria DDFS using STEEP criteria - Overall survival - Change from baseline in the physical functioning sub-scale score and global health status / QoL scale score as assessed by EORTC QLQ-C30. The final iDFS analysis was conducted after 40.3 months of median study follow-up, when patients were treated for a median duration of 36 months in both arms, with an additional 6.3 months of study follow- up from the primary analysis. Randomized to ribociclib + ET arm: 2549 patients Randomized to ET only arm: 2552 patients The study population consisted of female and male patients ≥18 years of age (and if female, with a known menopausal status at the time of randomizatio n) with histologically confirmed diagnosis of ER and/or PR-positive, HER2- negative eBC with Anatomic Stage Group A total of 393 centers across 20 countries NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 47 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. - Frequency and severity of AEs, laboratory and ECG abnormalities. - PK parameters such as Ctrough and other applicable parameters for ribociclib Exploratory endpoints: - LRRFS defined as time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, or death due to any cause. - Incidence of subsequent anti-neoplastic therapy and time to first subsequent anti- neoplastic therapy. - Number of patients hospitalized, total number of hospitalizations, and length of stay in hospitals, number of patients with Emergency Room and additional visits. III, IIB, or a subset of IIA cases, after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherap y (if indicated), and who were deemed eligible for adjuvant ET for at least a 60-month duration. Stage IIA patients with no nodal involvement had either tumor grade 3 or tumor grade 2 with high-risk genomic profile or Ki67 ≥20%. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 48 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: For the sNDA, the Applicant submitted the results from the NATALEE trial in patients with high-risk Stage II or III HR+, HER2-negative early breast cancer comparing ribociclib + ET to ET only in the adjuvant setting. FDA generally agrees with the Applicant’s description of the design of the NATALEE trial above. 49 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 8 Statistical and Clinical Evaluation 8.1 Review of Relevant Individual Trials Used to Support Efficacy 8.1.1 Study CLEE011O12301C Trial Design The Applicant’s Description: Study CLEE011O12301C is a Phase III, multicenter, randomized, open-label study to evaluate the efficacy and safety of ribociclib with ET versus ET alone as an adjuvant treatment in pre- and postmenopausal women plus men with HR-positive, HER2-negative eBC. Approximately 5,000 patients were planned to be randomized (using an IRT system) in a 1:1 ratio to either the investigational arm (ribociclib + ET) or the control arm (ET only). Randomization to the two treatment arms was stratified by menopausal status (premenopausal women, and men vs. postmenopausal women), AJCC 8th edition Stage II vs. Stage III, prior neoadjuvant/adjuvant chemotherapy (yes vs. no), and Geographical region (North America/Western Europe/Oceania vs. rest of the world). The planned study treatment phase duration was 60 months. In total, 5101 female and male patients were randomized in a 1:1 ratio; 2549 patients to the ribociclib + ET arm and 2552 patients to the ET only arm (Figure 1: Study design). 50 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Figure 1: Study design The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the design of the NATALEE trial. Letrozole and anastrozole were used as endocrine therapy in NATALEE, due to the following reasons provided by the Applicant in an IR response from Sept 9, 2024: • Exemestane was not excluded explicitly in the protocol as safety and efficacy data have been generated in combination of ribociclib and exemestane in the metastatic disease setting. 51 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. • The AROMASIN (exemestane) indication for adjuvant treatment is as follows: adjuvant treatment of postmenopausal women with estrogen-receptor positive eBC who have received two or three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy. • Therefore, given the protocol eligibility criteria for prior ET duration of up to 1 year, patients eligible to receive exemestane would have had to receive at least 2 years of prior tamoxifen, thus becoming ineligible for NATALEE • From a purely practical and operational perspective, and in light of the above, only anastrozole or letrozole were made available. The rationale for primarily using letrozole and anastrozole in the NATALEE trial is reasonable for the reasons outlined by the Applicant, and does not impact the overall benefit-risk assessment. Eligibility Criteria The Applicant’s Description: The pivotal study O12301C supporting this submission has participation across all demographic patient populations and included patients of diverse race and ethnicities with the majority of patients being White (73.4%) and not of Hispanic or Latino origin (81.0%). Details are presented in Table 10: Demographic Characteristics. The study population consisted of female and male patients ≥18 years of age (and if female, with a known menopausal status at the time of randomization) with histologically confirmed diagnosis of ER and/or PgR-positive, HER2- negative eBC with Anatomic Stage Group III, IIB, or a subset of IIA cases, after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who were deemed eligible for adjuvant ET for at least a 60-month duration. Stage IIA patients with no nodal involvement had either tumor grade 3 or tumor grade 2 with high-risk genomic profile or Ki67 ≥20%. In general, the patients enrolled in this study were representative of the intended target patient population and allow the resultant data to be extrapolated to all patients with the proposed indication. Detailed demographic and baseline characteristics are discussed in Section 8.1.2. Trial location 393 sites across 20 countries in Europe, North America/Australia, Asia, and Latin America enrolled a total of 5101 patients [Study O12301C Primary Analysis CSR-Section 2]. Choice of control group The choice of control treatment (ET) was based on its recommended use as a standard of care in patients with ER-positive eBC. Another consideration behind the choice of ET for this study was the fact that, as per the Kisqali® prescribing information, ribociclib is not indicated for use in combination with tamoxifen due to the increased risk of QT prolongation. Hence, for this study, patients in the control arm were treated with standard AI, either letrozole or anastrozole, administered for a duration of at least 60 months from randomization, according to the local 52 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. clinical guidelines and current prescribing information. Gonadal suppression was achieved by using the GnRH agonist goserelin [CO Study O12301C-Section 1.3.2]. Diagnostic criteria The study population had histologically confirmed diagnosis of ER and/or PgR-positive, HER2- negative breast cancer within 18 months prior to randomization. Patients with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis within 18 months prior to randomization were included. Patients with a multicentric and/or multifocal tumor were eligible if all the histopathologically examined lesions met the pathologic inclusion criteria [Study O12301C Primary analysis CSR- Section 9.3.1] In the United States, breast cancer is projected to be the most common cancer diagnosed in 2023 with an estimated incidence of 297,790 new cases and 43,170 deaths (SEER 2023). Almost all newly diagnosed BC cases are early BC (eBC), localized to the breast tissue and regional lymphatics, which are potentially curable with surgical resection and a variety of treatment modalities. Based on SEER Program data collected between the years 2010 and 2019, among all HR-positive, HER2-negative breast cancer cases in females, 94.8% of cases diagnosed were eBC, with 68.9% localized to the breast tissue and 25.9% within both the breast tissue and regional lymph nodes (SEER 2022) [CO Study O12301-Section 1.1]. Key inclusion/exclusion criteria The study population consisted of female and male patients ≥ 18 years of age (and if female with a known menopausal status at the time of randomization) with HR-positive, HER2-negative eBC. Patients were included if they had a histologically confirmed diagnosis of ER and/or PgR positive (HR-positive), HER2-negative eBC (Anatomic Stage Group III, IIB, IIA), irrespective of nodal status, after adequate surgical resection and radiotherapy (if indicated), within 18 months prior to randomization and who were deemed eligible for adjuvant ET for at least a 60- month duration. Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of informed consent, but randomization was to occur within 12 months of the initial start date of ET. Note, Stage IIA patients who were node negative were required to have either tumor grade 3 or tumor grade 2 with high risk genomic profile or Ki67 ≥ 20%. Eligible patients were also required to have adequate bone marrow and organ function as defined in the Study Protocol, and standard 12-lead ECG values assessed by a central laboratory. Key exclusion criteria included prior treatment with any CDK4/6 inhibitor; tamoxifen, raloxifene or AIs for chemoprevention of breast cancer and/or treatment for osteoporosis (within 2 years of randomization); anthracyclines (specified doses of doxorubicin and epirubicin); and systemic corticosteroids (within 2 weeks of starting trial treatment). Patients receiving treatment with any other antineoplastic therapy (except for adjuvant ET) were not eligible. Patients with breast cancer metastases beyond regional lymph nodes (Stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery; patients who had major surgery, chemotherapy, or radiotherapy (within 14 days of randomization); patients with a known hypersensitivity to any of the excipients of ribociclib and/or ET; and patients with clinically significant, uncontrolled heart 53 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. disease and/or cardiac repolarization abnormality were excluded [Study O12301C-Section 2 synopsis]. Dose selection As extended duration of treatment is critical to prolong cell cycle arrest and drive more tumor cells into senescence/death, a 3-year duration of treatment was chosen at a dose of 400 mg to improve tolerability while maintaining efficacy. Of note, there are sufficient safety data on long- term use of ribociclib (> 60 months) in the aBC setting to support the longer treatment duration in Study O12301C. The 400 mg dose was selected based on consistent efficacy in post hoc exploratory analyses from the MONALEESA program, and a potentially improved safety profile in terms of dose-dependent toxicities such as QTc prolongation and neutropenia as compared to the 600 mg starting dose. Therefore, this dose and treatment duration were chosen to optimize efficacy while improving tolerability in this patient population with no detectable disease [SCE Study O12301C-Section 4.1]. Study treatments, assignment, and blinding Ribociclib, the investigational drug for this study, was considered an IMP. The other drugs used in this study were NSAIs (letrozole or anastrozole) and goserelin. Ribociclib was administered orally on a 28-day cycle; on Days 1 to 21 at a dose of 400 mg (two 200 mg film-coated tablets once daily), followed by 7 days off ribociclib (days 22 to 28). ET was administered (in both the investigational and control arms) as follows: for postmenopausal women, letrozole 2.5 mg (orally) once daily and continuously or anastrozole 1 mg (orally) once daily and continuously; for premenopausal women and men, letrozole 2.5 mg (orally) once daily and continuously or anastrozole 1 mg (orally) once daily and continuously, combined with goserelin 3.6 mg (subcutaneously) once every 4 weeks [Study O12301C Primary analysis CSR-Section 2]. Patients were randomized via IRT to the investigational or control arm, in a ratio of 1:1, as per the stratification factors. Although this is an open-label study, to minimize bias during data review, the study team was blinded to aggregate reports by treatment arm until the time of the final iDFS analysis (or until after interim iDFS analysis if futility or superiority was declared). At the time of interim analyses for iDFS, unblinded results from the interim analyses were not communicated to the Novartis clinical team or to any party involved in the study conduct (apart from the independent statistician and DMC members) until the DMC had determined that either (i) iDFS analysis had crossed the pre-specified boundary for efficacy, or (ii) the study needed to be terminated due to any cause including futility or safety reasons [Study O12301C Primary analysis CSR-Sections 9.4.1 and 9.4.3]. Dose modification, dose discontinuation Investigators were permitted to interrupt and/or reduce the ribociclib dose to allow patients to continue treatment. Dose modifications were considered for patients who did not tolerate the protocol-specified dosing schedule for ribociclib or where clinical judgment of the treating physician determined that ribociclib dose interruptions and/or reductions were recommended 54 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. (based on the individual benefit/risk assessment). For patients who did not tolerate the protocol-specified dosing schedule, one dose reduction was permitted to allow patients to continue ribociclib. If a second dose reduction was required to manage ribociclib-related AEs, then ribociclib was discontinued. No dose re-escalation was permitted. ET-related AEs were managed according to local clinical guidelines and Investigators’ judgment. In cases when ET required interruption for more than 4 weeks due to ET-related AEs, discussions on the risks/benefits of study treatment continuation were held with the Medical Monitor [Study O12301C Primary analysis CSR-Sections 9.4.4 and 9.4.6]. Discontinuations are discussed in the sections below. Administrative structure The administrative structure of the study, including internal and external participants, the list of Investigators, as well as members of the Data Monitoring Committee and Study Steering Committee, is provided in [Study O12301C-Appendix 16.1.4]. Concurrent medications Medications required to treat AEs, manage cancer symptoms, concurrent diseases, and supportive care agents, such as pain medications, antiemetics and antidiarrheals were allowed. Permitted concomitant therapy included bisphosphonates and denosumab, corticosteroids (topical applications, inhaled sprays, eye drops or local injections or short duration of systemic corticosteroids less than or equal to the anti-inflammatory potency of 4 mg dexamethasone), hematopoietic growth factors, concomitant surgery during Ribociclib treatment ‘week-off’. Medications to be used with caution during ribociclib treatment included medications that carry a possible risk for QT prolongation and/or TdP, moderate inhibitors or inducers of CYP3A4/5, sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index, strong inhibitors of Bile Salt Export Pump, sensitive substrates of the renal transporters, MATE1 and OCT2, and sensitive substrates of transporter of Breast Cancer Resistance Protein. Prohibited concomitant therapy included strong inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow therapeutic index, medications with a known risk for QT prolongation and/or TdP, concomitant tamoxifen or toremifene use [Study O12301C Primary analysis CSR-Sections 9.4.5] Treatment compliance Patients were instructed on how to take the study treatment as per protocol. Site staff ensured that the patient clearly understood the treatment schedule and that the appropriate dose of study treatment was provided at each cycle. Additionally, patients completed a diary to record their daily intakes. The administration of study treatment was recorded in the appropriate sections of the eCRF. Study treatment compliance was assessed by the Investigator and/or study personnel at each visit using pill counts and information provided by the patient and/or caregiver. Patients were instructed to return all unused ribociclib (and ET if provided by Novartis), including all partially used and empty containers, at each visit during the Treatment phase. A record of study 55 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. treatment receipt and dispensing was maintained in a drug accountability log which was reviewed by a study monitor during regular site visits. [Study O12301C Primary analysis CSR- Sections 9.4.1 and 9.4.3.4] Subject completion, discontinuation, or withdrawal Study completion: If the primary endpoint, iDFS, was statistically significant at the second, third interim or at final analysis, data collection was to continue, and end of study was to be declared when 60 months + 30 days (Safety follow up) have elapsed from the date the last patient has been randomized. [Study O12301C Primary analysis CSR-Sections 9.4.7] Study discontinuation or withdrawal: The Investigator was obliged to discontinue study treatment for a given patient if he/she believed that continuation would be detrimental to the patient’s well-being. In the investigational arm, patients were discontinued from ribociclib treatment for any of the following reasons: completion of 36 months of treatment from the randomization date (approximately 39 cycles), regardless of any treatment interruption, first recurrence (any of the following or combination of local, regional, or distant recurrences, or contralateral invasive BC, or second primary non-breast invasive cancer), adjustments to study treatment due to toxicity that result in treatment discontinuation, ribociclib dosing was interrupted for > 28 days due to ribociclib-related toxicity, withdrawal of consent by the patient, patient is lost to follow-up, death, discontinuation from the study treatment due to any other reason, or Novartis termination of the study. [Study O12301C Primary analysis CSR-Sections 9.4.6] Censoring pattern of iDFS: Number of patients with an iDFS event and number of patients censored for the iDFS analysis were summarized. In addition, a summary of reasons for iDFS censoring was provided by treatment arm. For patients without an iDFS event, the iDFS censoring date was determined as the last assessment before the earliest of the following dates, with the earliest of these also determining the censoring reason (as indicated in parentheses): • Analysis cut-off date (censoring reason: ‘Ongoing without event’) • Date of consent withdrawal (censoring reason: ‘Withdrew consent’) • Date of Last Contact for patients lost to follow-up at EOT or Date of Visit/contact for patients lost to follow-up during follow-up phase (censoring reason: ‘Lost to follow up’) [Study O12301C Primary Analysis CSR Appendix 16.1.9-Section 2.5.6] The FDA’s Assessment: 56 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. FDA generally agrees with the Applicant’s description of the design of the NATALEE trial as stated above. Analysis sets The Applicant’s Description: The Full analysis set (FAS) comprised all patients to whom study treatment has been assigned by randomization. According to the intent to treat principle, patients were analyzed according to the treatment and strata they had been assigned to during the randomization procedure. The Per protocol set (PPS) consisted of a subset of patients in the FAS who were compliant with requirements of the protocol. Sensitivity analyses of the primary endpoint of iDFS could be performed using data from the PPS if the FAS and PPS differ and if the primary analysis was significant. The Safety set included all randomized patients who received any study treatment (i.e., at least one dose of ribociclib or ET). Patients were analyzed according to the study treatment received. The actual treatment received corresponded to: • Ribociclib + ET if patients took at least one dose of ribociclib • ET if patients took at least one dose of ET but ribociclib was never received The Pharmacokinetic analysis set (PAS) consisted of all patients who provided at least one evaluable PK concentration [Study O12301C Primary Analysis CSR-Section 9.7.2] Study Endpoints The Applicant’s Description: Objective Endpoint Primary To compare iDFS for ribociclib + ET versus ET in patients with HR-positive, HER2-negative, eBC iDFS using STEEP criteria, as assessed by Investigator Secondary To evaluate the two treatment arms with respect RFS RFS using STEEP criteria To evaluate the two treatment arms with respect to DDFS DDFS using STEEP criteria To evaluate the two treatment arms with respect to OS OS defined as time from date of randomization to date of death due to any cause To evaluate PRO for health-related QoL in the two treatment arms Change from baseline in the physical functioning sub- scale score and global health status / QoL scale score as assessed by EORTC QLQ-C30 To evaluate safety and tolerability of the treatment regimen Frequency and severity of AEs, laboratory and Electrocardiogram (ECG) abnormalities To characterize the PK of ribociclib when given in combination with NSAI (and goserelin if applicable) PK parameters such as Ctrough and other applicable parameters for ribociclib Exploratory 57 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Objective Endpoint To explore the two treatment arms with respect to LRRFS LRRFS defined as time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, or death due to any cause To explore use of subsequent antineoplastic therapy Incidence of subsequent antineoplastic therapy and time to first subsequent antineoplastic therapy To explore healthcare resource utilization Number of patients hospitalized, total number of hospitalizations, and length of stay in hospitals, number of patients with Emergency Room and additional visits Source: [Study O12301C Primary Analysis CSR-Section 8]. The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the design and protocol aspects of the NATALEE trial as stated above. Note that the NATALEE trial opened in December 2018, at which time iDFS using STEEP v1.0 criteria was the standard endpoint for most adjuvant breast cancer trials in the US. That endpoint includes second non-breast primary malignancy as one of the components of the definition. STEEP v2.0 recommended use of invasive breast cancer-free survival (IBCFS), which excludes second non-breast primary malignancy from the endpoint, over iDFS in most adjuvant trials, but these criteria were not published until May 2021. Given the concern for potentially increased risk of second primary malignancies related to nitrosamine impurities with ribociclib, the FDA review team considers the iDFS endpoint to be particularly relevant in NATALEE. As the number of second primary malignancies was ultimately very similar in the two treatment arms, inclusion of these events would be expected to increase the chance of a false negative outcome to the study. Statistical Analysis Plan and Amendments The Applicant’s Description: Efficacy analysis: All efficacy analyses were performed using the FAS which consisted of all patients to whom study treatment has been assigned by randomization. According to the intent to treat principle, patients were analyzed according to the treatment and strata they had been assigned to during the randomization procedure. The primary efficacy variable of the study, iDFS, was defined as the time from the date of randomization to the date of the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). The primary efficacy analysis was the comparison of the distribution of iDFS between the two treatment arms. The null hypothesis stating that iDFS survival distributions of the two treatment arms are equivalent was tested against a one-sided alternative. iDFS was analyzed using a Lan-DeMets (O’Brien-Fleming) alpha spending function and a non-binding Lan-DeMets (O’Brien-Fleming) beta spending function based on the data observed in the FAS up to the cut-off date, according to the treatment arm and strata assigned at 58 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. randomization. The survival distribution of iDFS was estimated using the Kaplan-Meier method. A stratified Cox regression was used to estimate the hazard ratio (HR) of iDFS along with 95% confidence interval (CI) using the same strata information as the primary efficacy comparison. As a sensitivity analysis to assess the impact of stratification, the two treatment arms were compared using the unstratified log-rank test. The HR together with the associated 95% confidence interval obtained using the unstratified Cox regression model was also presented. A multivariate stratified Cox regression model was fitted to evaluate the effect of other baseline demographic and disease characteristics on the estimated HR. The distributions of the secondary efficacy endpoints RFS, DDFS and OS were estimated using the Kaplan-Meier method and compared between treatment groups using a stratified log-rank test at one-sided 2.5% level of significance. The HR for RFS, DDFS and OS were calculated, along with their 95% CI, using a stratified Cox model based on strata assigned at randomization. Analysis of patient reported outcomes: As the main analysis and to best utilize the repeated PRO assessments, a repeated measures model for longitudinal data was used to estimate differences in PRO scores in all sub-scales obtained from EORTC QLQ-C30, the breast symptoms score of QLQ-BR23, the VAS of EQ-5D-5L and the anxiety domain and depression domain scores of HADS between treatment arms. The repeated measures model included terms for treatment, stratification factors assigned at randomization, time, baseline value as main effects, and an interaction term for treatment by time. All data collected until confirmation of first recurrence (including the assessment at confirmation of first recurrence) was included in the analysis. Pharmacokinetic analysis: All PK analyses were based on the PAS, unless otherwise specified. Only evaluable PK concentrations which were not flagged for exclusion were used for summaries. Safety analysis: All safety analyses were performed using the Safety set, which consisted of all randomized patients who received any study treatment (i.e., at least one dose of ribociclib or ET). Patients were analyzed according to the study treatment received. Separate AE summaries were presented by number and percentage of patients who had at least one AE, having at least one AE in each primary system organ class SOC and for each preferred term PT using MedDRA (version 25.1) coding. The safety summary tables within included treatment-emergent events/assessments with on-treatment AEs (new or worsened). Separate summaries for on-treatment deaths and all deaths (including post-treatment deaths), were produced by treatment arm, system organ class and preferred term. The primary cause of death was also displayed [Study O12301C Primary Analysis CSR-Section 2]. The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the design and protocol aspects of the NATALEE trial as stated above. The statistical test for iDFS was based on ~5,000 patients randomized in a 1:1 ratio, where 500 iDFS events would provide a power of approximately 93% to detect a hazard ratio (HR) of 0.73, or approximately 85% to detect a HR of 0.76, with a 1-sided type 1 error of 0.025. There were three planned interim analyses 59 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. for iDFS (at 200, 350, and 425 iDFS events) in addition to the final analysis (at 500 iDFS events), using a Lan-DeMets (O’Brien-Fleming) alpha spending function. There was no type-1 error control for any secondary endpoint, including OS. Protocol Amendments The Applicant’s Description: The study protocol and the SAP were amended 3 times during the study. The key features of each protocol amendment are provided in the below table: Amendment 1 (20-Jun-2019): Clinical safety was updated to include a statement that ribociclib is not recommended for use in combination with tamoxifen (due to increased risk of QT prolongation). Following consultation with EMA Scientific Advice Working Party and with the Steering Committee, the enrollment criteria were updated to include a subset of higher risk Stage II patients to reduce the heterogeneity of the study population. Also, identification of higher risk Stage II patients via gene expression tests was included. Study design rationale was updated to justify the open label study-design. Capping rule was amended to allow for a better representation of stage II and III patients. OS analysis at approximately two years after primary iDFS was added to OS analysis timelines. Statistical calculations were updated to reflect the increase in power for the iDFS endpoint (iDFS event rate was expected to increase as result of the change in population). Amendment 2 (23-Jan-2020): Inclusion criteria was updated to reflect the postmenopausal definition as outlined in the breast cancer clinical guideline from the National Comprehensive Cancer Network (version 3.2019). Wording was added to provide clear guidance on ribociclib discontinuation when TEN is diagnosed, based on updates made to IB Ed.14. Urinalysis was removed from the Clinical Laboratory Collection Plan. Amendment 3 (27-Aug-2020): Role of the CDK4/6 pathway in breast cancer was updated to describe emerging data from other CDK4/6 inhibitor studies. The study design rationale was updated to include an additional 1000 patients with Stage III eBC, with Stage II capped at 40% of total study population of approximately 5,000, based on emerging information external to the study. "Interim and final iDFS" and "Sample size calculation" sections updated because of the sample size increase. The required number of events for the final analysis of iDFS was updated to approximately 500 events to ensure the study power is retained at 85% for a hazard ratio of up to 0.76. An additional interim efficacy analysis at 85% information fraction) was added. Number of randomized patients required to observe the new targeted number of iDFS events was updated from 4,000 to 5,000 [Study O12301C Primary Analysis CSR-Section 9.8.1]. SAP amendments The SAP was amended 3 times with key features outlined below: • Amendment 1 (26-Jul-2021) was mainly to implement changes due to Protocol amendment 3 (protocol v4.0) and to align with Novartis guidelines and program standards. The main 60 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. changes were the increase in sample size to 5000 patients, addition of an interim analysis at 85% IF, and updated futility boundary for IA 1. • Amendment 2 (15-Aug-2022): The key changes were clarifications of some analysis conventions such as central ECG assessments being a primary source of QT analysis , sensitivity analyses to assess the impact of COVID-19 deaths on iDFS and OS, gap analysis for iDFS and OS, subgroup definitions, updated time to event and duration of event endpoints, updated RDI/DI presentations, addition of a stratified multivariate Cox model, clarification of date derivations, and handling of censoring dates. • Amendment 3 (30-Aug-2023): The key changes were update for on-treatment window to align with the 3-year duration of ribociclib treatment, OS subgroup analysis added for stratification factors, and OS subgroup analysis added for stratification factors censoring COVID-19 deaths. Additional OS sensitivity analysis was performed to further evaluate the robustness of OS survival benefit. The OS analysis was repeated using the PPS, using the unstratified log-rank test and a multivariate stratified Cox regression model (fitted to evaluate the effect of other baseline demographic and disease characteristics on the estimated hazard ratio). The fitted model adjusted the treatment difference for key baseline and prognostic factors and included the following covariates: age (< 45 vs. 45-54 vs. 55-64 vs. ≥ 65), ER/PR status (ER+PR+ vs. other) and type of ET (letrozole vs. anastrozole). Based on its clinical relevance, the on-treatment death period was redefined taking the 36- month treatment period for ribociclib into account, i.e., deaths reported during and up to 30 days after the last dose of the treatment, up to a maximum of 36 months plus 30-days in either study arm. The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the key elements of amendments to the protocol and SAP for the NATALEE trial. 8.1.2 Study Results Compliance with Good Clinical Practices The Applicant’s Position: The study was conducted in full conformance with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in conformance with the principles of the Declaration of Helsinki. Written informed consent was obtained from each participant in the study. The study protocol and 3 amendments were approved by local Independent Ethics Committees (IEC) or Institutional Review Boards (IRB). The FDA’s Assessment: 61 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. FDA generally agrees with the Applicant’s statement of compliance with GCP in the NATALEE trial. Financial Disclosure The Applicant’s Position: Details are presented in Appendix 19.2. The FDA’s Assessment: The financial disclosure information in Appendix 19.2 was reviewed. There were no financial conflicts identified that would be expected to compromise the integrity of NATALEE trial results. Patient Disposition Data: Table 8: Patient disposition (final iDFS analysis, 21-Jul-2023 data cut-off) by treatment arm (FAS) Disposition/Reason ET + ribociclib N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Number of patients randomized 2549 (100) 2552 (100) 5101 (100) Number of patients randomized but not treated 23 (0.9) 111 (4.3) 134 (2.6) Number of patients treated with any treatment 2526 (99.1) 2441 (95.7) 4967 (97.4) Number of patients who discontinued all treatment components 612 (24.0) 693 (27.2) 1305 (25.6) Number of patients who discontinued ribociclib 1996 (78.3) 1 (< 0.1) 1997 (39.1) Number of patients who discontinued NSAI 612 (24.0) 693 (27.2) 1305 (25.6) Number of patients still on treatment 1914 (75.1) 1748 (68.5) 3662 (71.8) Primary reason for ribociclib discontinuation Completed 1091 (42.8) 0 1091 (21.4) Adverse event 498 (19.5) 0 498 (9.8) Patient decision to discontinue treatment 135 (5.3) 0 135 (2.6) Disease recurrence 122 (4.8) 0 122 (2.4) Withdrawal by patient 82 (3.2) 0 82 (1.6) Physician decision 24 (0.9) 0 24 (0.5) Other 23 (0.9) 0 23 (0.5) Lost to follow-up 8 (0.3) 0 8 (0.2) Protocol deviation 6 (0.2) 1 (< 0.1) 7 (0.1) Death 4 (0.2) 0 4 (0.1) Endocrine therapy discontinuation 3 (0.1) 0 3 (0.1) Primary reason for NSAI discontinuation Disease recurrence 168 (6.6) 224 (8.8) 392 (7.7) Patient decision to discontinue treatment 138 (5.4) 126 (4.9) 264 (5.2) Adverse event 131 (5.1) 113 (4.4) 244 (4.8) Withdrawal by patient 117 (4.6) 162 (6.3) 279 (5.5) Physician decision 28 (1.1) 32 (1.3) 60 (1.2) Lost to follow-up 10 (0.4) 18 (0.7) 28 (0.5) 63 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. part due to the design of the trial, which provides for 3 years of ribociclib and at least 5 years of ET, discontinuations due to AE were also much more common on the ribociclib + ET arm compared to the arm receiving ET alone (19.5% vs 5.1%). In addition, see FDA analyses of the primary endpoint in Section 8.1.2 below. Protocol Violations/Deviations Data: Table 9: Protocol deviations (FAS) PD Term Deviation Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Number of patients with at least one protocol deviation 1868 (73.3) 1713 (67.1) 3581 (70.2) IMP/NIMP 659 (25.9) 370 (14.5) 1029 (20.2) Dosing & Administration 606 (23.8) 284 (11.1) 890 (17.4) Supply 93 (3.6) 97 (3.8) 190 (3.7) Wrong Treatment Administration 3 (0.1) 4 (0.2) 7 (0.1) Informed Consent 477 (18.7) 480 (18.8) 957 (18.8) Consenting Process 278 (10.9) 305 (12.0) 583 (11.4) Timing of Consent 176 (6.9) 161 (6.3) 337 (6.6) Failure to Obtain 54 (2.1) 38 (1.5) 92 (1.8) Version 10 (0.4) 10 (0.4) 20 (0.4) Other 9 (0.4) 14 (0.5) 23 (0.5) Protocol Compliance 1591 (62.4) 1522 (59.6) 3113 (61.0) Study Assessments & Procedures 1201 (47.1) 1259 (49.3) 2460 (48.2) Inclusion / Exclusion 586 (23.0) 571 (22.4) 1157 (22.7) Prohibitive Medication or Treatment 304 (11.9) 51 (2.0) 355 (7.0) Other 26 (1.0) 11 (0.4) 37 (0.7) Safety 39 (1.5) 33 (1.3) 72 (1.4) Late / Unreported SAE / AESI / Pregnancy 39 (1.5) 33 (1.3) 72 (1.4) Major/Critical Deviation Leading to Exclusion from Analysis Sets 29 (1.1) 18 (0.7) 47 (0.9) Inclusion / Exclusion 29 (1.1) 17 (0.7) 46 (0.9) Wrong Treatment Administration 0 1 (0.0) 1 (0.0) A patient with multiple protocol deviations within the same PD term is counted only once for this PD term. Patients may have protocol deviations in more than one PD term. Source: [Study O12301C Primary analysis CSR-Table 10-2] The Applicant’s Position: Overall, 70.2% of patients reported at least one protocol deviation. The percentage of patients with deviations was slightly higher in the ribociclib + ET arm compared to that in the ET only arm (73.3% vs. 67.1%). A total of 47 patients (0.9%) were excluded from the PPS due to major deviations. Forty-six patients (0.9%) were excluded from the PPS due to inclusion/exclusion criteria not being met. In total, 2460 patients (48.2%) reported at least one study assessment and procedure PD and 1157 patients (22.7%) reported at least one inclusion/exclusion PD. The most commonly reported study assessment and procedure PD was mammography not regularly 64 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. assessed as per protocol (1062 patients, 20.8%). The most commonly reported inclusion/exclusion PD was baseline laboratory results criteria (blood salts i.e., potassium, calcium and magnesium) not met (218 patients, 4.3%) [Study O12301C Primary analysis CSR- Section 10.2]. The FDA’s Assessment: FDA reviewed the Applicant’s position above. While the majority of protocol deviations was balanced between the two arms, the ribociclib + ET arm had higher protocol deviations due to “Dosing & Administration” and “Prohibitive Medication or Treatment.” In response to an Information Request (IR), the Applicant provided additional information on the cause of the higher incidence of protocol deviations due to these two reasons, particularly on the ribociclib + ET arm. Protocol deviations due to “Dosing & Administration”: The primary cause was due to ribociclib “dose greater than the prescribed dose for >3 days or duration exceeded by 3 days or single dose >900 mg/day”, in 245 patients. These patients received a mean of 2.7 extra days of ribociclib (median 2.0 days). The TEAEs experienced by these patients was compared with the TEAEs experienced overall by the patients who received ribociclib + ET, and generally comparable. No patient received a single dose >900 mg/day, and only one patient received ribociclib 600 mg for 147 days before this dose error was identified; the patient subsequently received ribociclib 400 mg. Section 2 Dosage & Administration of the ribociclib product labeling will clearly state that in the adjuvant treatment setting, the approved ribociclib dosage is 400 mg days orally for 21 days out of a 28 day cycle. For the prohibited concomitant medications, the primary cause was due to short-term co- administration. One safety concern of prohibited concomitant medications for patients who received ribociclib + ET is QT prolongation. FDA’s analysis of QT prolongation is provided in Section 8.2.4 below, and QT prolongation is already included in the ribociclib USPI as a Section 5 Warning and Precaution. The ribociclib USPI already clearly states prohibited concomitant medications. Overall, the protocol deviations do not significantly impact the finding of a favorable benefit-risk assessment of ribociclib. Table of Demographic Characteristics Data: Table 10: Demographic Characteristics Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Age group <45 611 (24.0) 591 (23.2) 1202 (23.6) 45 to 54 849 (33.3) 895 (35.1) 1744 (34.2) 55 to 64 682 (26.8) 700 (27.4) 1382 (27.1) 65 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) ≥ 65 407 (16.0) 366 (14.3) 773 (15.2) Age (years) n 2549 2552 5101 Mean 52.9 52.7 52.8 SD 10.75 10.77 10.76 Min 24 24 24 Median 52.0 52.0 52.0 Max 90 89 90 Gender Male 11 (0.4) 9 (0.4) 20 (0.4) Female 2538 (99.6) 2543 (99.6) 5081 (99.6) Race White 1876 (73.6) 1868 (73.2) 3744 (73.4) Black or African American 42 (1.6) 47 (1.8) 89 (1.7) Asian 341 (13.4) 334 (13.1) 675 (13.2) Native Hawaiian or Other Pacific Islander 3 (0.1) 1 (0.0) 4 (0.1) American Indian or Alaska Native 4 (0.2) 3 (0.1) 7 (0.1) Other 145 (5.7) 172 (6.7) 317 (6.2) Missing 138 (5.4) 127 (5.0) 265 (5.2) Ethnicity Hispanic or Latino 212 (8.3) 223 (8.7) 435 (8.5) Not Hispanic or Latino 2076 (81.4) 2054 (80.5) 4130 (81.0) Unknown 172 (6.7) 201 (7.9) 373 (7.3) Missing 89 (3.5) 74 (2.9) 163 (3.2) Region* Asia 281 (11.0) 290 (11.4) 571 (11.2) Europe 1505 (59.0) 1506 (59.0) 3011 (59.0) North America/Australia 624 (24.5) 612 (24.0) 1236 (24.2) Latin America 139 (5.5) 144 (5.6) 283 (5.5) ECOG performance status 0 2106 (82.6) 2132 (83.5) 4238 (83.1) 1 440 (17.3) 418 (16.4) 858 (16.8) Missing 3 (0.1) 2 (0.1) 5 (0.1) Weight (kg) n 2534 2542 5076 Mean 72.4 72.2 72.3 SD 16.20 15.53 15.86 Min 38 41 38 Median 70.0 70.0 70.0 Max 166 169 169 Height (cm) n 2523 2522 5045 Mean 162.9 162.7 162.8 SD 6.78 6.85 6.81 Min 140 140 140 Median 163.0 163.0 163.0 Max 198 191 198 BMI (kg/m²) 66 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) n 2518 2521 5039 Mean 27.3 27.3 27.3 SD 5.81 5.70 5.76 Min 16 15 15 Median 26.3 26.5 26.4 Max 56 59 59 Weight and height are the last non-missing assessments on or before the date of randomization. BMI: body mass index is calculated based on raw data measurements. Asia includes China, Republic of Korea, and Taiwan. Europe includes Austria, Belgium, France, Germany, Hungary, Ireland, Italy, Poland, Romania, Russian Federation, Spain, and United Kingdom. North America/Australia includes Australia, Canada, and United States. Latin America includes Argentina and Brazil. Source: [Study O12301C Primary analysis CSR-Table 10-7] The Applicant’s Position: Demographic characteristics were well-balanced between the two treatment arms. Patients were representative of the population of pre- and postmenopausal women plus men with HR-positive, HER2-negative eBC. The median age of patients in the study was 52 years (range: 24 to 90), with 34.2% of patients within the 45 to 54 years age group. Overall, 99.6% of patients were women and 0.4% of patients were men. The patients included were White (73.4%), Asian, (13.2%), Black or African American (1.7%), American Indian or Alaska Native (0.1%) and Pacific Islander (0.1%) The most frequent ethnicity was non-Hispanic or Latino (81.0%), followed by Hispanic or Latino (8.5%). Over half the patients (59.0%) in each treatment arm were based in Europe followed by North America/Australia (24.2%), Asia (11.2%) and Latin America (5.5%). The vast majority of patients (83.1%) had an ECOG performance status of zero at baseline [Study O12301C Primary analysis CSR-Section 10.4.1] The FDA’s Assessment: FDA disagrees with the Applicant’s characterization of the NATALEE trial as representative of the racial demographics of the U.S. population. More than half of the trial was enrolled in the European Union, and nearly three-quarters of the overall trial population was White. In 2022, according to the Pew Research Center, there were approximately 48 million people in the United States who identified as Black, which is about 14% of the U.S. population. Black patients are markedly underrepresented (total n=89; 1.7%) in the NATALEE trial. According to American Cancer Society, among U.S. patients who develop breast cancer, Black patients were less likely to have HR+, HER2-negative subtype than white patients overall (57% vs 71%), but more likely to have regional disease (31% vs 24%) at diagnosis, with much higher mortality rates. The stage-matched five-year relative survival rates for patients with regional disease at diagnosis are 10% lower for Black 67 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. patients than for white patients. Black men are also more likely than men of other races to develop breast cancer both overall and considering the HR+, HER2-negative breast cancer subtype specifically. Black patients therefore have a very high degree of unmet medical need. Given that the NATALEE trial enrolled patients with high-risk Stage II or III HR+, HER2-negative disease, it should have been enriched for Black patients. While this underrepresentation does not preclude approval of ribociclib in the adjuvant setting, it provides limited information with which to counsel Black patients on the risks and benefits of adding ribociclib to ET. More efforts to increase the diversity of the patients enrolled on cancer clinical trials to reflect the diversity of the U.S. patient population are urgently needed. A postmarketing commitment (PMC) will ask the Applicant to provide data from ongoing/planned clinical trials (e.g., adjuvant WIDER trial) or other sources to better characterize the efficacy and safety of ribociclib in racial minority subgroups, including the Black or African-American population. The rationale for and details of the PMC are discussed further in Section 13. Other Baseline Characteristics Data: Table 11: Disease characteristics (FAS) Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Tumor Location Right 1277 (50.1) 1258 (49.3) 2535 (49.7) Left 1271 (49.9) 1287 (50.4) 2558 (50.1) Bilateral 1 (0.0) 7 (0.3) 8 (0.2) Missing 0 0 0 Histopathological grade at diagnosis - n (%) GX 30 (1.2) 32 (1.3) 62 (1.2) G1 218 (8.6) 240 (9.4) 458 (9.0) G2 1458 (57.2) 1451 (56.9) 2909 (57.0) G3 521 (20.4) 549 (21.5) 1070 (21.0) Not Done 292 (11.5) 258 (10.1) 550 (10.8) Missing 30 (1.2) 22 (0.9) 52 (1.0) T stage at diagnosis - n (%) TX 175 (6.9) 173 (6.8) 348 (6.8) T0 4 (0.2) 7 (0.3) 11 (0.2) Tis 2 (0.1) 3 (0.1) 5 (0.1) T1 471 (18.5) 442 (17.3) 913 (17.9) T2 1181 (46.3) 1235 (48.4) 2416 (47.4) T3 471 (18.5) 472 (18.5) 943 (18.5) T4 200 (7.8) 184 (7.2) 384 (7.5) Missing 45 (1.8) 36 (1.4) 81 (1.6) N stage at diagnosis - n (%) NX 272 (10.7) 264 (10.3) 536 (10.5) N0 694 (27.2) 737 (28.9) 1431 (28.1) N1 1050 (41.2) 1049 (41.1) 2099 (41.1) 68 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) N2 332 (13.0) 292 (11.4) 624 (12.2) N3 151 (5.9) 175 (6.9) 326 (6.4) Missing 50 (2.0) 35 (1.4) 85 (1.7) Ki67 score at initial diagnosis n 1861 1908 3769 Mean 27.1 27.1 27.1 SD 19.88 19.50 19.69 Min 0 0 0 Median 20.0 20.5 20.0 Max 99 100 100 Ki67 category at initial diagnosis ≤ 14% 508 (19.9) 508 (19.9) 1016 (19.9) > 14% 1353 (53.1) 1400 (54.9) 2753 (54.0) ≤ 20% 938 (36.8) 954 (37.4) 1892 (37.1) >20% 923 (36.2) 954 (37.4) 1877 (36.8) Missing 688 (27.0) 644 (25.2) 1332 (26.1) Histopathological grade on surgical specimen - n (%) GX 32 (1.3) 30 (1.2) 62 (1.2) G1 213 (8.4) 217 (8.5) 430 (8.4) G2 1460 (57.3) 1432 (56.1) 2892 (56.7) G3 684 (26.8) 702 (27.5) 1386 (27.2) Not Done 159 (6.2) 168 (6.6) 327 (6.4) Missing 1 (0.0) 3 (0.1) 4 (0.1) T stage on surgical specimen - n (%) TX 20 (0.8) 9 (0.4) 29 (0.6) T0 56 (2.2) 52 (2.0) 108 (2.1) Tis 16 (0.6) 19 (0.7) 35 (0.7) T1 774 (30.4) 761 (29.8) 1535 (30.1) T2 1162 (45.6) 1198 (46.9) 2360 (46.3) T3 427 (16.8) 422 (16.5) 849 (16.6) T4 92 (3.6) 91 (3.6) 183 (3.6) Missing 2 (0.1) 0 2 (0.0) N stage on surgical specimen - n (%) NX 2 (0.1) 5 (0.2) 7 (0.1) N0 378 (14.8) 418 (16.4) 796 (15.6) N1 1062 (41.7) 1039 (40.7) 2101 (41.2) N2 733 (28.8) 690 (27.0) 1423 (27.9) N3 372 (14.6) 399 (15.6) 771 (15.1) Missing 2 (0.1) 1 (0.0) 3 (0.1) Ki67 score on surgical specimen 1 n 1269 1332 2601 Mean 20.6 20.9 20.7 SD 17.82 18.15 17.99 Min 0 0 0 Median 15.0 15.0 15.0 Max 99 98 99 Ki67 category on surgical specimen 69 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) ≤ 14% 541 (21.2) 577 (22.6) 1118 (21.9) > 14% 728 (28.6) 755 (29.6) 1483 (29.1) ≤ 20% 817 (32.1) 864 (33.9) 1681 (33.0) > 20% 452 (17.7) 468 (18.3) 920 (18.0) Missing 1280 (50.2) 1220 (47.8) 2500 (49.0) Time since initial diagnosis (months) n 2517 2528 5045 Mean 11.8 11.8 11.8 SD 3.53 3.58 3.55 Min 1 1 1 Median 11.7 11.7 11.7 Max 23 27 27 Predominant histology - n (%) Invasive ductal carcinoma NOS 1857 (72.9) 1881 (73.7) 3738 (73.3) Invasive lobular 455 (17.9) 450 (17.6) 905 (17.7) Carcinoma medullary 1 (0.0) 1 (0.0) 2 (0.0) Mucinous 17 (0.7) 16 (0.6) 33 (0.6) Papillary 18 (0.7) 12 (0.5) 30 (0.6) Tubular 5 (0.2) 3 (0.1) 8 (0.2) Ductal Carcinoma In Situ 1 (0.0) 0 1 (0.0) Lobular Carcinoma In Situ 0 0 0 Other 194 (7.6) 189 (7.4) 383 (7.5) Missing 1 (0.0) 0 1 (0.0) Prior surgery - n (%) Mastectomy 1664 (65.3) 1691 (66.3) 3355 (65.8) Breast conserving surgery 978 (38.4) 963 (37.7) 1941 (38.1) Axillary lymph node dissection 2165 (84.9) 2149 (84.2) 4314 (84.6) Sentinel lymph node biopsy 926 (36.3) 920 (36.1) 1846 (36.2) Other 143 (5.6) 162 (6.3) 305 (6.0) Missing 0 0 0 HER2 ISH result prior to surgery (reported only if performed) - n (%) Amplification 4 (0.2) 7 (0.3) 11 (0.2) Non-Amplification 612 (24.0) 653 (25.6) 1265 (24.8) Equivocal 19 (0.7) 13 (0.5) 32 (0.6) Unknown 6 (0.2) 11 (0.4) 17 (0.3) HER2 ISH result from the surgical specimen (reported only if performed) - n (%) Amplification 2 (0.1) 1 (0.0) 3 (0.1) Non-Amplification 417 (16.4) 423 (16.6) 840 (16.5) Equivocal 1 (0.0) 1 (0.0) 2 (0.0) Unknown 2 (0.1) 2 (0.1) 4 (0.1) HER2 IHC score prior to surgery (reported only if performed) - n (%) 0 856 (33.6) 881 (34.5) 1737 (34.1) 1+ 862 (33.8) 813 (31.9) 1675 (32.8) 2+ 464 (18.2) 480 (18.8) 944 (18.5) 3+ 5 (0.2) 5 (0.2) 10 (0.2) 70 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Unknown 21 (0.8) 21 (0.8) 42 (0.8) HER2 IHC score from the surgical specimen (reported only if performed) - n (%) 0 625 (24.5) 610 (23.9) 1235 (24.2) 1+ 513 (20.1) 516 (20.2) 1029 (20.2) 2+ 235 (9.2) 262 (10.3) 497 (9.7) 3+ 1 (0.0) 3 (0.1) 4 (0.1) Unknown 6 (0.2) 10 (0.4) 16 (0.3) ER/PR combination statuses - n (%) ER+/PR+ 2172 (85.2) 2132 (83.5) 4304 (84.4) ER+/PR- 359 (14.1) 392 (15.4) 751 (14.7) ER-/PR+ 3 (0.1) 12 (0.5) 15 (0.3) ER+/UNK 10 (0.4) 13 (0.5) 23 (0.5) UNK/PR+ 2 (0.1) 2 (0.1) 4 (0.1) UNK/PR- 1 (0.0) 1 (0.0) 2 (0.0) UNK/UNK 2 (0.1) 0 2 (0.0) AJCC 8th ed. anatomic stage - n (%) Stage 0 0 0 0 Stage I 9 (0.4) 5 (0.2) 14 (0.3) Stage II 1011 (39.7) 1034 (40.5) 2045 (40.1) Stage III 1528 (59.9) 1512 (59.2) 3040 (59.6) Stage IV 0 0 0 Missing 1 (0.0) 1 (0.0) 2 (0.0) Genomic test Endopredict 23 (0.9) 28 (1.1) 51 (1.0) Mammaprint 46 (1.8) 51 (2.0) 97 (1.9) Oncotype DX 120 (4.7) 129 (5.1) 249 (4.9) Pam50 38 (1.5) 29 (1.1) 67 (1.3) Other 109 (4.3) 103 (4.0) 212 (4.2) N status for subgroup analysis used in AJCC Stage derivation 2 N0 285 (11.2) 328 (12.9) 613 (12.0) N1-N3 2261 (88.7) 2219 (87.0) 4480 (87.8) >N3 0 0 0 Missing 3 (0.1) 5 (0.2) 8 (0.2) 71 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Subjects may have had more than one prior surgery but are only counted once per category. T stage category T1 collects T1mi, T1a, T1b, and T1c. Category T4 collects T4a, T4b, T4c, and T4d. N stage category N0 collects N0 and N0(i+). Category N1 collects N1, N1a, N1c, and N1mi. Category N2 collects N2a, N2b, and N2c. Category N3 collects N3a, N3b, and N3c. AJCC 8th ed. category Stage 1 collects Stage IA and Stage IB. Category Stage II collects Stage IIIA and Stage IIB. Category Stage III collects Stage IIIA, Stage IIIB, and Stage IIIC. Stage is derived using TNM from surgery for patients having not received neo-/adjuvant treatment, or as worst stage derived using TNM at diagnosis and TNM from surgery for patients having received neo-/adjuvant treatment. Patients may have had more than one Genomic test type but are only counted once per type. 1 Ki67 per surgical specimen (if available, otherwise at diagnosis) was used for subgroup iDFS analysis. 2 Included in missing category are patients having Nx. These patients are either unable to be staged or have been staged with Nx and T4(x) as Stage IIIB. Source: [Study O12301C Primary analysis CSR-Table 10-8] The Applicant’s Position: Treatment arms were generally well balanced and represented the intended eBC patient population with respect to baseline characteristics (including Anatomic Stage Group and nodal status). The proportion of patients with Anatomic Stage Group II disease was well balanced between both treatment arms (39.7% of patients in the ribociclib + ET arm vs. 40.5% of patients in the ET only arm). Similarly for Anatomic Stage Group III disease, a balance between both treatment arms was observed (59.9% of patients in the ribociclib + ET arm vs. 59.2% of patients in the ET only arm). A total of 285 patients (11.2%) in the ribociclib + ET arm and 328 patients (12.9%) in the ET only arm were N0 based on nodal status used in AJCC Stage derivation. The predominant histology was invasive ductal carcinoma (reported in 72.9% of patients in the ribociclib + ET arm and 73.7% of patients in the ET only arm. Although not required for all patients (and performed locally), the total number of patients enrolled with Ki67 scores ≤ 20% and > 20% were comparable (37.1% vs. 36.8%). All patients were HER2-negative (by protocol definition) with the exception of 8 patients (0.3%) in the ribociclib + ET arm and 10 patients (0.4%) in the ET only arm who were excluded from the Per Protocol Set [Study O12301C Primary analysis CSR-Section 10.4.2]. The FDA’s Assessment: FDA agrees that the disease characteristics at baseline are generally well-balanced between the two treatment arms and are reflective of the population for which the Applicant is seeking an indication in early breast cancer. As discussed elsewhere in the review, the patients in the NATALEE trial were much higher risk than the overall population with HR+, HER2-negative breast cancer in the US, based upon the grade, stage, and extent of nodal involvement, and therefore these results should not be extrapolated to a lower-risk population of patients. The proposed indication in patients with stage II and III HR+, HER2-negative breast cancer accurately reflects the study population; however, there is more limited information 72 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. on the benefit of ribociclib in patients with node-negative breast cancer as only 613 (12%) patients on NATALEE had N0 disease based upon nodal status used in AJCC staging, including 285 (11.2%) of patients on the ribociclib + ET arm. In subgroup analyses by nodal status, the iDFS favored ribociclib + ET over ET alone regardless of nodal status; the hazard ratio point estimates were similar for patients with N0 disease [HR 0.72 (95% CI: 0.41, 1.27)] and with N1-N3 disease [HR 0.76 (95% CI: 0.63, 0.91)], albeit with wider confidence intervals that cross 1, given the smaller sample size in the N0 subgroup. See FDA’s analysis of iDFS by Stage and nodal status in Section 8.1.2 and Table 20. Stratification Data: Table 12: Randomization by stratification factor (Full analysis set) Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) All patients N=5101 n (%) Stratification factor at randomization Menopausal Status Premenopausal women and men 1125 (44.1%) 1128 (44.2%) 2253 (44.2%) Postmenopausal women 1424 (55.9%) 1424 (55.8%) 2848 (55.8%) AJCC Stage Anatomic Stage Group II 1076 (42.2%) 1078 (42.2%) 2154 (42.2%) Anatomic Stage Group III 1473 (57.8%) 1474 (57.8%) 2947 (57.8%) Prior Chemotherapy Yes 2214 (86.9%) 2218 (86.9%) 4432 (86.9%) No 335 (13.1%) 334 (13.1%) 669 (13.1%) Geographic Region NA/WE/O 1563 (61.3%) 1565 (61.3%) 3128 (61.3%) ROW 986 (38.7%) 987 (38.7%) 1973 (38.7%) Strata as entered in the IRT during randomization NA/WE/O: North America/Western Europe/Oceania; ROW: Rest of World Source: Study O12301C Primary analysis CSR-Table 10-5 The Applicant’s Position: Stratification according to menopausal status (premenopausal women, and men vs. postmenopausal women), AJCC 8th edition Stage (Stage II vs. Stage III), prior neoadjuvant/adjuvant chemotherapy (yes vs. no), and geographical region (North America/Western Europe/Oceania vs. rest of the world) was incorporated in the randomization design. The number of patients randomized according to each stratification factor (by IRT) was comparable between the ribociclib + ET arm and ET only arms [Study O12301C Primary analysis CSR-Section 10.3.1]. 73 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: FDA agrees that stratification factors are generally well-balanced between the two treatment arms. In addition, the concordance rates were high between IRT and CRF, with 98% concordance in menopausal status, 95% concordance in AJCC 8th edition staging, 98% concordance in prior neoadjuvant/adjuvant chemotherapy, and 100% concordance in geographical region. Of note, consistent with the baseline characteristics noted above, including a high rate of node positivity and grade 2 or 3 tumors, 87% of participants received (neo)adjuvant chemotherapy, which reflects the high-risk nature of the NATALEE population. The benefit-risk assessment should not be extrapolated to a lower-risk U.S. population of patients with HR+, HER-2 negative early breast cancer. Treatment Compliance, Concomitant Medications, and Rescue Medication Use The Applicant’s Position: Treatment compliance: No formal treatment compliance measurements for ribociclib, letrozole, anastrozole and goserelin were performed. Compliance was assessed by the Investigator examining the records of drug administration and the numbers of boxes as well as the tablets/capsules dispensed, received, and returned. The records of administration for ribociclib, NSAI (letrozole or anastrozole), and goserelin are provided [Study O12301C Primary analysis CSR-Section 10.6.3]. Concomitant therapy: Overall, a similar proportion of patients received concomitant medications during the study in the ribociclib + ET arm and in the ET only arm (92.3% vs. 85.9%). No imbalance was evident in the frequency or type of medication used. Concomitant use of bisphosphonates was similar between treatment arms (15.1% of patients in the ribociclib + ET arm and 15.2% of patients in the ET only arm). Concomitant use of denosumab, primarily for the treatment of osteoporosis and to increase bone mass due to high risk of fracture in the adjuvant setting, was also reasonably well balanced between treatment arms (2.35% of patients in the ribociclib + ET arm and 2.94% of patients in the ET only arm). The use of concomitant systemic corticosteroids was low and comparable in both treatment arms (0.4% of patients in ribociclib + ET arm and 0.5% of patients in the ET only arm). Systemic corticosteroid combinations were concomitantly used by 0.3% of patients in the ribociclib + ET arm and 0.1% of patients in the ET only arm. Overall, 17.8% of patients in the ribociclib + ET arm and 18.4% of patients in the ET only arm received at least one concomitant medication that was prohibited by this study. The most commonly (≥ 2.5%) used prohibited medications in the ribociclib + ET arm compared to the ET only arm were ondansetron (3.7% vs. 2.5%), azithromycin (3.1% vs. 2.5%) and ciprofloxacin (2.5% vs. 2.4%) [Study O12301C Primary analysis CSR-Section 10.5.2]. Rescue medication Not applicable as no rescue medications were allowed in the study. 74 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: FDA generally agrees with the Applicant’s summary of the data. The number of patients who received a concomitant medication prohibited by the study (approximately 18% in each arm) is high and of concern given that many of these drug-drug interactions, including the three most common prohibited concomitant medications used in the study, can increase the risk of QT prolongation and Torsades de Pointes. The use of prohibited concomitant medications was distributed equally across study arms. This likely reflects what will inadvertently occur in more typical use in the postmarket setting with three years of ribociclib in a curative intent population. It is therefore reassuring that even with 1 in 5 patients on study having received a prohibited medication, both QT prolongation of >60 ms from baseline or to >480 ms in patients on ribociclib + ET, as well as AESIs that may reflect undetected QT prolongation, were uncommon, likely due to the lower dose of 400 mg used in the adjuvant setting. See additional safety information regarding this issue in Section 8.2. Efficacy Results Efficacy claims for use of ribociclib 400 mg in combination with ET (AI: anastrozole or letrozole) and goserelin, if applicable, as adjuvant therapy for HR-positive, HER2-negative eBC are based on results from the final iDFS analysis (data cut-off date: 21-Jul-2023) and primary iDFS analysis at IA3 (data cut-off date: 11-Jan-2023) from the Phase III Study O12301C [CO Study O12301C-Section 4]. • The prespecified primary iDFS analysis IA3 was performed at 426 iDFS events, after which the DMC concluded that the iDFS results met the criteria to demonstrate statistically significant efficacy. As of the DCO date for IA3, the median duration of study follow-up from randomization to DCO was 34.0 months. The median follow-up for iDFS was 27.7 months. • The results of the final iDFS analysis (509 iDFS events) are reported in this document. The median duration of study follow-up for this DCO was 40.3 months (from randomization to DCO), with a minimum duration of follow-up of 27 months. The median follow-up for iDFS is 33.3 months for both arms. The totality of the data for the primary iDFS analysis (IA3) is provided in [Study O12301C Primary analysis CSR]. The updated data from the final iDFS analysis is provided in [Study O12301C EA&SU]. Primary Endpoint - Magnitude of treatment effect and robustness of iDFS analysis Data: Table 13: Log-rank test results for iDFS (FAS) Treatment n/N (%) Comparison Z-statistic p-value Primary iDFS Analysis (DCO 11-Jan-2023) Ribociclib + ET 189/2549 (7.4) vs. ET Only -2.9847 0.0014 75 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Treatment n/N (%) Comparison Z-statistic p-value* ET Only 237/2552 (9.3) Final iDFS Analysis (DCO 21-Jul-2023) Ribociclib + ET 226/2549 (8.9) vs. ET Only -3.2528 0.0006 ET Only 283/2552 (11.1) n is the number of iDFS events. N = total number of patients included in the analysis. * 1-sided p-value for log-rank test stratified by premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world. Source: [CO Study O12301C-Table 4-2] Figure 2: Kaplan-Meier plot for iDFS (FAS) - final iDFS analysis (21-Jul-2023 data cut-off) Source: [SCE Study O12301C-Figure 3-1] The Applicant’s Position: The ribociclib + ET arm demonstrated statistically significant and clinically superior efficacy over the ET only arm for the primary endpoint of iDFS per Investigator assessment [Study O12301C Primary analysis CSR], which was maintained over time. At the final iDFS analysis, 76 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. there was an estimated 25.1% relative reduction in the risk of an iDFS event (HR 0.749; 95% CI: 0.628, 0.892; one-sided stratified log-rank test nominal p-value = 0.0006) [SCE Study O12301C- Tables 3-10 and 3-11], [SCE Add. Study O12301C-Tables 3-2 and 3-3]. At the final iDFS analysis, the Kaplan-Meier iDFS curves diverged from approximately 3 months after start of treatment, corresponding to time of first STEEP clinical evaluation. In general, the iDFS event-free probability remained higher in the ribociclib + ET arm, indicating an early, sustained benefit with the ribociclib combination, which was maintained over time (Figure 2). As of the data cut-off date for the final iDFS analysis, there were approximately 5.6 months of additional follow-up for iDFS, with median duration of iDFS follow-up (from randomization to last recurrence assessment) of 33.3 months for both arms. The 3-year iDFS rates for the final iDFS analysis were 90.7% (95% CI: 89.3, 91.8) in the ribociclib + ET arm and 87.6% (95% CI: 86.1, 88.9) in the ET only arm, reflecting a 3.1% absolute benefit favoring ribociclib + ET. There were fewer iDFS events (8.9% vs. 11.1%) reported in the ribociclib + ET arm compared to the ET only arm. This trend is consistent with the primary iDFS analysis results (4.7% vs. 6.7%, distant recurrence events). Robustness and consistency of iDFS analysis Results of the iDFS analysis based on the PPS were consistent with the final iDFS analysis based on the FAS (one-sided stratified log-rank test p-value=0.0005; stratified Cox regression model HR=0.746; 95% CI: 0.626, 0.890). In addition, multiple sensitivity analyses based on excluding missing iDFS assessment, backdating iDFS, new anticancer therapy, clinical recurrence, and death due to COVID-19, were supportive of the final iDFS analysis results. Consistent treatment effect-iDFS subgroup analyses Consistency of iDFS benefit was evident across stratification factors of anatomic stage, prior (neo)adjuvant chemotherapy, menopausal status, and geographic region, and other subgroups. The ITT results of IDFS did not appear to be driven by any particular subgroup [CO Study O12301-Section 4.3.1.1]. The FDA’s Assessment: FDA agrees that the ribociclib + ET arm demonstrated a statistically significant improvement compared to the ET only arm for the primary endpoint of iDFS per investigator assessment at IA3. However, at IA3, there was a large amount of censoring for iDFS as only 20% of patients had completed 3-years of adjuvant ribociclib. Due to the FDA’s concern for a possible diminishing iDFS effect with longer follow-up, FDA requested that the Applicant continue NATALEE until the final iDFS analysis. At the final iDFS analysis (DCO: July 21, 2023), 43% of patients had completed 3 years of adjuvant ribociclib. There were 226 iDFS events in 2549 patients in the ribociclib + ET arm compared to 283 iDFS events in 2552 patient in the ET only arm at the final iDFS analysis. The final iDFS HR was 0.75 (95% CI: 0.63, 0.89), which was consistent with iDFS results at 77 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. IA3. The reasons for iDFS censoring at the time of final iDFS analysis are summarized in Table 14 below. Table 14: FDA – iDFS Censoring Reasons (final iDFS analysis) Ribociclib + ET N=2549 (%) ET only N=2552 (%) Number of patients with iDFS event 226 (8.9) 283 (11.1) Number of patients censored 2323 (91.1) 2269 (88.9) Reason for censoring Ongoing without event 2073 (81.3) 1901 (74.5) Withdrew consent 233 (9.1) 343 (13.4) Lost to follow-up 17 (0.7) 25 (1.0) Source: FDA Analysis Of note, FDA was concerned that there appeared to be an imbalance in the number of patients censored due to withdrawal of consent. FDA further examined the timing of censoring for patients who were censored for withdrawal of consent, as shown in Table 15. Table 15: FDA – Timing of Censoring for Patients Censored for Withdrawal of Consent Time Censored Ribociclib + ET N=2549 (%) ET Only N=2552 (%) Randomization 84 (3.3) 201 (7.9) >0-6 Months 66 (2.6) 43 (1.7) 6-12 Months 30 (1.2) 21 (0.8) 12-24 Months 31 (1.2) 47 (1.8) 24-48 Months 22 (0.9) 31 (1.2) Total 233 (9.1) 343 (13.4) Source: FDA Analysis From this, it appeared that the imbalance was largely due to patients who were censored at randomization for withdrawal of consent. Therefore, FDA conducted several sensitivity analyses to assess the impact of the imbalance in patients who were censored at randomization due to withdrawal of consent. The sensitivity analyses considered various approaches to impute iDFS data for these patients, and results are summarized in Table 16. 78 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 16: FDA – iDFS Sensitivity Analyses to Account for Imbalance in Patients Censored at Randomization for Withdrawal of Consent Sensitivity Analysis Description HR (95% CI) For patients censored at randomization for withdrawal of consent: 1. Impute iDFS for patients in both arms from the best 20% for iDFS in both arms 0.80 (0.67, 0.95) 2. Impute iDFS for patients in both arms from the best 20% for iDFS in ET Only arm only 0.82 (0.69, 0.98) 3. Impute iDFS for patients in the ET Only arm from the best 20% for iDFS in both arms 0.81 (0.68, 0.97) 4. Impute iDFS for patients in the ET Only arm from the best 20% for iDFS in the ET Only arm only 0.82 (0.69, 0.97) Source: FDA Analysis Results of the sensitivity analyses were generally consistent with results of the final iDFS analysis (iDFS HR of 0.75 [95% CI: 0.63, 0.89]), even when considering the most conservative scenario in which only patients on the ET only arm had iDFS times imputed from the best 20% for iDFS in both arms. FDA also examined the baseline characteristics for the patients who were censored at baseline for withdrawal of consent and did not identify any major difference in prognosis for this group of patients. Thus, it does not appear that this imbalance impacted results in a way that would change the overall benefit- risk assessment. In addition, FDA agrees that the iDFS results at the final analysis were consistent across multiple sensitivity analyses, including those excluding missing assessments and those considering different censoring rules. Results of iDFS in exploratory subgroups of interest are shown in the next section and were generally consistent with the primary analysis. Efficacy Results – Secondary and other relevant endpoints Data: Table 17: Secondary efficacy results (Study O12301C) - final iDFS analysis (21-Jul-2023 data cut-off) Overall study population N FAS = 5101: 2549 patients in ribociclib + ET arm, and 2552 patients in ET only arm RFS 7.5% vs. 9.7% in favor of ribociclib + ET (one sided stratified log-rank test p-value=0.0004) Cox regression model: estimated 27.3% reduction in the risk of RFS in the ribociclib + ET arm; hazard ratio=0.727 (95% CI: 0.602, 0.877) Kaplan-Meier method: 3-year RFS rates of 92.1% (95% CI: 90.9, 93.2) in the ribociclib + ET arm and 89.1% (95% CI: 87.6, 90.4) in the ET only arm, translating to a 3.0% improvement in the 3-year rate of RFS in favor of ribociclib + ET 79 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Overall study population DDFS 8.0% vs. 10% in favor of ribociclib + ET (one sided stratified log-rank test p-value=0.0010) Cox regression model: estimated 25.1% reduction in the risk of DDFS in the ribociclib + ET arm; hazard ratio=0.749 (95% CI: 0.623-0.900) Kaplan-Meier method: 3-year DDFS rates of 91.5% (95% CI: 90.2, 92.7) in the ribociclib + ET arm and 88.9% (95% CI: 87.4, 90.2) in the ET only arm, translating to a 2.6% improvement in the 3-year rate of DDFS in favor of ribociclib + ET OS No detriment observed for patients in the ribociclib + ET arm Log-rank analysis: 84 (3.3%) deaths in the ribociclib + ET arm, and 88 (3.4%) in the ET only arm: (one-sided stratified log-rank test nominal p-value = 0.2263) Cox regression model: estimated 10.8% reduction in the risk of death in the ribociclib + ET arm; hazard ratio=0.892 (95% CI: 0.661, 1.203) Kaplan-Meier method: 3-year OS rates were 97.0% (95% CI: 96.2, 97.6) in the ribociclib + ET arm and 96.1% (95% CI: 95.1, 96.9) in the ET only arm Sensitivity analyses for OS (including based on PPS, per CRF, unstratified log-rank test and Cox model, stratified Cox model adjusting for baseline covariates, and censoring for patients with death due to COVID) provide further support that there is a positive trend in favor of the ribociclib + ET arm, with HRs ranging from 0.837 to 0.910 Exploratory Source: [CO Study O12301C-Section 4.3.2] The Applicant’s Position: Secondary efficacy endpoints Results for the secondary efficacy endpoints support the clinical benefit of ribociclib in combination with ET as adjuvant therapy, with no detriment in OS. Ribociclib + ET was associated with significant improvements in RFS and DDFS, with HRs of 0.72 (95% CI: 0.584, 0.884) and 0.74 (95% CI: 0.603-0.905) for the primary analysis/IA3, and HRs of 0.73 (95% CI: 0.602, 0.877) and 0.75 (95% CI: 0.623-0.900) for the final iDFS analysis, respectively. While OS results were immature, OS data at this final iDFS analysis showed no detriment in OS with the addition of ribociclib to ET. A numerically lower mortality rate in the ribociclib + ET arm has been reported, with a total of 84 (3.3%) events in the ribociclib + ET arm, and 88 (3.4%) in the ET only arm. Of note, in this analysis, the OS event rate is lower than anticipated (172 deaths observed vs. 271 deaths anticipated in the protocol at the final iDFS analysis) [CO Study O12301C- Section 4.3.2]. DRFS (exploratory efficacy analysis) For the final iDFS analysis, there was an estimated 26.2% relative reduction in the risk of DRFS for patients in the ribociclib + ET arm (hazard ratio = 0.738; 95% CI: 0.606, 0.898). The DRFS distribution was estimated using the Kaplan-Meier method. There were 178 events in the ribociclib + ET arm vs. 227 events in the ET only arm; one-sided nominal p-value = 0.0012 [CO Study O12301C-Section 4.3.2.1]. 80 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Efficacy in subpopulations Data: Figure 3: Forest plot of iDFS by stratum (final iDFS analysis, 21-Jul-2023 data cut-off (FAS) * Hazard rate in group ET + ribociclib versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors. The group ET only is the reference in the hazard ratio calculation. Source: [SCE Add. Study O12301C-Figure 3-7] Figure 4: Forest plot of iDFS – subgroup analysis (final iDFS analysis, 21-Jul-2023 data cut-off (FAS) 81 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 82 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 83 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 84 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. NE=not evaluable. -Hazard rate in group ribociclib + ET versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors. Th group ET only is the reference in the hazard ratio calculation. Source: [SCE Add. Study O12301C-Figure 3-8] 85 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The Applicant’s Position: Subgroup analyses of iDFS (21-Jul-2023 cut-off) demonstrated a treatment benefit of ribociclib + ET across stratification factors of anatomic stage, prior (neo)adjuvant chemotherapy, menopausal status, and geographic region (Figure 3), as well as other predefined clinically relevant subgroups, including nodal status (Figure 4) [CO Study O12301C-Section 4.4.1]. The FDA’s Assessment: FDA agrees with the Applicant’s assessment that a variety of exploratory subgroup analyses by sex, menopausal status, stage, prior therapy, and pathology results generally were supportive of the addition of ribociclib to ET with point estimates for the iDFS HR <1. FDA emphasizes that NATALEE was not designed to formally test any secondary endpoints, including OS, and cannot support a labeling claim for the other efficacy endpoints but generally agrees with the Applicant’s summary of the efficacy data for the secondary endpoints of RFS, DDFS, and OS. These secondary endpoint results are considered supportive of the iDFS benefit for the addition of ribociclib to ET. The endpoints of RFS and DDFS, which include events earlier than death, are clinically informative in view of the unexpectedly low number of deaths observed in NATALEE at the time of the final iDFS analysis. Given that the number of deaths was lower than anticipated at the final iDFS analysis, prior to the sNDA submission, FDA requested that the applicant provide simulations to estimate the probability of OS detriment with addition of ribociclib to ET based on a total of 340 events projected to occur at end of study. Results of the simulation provided by the Applicant are shown in Table 18 below: Table 18: Applicant's OS Simulation True HR for future OS events Mean est.HR at 340 events (95% CI) P(est.HR>1) (%) P(est.HR>1.1) (%) P(est.HR>1.2) (%) 0.8920.7=0.624 0.752 (0.580, 0.976) 0 0 0 0.8920.8=0.714 0.802 (0.618, 1.041) 0.3 0 0 0.8920.9=0.802 0.849 (0.653, 1.103) 1.3 0.2 0 0.892 0.894 (0.688, 1.162) 7.3 0.3 0 0.8921.1=0.981 0.937 (0.722, 1.217) 20.3 1.7 0.1 0.8921.2=1.070 0.978 (0.753, 1.270) 37.3 5.9 0.4 0.8921.3=1.160 1.017 (0.783, 1.321) 58.6 15.8 1.5 Source: Provided by Applicant In addition, FDA requested an additional OS analysis with the 90-day safety update. At the 90-day safety update, with a data cutoff of October 26, 2023, there were a total of 91 (3.6%) deaths in the ribociclib + ET arm, and 98 (3.8%) deaths in the ET only arm. The OS HR was 0.88 (95% CI: 0.66, 1.17) for the ribociclib + ET arm vs the ET only arm. 86 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Overall, results of OS at the time of final iDFS and at the 90-day safety update support that there appears to be no detriment in OS at this time with addition of ribociclib to ET. A postmarketing requirement (PMR) will be issued for the applicant to provide all additional OS analyses as prespecified in the protocol and SAP, including OS at the time of end of trial. This is discussed further in Section 13. Data Quality and Integrity The Applicant’s Position: No data integrity concerns were reported following Investigator site audits [Study O12301C Primary analysis CSR-Section 9.6.5.1]. The FDA’s Assessment: FDA inspected 5 clinical sites for NATALEE. Table 19: FDA – Clinical Site Inspections Site Contact Site # Pt # Primary Endpoint Verification Dr. Bozena Kukielka-Budny Doktora Kazimierza Jaczewskiego 7 LUBLIN, NA 20-090 Poland Phone: 48509518811 Email: bozena-budny@wp.pl 1810 84 Please ask inspector to verify all subjects in the investigational arm (patients who received ribociclib and endocrine therapy) who were reported as not having an iDFS event by July 21, 2023. Please audit 10% of the subjects in the investigational arm at each site reported to have an iDFS event by July 21st, 2023. If 50% of these positive events are misclassified, please verify all subjects in the investigational arm reported to have an iDFS event by July 21, 2023. Specifically, verify the iDFS Event Type (i.e. NPM, death, recurrence) and Date of Event. If time permits, please also audit 10% of the subjects on the control arm (patients who received endocrine therapy only) at each site reported to have an iDFS event and those without an iDFS event by July 21, 2023. Dr. Zbigniew Nowecki I The Maria Sklodowska Curie Memorial Cancer Centre And Institute Of Oncology (Mcmcc) WARSAW, NA 02-78 Poland Phone: 48225462522 Email: zbigniew.nowecki@pib-nio.pl 1811 131 Dr. Shaker Dakhil R 818 North Emporia Wichita, KS 67214 Phone: 3162624467 Email: shaker.dakhil@cancercenterofkansas.com 5007 21 Dr. Priyanka Sharma 2330 Shawnee Mission Pkwy Westwood, KS 66205 Phone: 9135886029 Email: psharma2@kumc.edu 5057 25 87 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Site Contact Site # Pt # Primary Endpoint Verification Dr. Lowell Hart 3840 Broadway Fort Myers, FL 33901 Phone: 2392749930 Email: llhart@flcancer.com 5075 40 Refer to Section 4.1 for further details on the findings of inspections. Complete information can be found in the FDA OSI review memo. Overall, no action was indicated for the sites. Dose/Dose Response The Applicant’s Position: Results of Study O12301C demonstrated that the 400 mg ribociclib dose is safe and efficacious for use for eBC in the adjuvant setting, where patients have a lower tumor burden than in the advanced or metastatic setting. Thus, the recommended dose of ribociclib for the adjuvant setting for eBC is 400 mg (two 200-mg film-coated tablets) of ribociclib once daily, Days 1 to 21 of each 28-day cycle for 3 years combined with 5 years of ET. Dose reductions: Recommended dose modification guidelines in the adjuvant setting are as follows: • Starting dose 400 mg/day (two 200-mg tablets) • Dose reduction 200 mg/day (one 200-mg tablet) If further dose reduction below 200 mg/day is required, the treatment should be permanently discontinued [SCE Study O12301C-Section 4.2]. Dose justification: Both neutropenia and QTcF prolongation, the adverse events related to ribociclib PK exposure, are lower in eBC patients in Study O12301C at the dose of 400 mg than in aBC patients at the dose of 600 mg, supporting improved tolerability of the 400 mg dose in eBC patients. The PK-QT modeling confirmed the exposure-QTcF relationship in eBC patients, and patient population is a significant covariate where eBC patients showed less QTcF response than aBC patients. Efficacy in patients with eBC was demonstrated by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Due to limited sample size of patients with iDFS events, exposure-efficacy relationship cannot be characterized. In conclusion, based on the observed efficacy and safety data of Study O12301C, exposure- response analysis, and the historical data in patients with aBC, 400 mg ribociclib (once daily for 88 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 3 weeks on/1 week off in a 28-day cycle) is demonstrated to be a safe and effective dose in patients with eBC. The relationship between Ctrough concentration quartiles and iDFS events was examined for patients included in the PK-iDFS set; however, no conclusions could be drawn due to limited data [CO Study O12301-Sections 3.3 and 3.2.1.1]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. Refer to FDA’s clinical pharmacology review in Section 6.3.2. Durability of Response The Applicant’s Position: At the final iDFS analysis a substantial majority of patients, 1996 (78.3%) in the ribociclib + ET group, had discontinued ribociclib, with 1091 patients (42.8%) having completed 3 years of ribociclib treatment per protocol [SCE Add. Study O12301C-Section 3.1]. As of the data cut-off date of 21-Jul-2023 for the final iDFS analysis, there were approximately 5.6 months of additional follow-up for iDFS, with median duration of iDFS follow-up (from randomization to last recurrence assessment) of 33.3 months for both arms [SCE Add. Study O12301C-Section 3.2.1]. The statistically significant improvement in iDFS in the ribociclib + ET arm compared with the ET only arm seen at IA3 was further confirmed with more mature data at final iDFS analysis. With longer follow-up, additional iDFS events, and a larger proportion of patients completing the 3-year treatment regimen of ribociclib, the hazard ratios were very similar when comparing results from the second and third interim analyses, as well as the final iDFS analysis. These results reflect the stability of the data over time. In addition, the confidence intervals are narrowing, indicating that the data are becoming more mature. These results indicate that although the study is ongoing, it is not expected that the overall assessment of the benefit:risk of ribociclib in eBC would change [CO Study O12301C-Section 4.5.1]. The FDA’s Assessment: As noted in Section 8.1, the majority of iDFS events in HR+, HER2-negative early breast cancer occur in years 5-20+ after diagnosis. It would be very unlikely for the overall assessment of the benefit-risk of ribociclib to become unfavorable over time given the trend in iDFS HRs observed to this point; however, the impact of ribociclib on late recurrences cannot be determined from the available data with the current duration of follow-up. A PMC to provide further OS data is discussed in Section 13. 89 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Persistence of Effect The Applicant’s Position: The persistent, beneficial effect of ribociclib on the primary iDFS endpoint was further supported by a series of subgroup analyses. Consistency of the iDFS improvement was generally evident across all subgroups assessed for both the primary and final iDFS analyses, including stratification factors (anatomic stage, prior (neo)adjuvant chemotherapy, menopausal status, geographic region), and other predefined clinically relevant subgroups, demonstrating the validity of the results across the broad study population, with no particular subgroup driving these results. Results for secondary endpoints, including RFS and DDFS were also consistent with and supportive of the iDFS primary endpoint results. At the final iDFS analysis, ribociclib demonstrates persistent efficacy in patients with HR- positive, HER2-negative, Stage II and III eBC with continued separation of the KM curves, consistent HRs between the primary and final iDFS analyses, and narrower confidence intervals across the primary and secondary endpoints [CO Study O12301C-Section 4.5.2] The FDA’s Assessment: While there was no alpha spending on efficacy endpoints other than iDFS or on analysis of iDFS in these subgroups, and therefore these results cannot support any labeling claims, FDA agrees that the results of subgroup analyses and analysis of secondary endpoints were supportive of the results of the primary iDFS analysis in the ITT population. FDA requested that the Applicant conduct an additional OS analysis with the 90-day safety update. As of the data cutoff of October 26, 2023, there had been 91 deaths in 2549 patients in the ribociclib + ET arm compared to 98 deaths in 2552 patients in the ET only arm. Median OS was not reached in either arm. The OS HR was 0.88 (95% CI: 0.66, 1.17). A PMC will require the Applicant to submit pre-specified OS analyses, including the results of OS at the planned end of the study, as discussed in Section 13. Efficacy Results – Secondary or exploratory COA (PRO) endpoints The Applicant’s Position: Patient-reported outcomes (11-Jan-2023 cut-off) Overall, treatment with ribociclib + ET maintained HR QoL scores over time, further supporting the clinical benefit of the proposed treatment regimen in the target population. In general, the primary QoL measure of interest, EORTC QLQ-C30 physical functioning, of patients treated with ribociclib + ET was similar to that of patients treated with ET only. Physical functioning scores were generally similar between the two treatment arms throughout the study, with no meaningful differences at any post-baseline timepoint through to EOT. 90 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Furthermore, PRO scores in the ribociclib + ET arm, upon treatment, remained within 0.5 SD of their baseline scores. A longitudinal analysis of differences in physical functioning score between treatment arms using a repeated measures model (RMM) revealed no substantial or meaningful effect of treatment or treatment by time interaction on the physical functioning scores of EORTC QLQ- C30. In addition, results for the RMM were generally consistent with the change from baseline analyses and related time profile for physical functioning. Analysis of mean change from Baseline scores of global health status/QoL, emotional functioning and social functioning sub-scale scores of the EORTC QLQ-C30, the breast cancer symptoms scores of the EORTC QLQ-BR23, the VAS scores of the EQ-5D-5L, and the anxiety domain and depression domain scores of HADS indicated no meaningful differences between treatment arms over time. Results of the RMM for health status/QoL, emotional functioning and social functioning sub- scale scores of the EORTC QLQ-C30, the breast cancer symptoms scores of the EORTC QLQ- BR23, the VAS scores of the EQ-5D-5L, and the anxiety domain and depression domain scores of HADS confirmed that there was no evidence of a difference between treatment arms during the treatment period [CO Study O12301C-Section 4.3.2]. The FDA’s Assessment: FDA reviewed the PRO results submitted by the Applicant but did not independently verify all of the results. PRO data were collected at screening, every 12 weeks (±2 weeks) after randomization during the first 24 months and every 24 weeks (±2 weeks) thereafter, at EOT, at confirmation of first recurrence, at confirmation of distant recurrence (if the first recurrence was not a distant recurrence), and during the first 12 months after confirmation of distant recurrence (every 12 weeks [±2 weeks] if confirmation of distant recurrence happened during the first 24 months after date of randomization or every 24 weeks [±2 weeks] if confirmation of distant recurrence happened after the first 24 months after the date of randomization). In terms of data quality, from baseline through EOT, the compliance rate was >80% in both arms. The PRO results from this study cannot support any efficacy claims as PRO assessment was sparse, and there was no plan for formal testing of any PRO endpoints. FDA does not agree with the statement that the PRO results support the clinical benefit of the proposed treatment regimen in the target population as this study was not designed to support such conclusions. Furthermore, there was no observed difference in patient reported disease symptoms (e.g., breast cancer symptom scores of the EORTC WLW-BR23), which does not support the Applicant claim of clinical benefit based upon PROs. Lastly, the PRO strategy lacked a comprehensive tolerability assessment including side effects of treatment and overall side effect impact. No post-baseline PRO assessment occurred until week 12, obscuring important tolerability information. 91 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Additional Analyses Conducted on the Individual Trial The Applicant’s Position: Not applicable The FDA’s Assessment: FDA conducted exploratory subgroup analyses of iDFS by anatomic stage and nodal status (Anatomic Stage IIA [Node+ and Node-], Anatomic Stage IIB, and Anatomic Stage III. Results are presented below. Table 20: FDA – Final iDFS by Anatomic Stage and Nodal Status Ribociclib + ET Number of Events/N ET Only Number of Events/N HR (95% CI) Anatomic Stage IIA 15/480 32/521 0.48 (0.26, 0.89) Node positive 4/268 12/280 0.31 (0.10, 0.96) Node negative 11/212 20/241 0.65 (0.31, 1.36) Anatomic Stage IIB 40/531 48/513 0.82 (0.54, 1.26) Anatomic Stage III 170/1528 203/1512 0.76 (0.62, 0.93) Source: FDA Analysis 8.1.3 Integrated Review of Effectiveness The FDA’s Assessment: Not applicable. The Applicant submitted a single trial NATALEE conducted in the adjuvant setting. Ribociclib is already FDA-approved for adults with advanced or metastatic HR+, HER2-negative breast cancer in combination with fulvestrant or an aromatase inhibitor. 8.1.4 Assessment of Efficacy Across Trials The Applicant’s Position: Not applicable The FDA’s Assessment: Not applicable. The Applicant submitted a single trial NATALEE conducted in the adjuvant setting. 92 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Additional Efficacy Considerations The FDA’s Assessment: Not applicable. The Applicant submitted a single trial NATALEE conducted in the adjuvant setting. 8.1.5 Integrated Assessment of Effectiveness The Applicant’s Position: At the final iDFS analysis (509 events, DCO 21-Jul-2023), the addition of ribociclib to ET continued to show a statistically significant and clinically superior efficacy for iDFS, using STEEP criteria as per Investigator assessment, compared with ET only. The median duration of iDFS follow-up between randomization and the data cut-off date was 33.3 months, representing an additional 5.6 months of iDFS follow up since the primary analysis. • Based on a stratified Cox regression analysis, there was an estimated 25.1% relative reduction in the risk of an iDFS event (hazard ratio = 0.749; 95%CI: 0.628, 0.892 (one-sided stratified log-rank test nominal p-value = 0.0006). • The iDFS rate at 3 years is 90.7% (89.3%, 91.8%) for ribociclib + ET vs. 87.6% (86.1%, 88.9%) for ET only, representing a 3.1% absolute benefit in favor of ribociclib + ET. • Consistency of the iDFS improvement was generally evident across all subgroups assessed, including key subgroups (anatomic staging, menopausal status, nodal involvement), demonstrating the validity of the results across the broad study population. • Stage III – hazard ratio = 0.755 (95% CI: 0.616, 0.926); Stage II – hazard ratio = 0.700 (95% CI: 0.496, 0.986) • Premenopausal women & Men – hazard ratio = 0.688 (95% CI: 0.519, 0.913); Postmenopausal – hazard ratio = 0.806 (95% CI: 0.645, 1.007) • N0 subgroup – hazard ratio = 0.723 (95% CI: 0.412, 1.268); N1-N3 subgroup – hazard ratio = 0.759 (95% CI: 0.631, 0.912) • A statistically significant improvement in RFS was demonstrated for the ribociclib + ET arm compared with the ET only arm; RFS HR is 0.727, 95% CI (0.602,0.877) (nominal p-value = 0.0004), with an estimated 27.3% relative reduction in the risk of RFS per Cox regression model. • A statistically significant improvement in DDFS was demonstrated for the ribociclib + ET arm compared with the ET only arm: DDFS HR is 0.749, 95% CI (0.623,0.900) (nominal p- value = 0.0010), with an estimated 25.1% relative reduction in the risk of DDFS per Cox regression model. • There was an estimated 26.2% relative reduction in the risk of DRFS for patients in the ribociclib + ET arm (hazard ratio = 0.738; 95% CI: 0.606, 0.898) (nominal p-value = 93 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 0.0012). The 3-year DRFS rates at the final iDFS analysis (DCO 21-Jul-2023) were 92.6% (95% CI: 91.4, 93.7) in the ribociclib + ET arm and 90.1% (95% CI: 88.7, 91.3) in the ET only arm, reflecting a 2.5% absolute benefit favoring ribociclib + ET. • Although the OS data were still immature, there was no detrimental effect on OS for the final iDFS analysis. With this final iDFS analysis, a substantial majority of patients have completed 3 years of treatment, and efficacy has been sustained as demonstrated by continued separation of the KM curves, consistent HRs and narrower confidence intervals across the primary and secondary endpoints. This further confirms the benefit for a broad population of eBC patients receiving ribociclib for a 3-year duration [SCE Add. Study O12301C-Section 6]. The FDA’s Assessment: NATALEE was a randomized (1:1) multicenter trial for the adjuvant treatment of patients with HR+, HER2-negative stage II and III early breast cancer. Patient were randomized to receive ribociclib (400 mg daily 3 weeks on/1 week off for 3 years) + endocrine therapy (ET, non-steroidal aromatase inhibitor [NSAI], as well as goserelin in men and premenopausal women, dosage per SOC for 5 years) vs. ET only. The primary endpoint of NATALEE was invasive disease-free survival (iDFS) by investigator assessment in the intent to treat (ITT) population. A total of 2549 patients were randomized to the ribociclib + ET arm and 2552 patients to the ET only arm. NATALEE met its primary endpoint of iDFS at IA3 demonstrating a statistically significant improvement in iDFS (hazard ratio [HR] 0.748, 95% confidence interval [CI] 0.619-0.906). The 3-year iDFS was 90.4% (88.6-91.9) on the ribociclib + ET arm compared to 87.1% (85.3-88.8) on the ET only arm, for an absolute difference of 3.3%. However, at IA3, due to a large amount of censoring for iDFS with only 20% of patients having completed 3 years of adjuvant ribociclib and immature OS with 134 total deaths (OS HR 0.759, 95% CI 0.539-1.068), FDA advised the Applicant to continue to follow participants until the final iDFS analysis. The sNDA submission for 209092/S-018 was received on December 22, 2023, and the Applicant used a priority review voucher (PRV). The sNDA submission for 209935/S-027 (co-pack) was received on March 11, 2024, and cross-references sNDA 209092/S-018. The sNDA submission is based on final iDFS, with a data-cutoff date of July 21, 2023. At final iDFS analysis, the HR was 0.75 (95% CI 0.63-0.89). While the median iDFS was not estimable on either treatment arm, the 3-year iDFS rates were 90.7% (95% CI: 89.3, 91.8) in the ribociclib + ET arm and 87.6% (95% CI: 86.1, 88.9) in the ET only arm. The interim OS analysis at the time of final iDFS analysis was immature with 84 deaths (3%) on the ribociclib + ET arm and 88 deaths (3%) on the ET only arm. The OS HR was 0.89 (95% CI 0.66-1.20) with median OS not estimable. As of the July 21, 2023 data cut-off, 43% of patients had completed 3 years of ribociclib + ET, and 69% had completed ≥2 years of ribociclib + ET. There were 172 total deaths on 94 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. study as of the final iDFS analysis. On-treatment deaths were uncommon overall, but higher on the ribociclib + ET arm, 20 deaths (0.8%) compared to 9 deaths (0.4%) on the ET only arm, and more often due to adverse events. The 90-day safety update submitted on March 21, 2024 had a data-cut off of October 26, 2023 and provided approximately 3 additional months of information. At the safety update, there continued to be fewer overall deaths on study in the ribociclib + ET arm: 83 (3.3%) in the ribociclib + ET group and 89 (3.6%) in the ET only group, most of which were attributed to disease progression. Overall safety findings were consistent with the original submission and the known safety profile of ribociclib + ET as reflected in the current USPI. 95 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 8.2 Review of Safety The Applicant’s Position: The key safety data in support of this application are from the primary and final iDFS analyses of Study O12301C. In this large study (N=5101, FAS; N=4968; Safety set), ribociclib 400 mg in combination with standard adjuvant ET (AI; anastrozole or letrozole) is compared with standard of care adjuvant ET alone. The population enrolled in this study reflects the target population of adult patients (including pre- and postmenopausal women plus men) with HR-positive, HER2- negative, Stage II or Stage III eBC who are at risk of recurrence [SCS Study O12301C-Section 1.1.2]. Based on the Safety set, this study population consists of patients with anatomic Stage II (40.3%) or Stage III (59.4%) disease as per AJCC staging (eighth ed.) who had completed surgery, followed by chemotherapy, and/or radiotherapy with curative intent. In view of the stratification (by menopausal status, anatomic stage group, use of prior neoadjuvant/adjuvant chemotherapy, and geographic region), 1:1 randomization, and balanced demographic and disease characteristics between the two arms, comparisons between the ribociclib + ET and ET only groups allow for valid assessment of safety in this population. This population is also considered appropriate for the detection and characterization of AEs and to provide guidance on toxicity management [CO Study O12301C-Section 5.1.1]. The FDA’s Assessment: FDA agrees with the Applicant’s characterization of the safety population. The stratification criteria are appropriate for the population studied. The population enrolled includes sufficient numbers of patients with Stage II (approximately 40%) and III (approximately 60%) breast cancer to support the proposed indication. Baseline characteristics were well-balanced. Overall, the NATALEE participants, of whom 88% had N1-N3 disease, <10% had grade 1 disease, and 87% received (neo)adjuvant chemotherapy, represent a markedly higher risk subset of the broader US population of patients with HR+, HER2-negative early breast cancer; therefore, the efficacy and safety results of this study should not be extrapolated to a lower-risk population of patients. Black or African-American patients, who are more likely to be diagnosed with high-risk early breast cancer than patients of other races, and more likely to experience recurrence or death after a diagnosis of early breast cancer, are extremely under-represented in the NATALEE trial. A postmarketing commitment (PMC) to provide data from ongoing/planned clinical trials or other data sources to better characterize the efficacy and safety of ribociclib in racial minority subgroups, including Black or African-American patients, is planned as discussed in Section 13. 8.2.1 Safety Review Approach The Applicant’s Position: The key safety data include results for the 4967 patients with eBC in the Safety set of Study O12301C who received study treatment based on the final iDFS analysis (DCO of 21-Jul-2023). The final iDFS analysis was conducted after 40.3 months of median study follow-up, when 96 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. patients were treated for a median duration of 36 months in both arms, with an additional 6.3 months of study follow-up from the primary analysis. Additionally, long-term safety has already been established for the ribociclib 600 mg starting dose in the aBC setting for a pool of 1065 patients from Studies LEE011A2301, LEE011E2301 (excluding patients treated with tamoxifen), and LEE011F2301 based on a total exposure of 2262 patient-years. These pooled safety data provide further context for the safety of ribociclib at 400 mg in patients with eBC. Novartis considers the body of evidence based on Study O12301C as substantial to assess the ribociclib safety profile in patients with HR-positive, HER2-negative, eBC in the context of the known and established safety profile at 600 mg in the aBC setting (pooled aBC dataset = 1,065 patients exposed to ribociclib with an estimated exposure of 2081 patient-years [Study A2301 SCS Add.-Table 1-8]). The known important identified risks with ribociclib remain as: Myelosuppression, Hepatobiliary toxicity, QT interval prolongation, and Reproductive toxicity. One important potential risk with ribociclib is Renal toxicity. These are discussed in detail in [CO Study O12301C-Section 5.3] [SCS Add. Study O12301C-Section 2.6] and [SCS Study O12301C-Section 2.6]. The FDA’s Assessment: The size of the safety population from the NATALEE trial (N=4967) is appropriate for a trial conducted in the adjuvant setting. The safety data from the NATALEE trial, especially within the context of a well-characterized AE profile from multiple prior studies of ribociclib + ET in the metastatic setting and 7.5 years of postmarketing experience, is adequate for benefit-risk assessment of ribociclib in a curative intent population. FDA generally agrees with the Applicant’s assessment of the most important adverse events of special interest (AESI) as discussed later in the review with one addition. The risk of both SARS-CoV-2 infection and deaths attributed to COVID-19/COVID-19 pneumonia was increased in patients who received ribociclib + ET. This is discussed in further detail in Section 8.2.4. 8.2.2 Review of the Safety Database Overall Exposure Data: Table 21: Duration of exposure to study treatment by group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Adherence Ribociclib + ET N=2525 n (%) ET only N=2442 n (%) Duration of exposure 0 to < 3 months 122 (4.8) 167 (6.8) 3 to < 6 months 84 (3.3) 79 (3.2) 6 to < 9 months 58 (2.3) 50 (2.0) 9 to < 12 months 48 (1.9) 54 (2.2) 12 to < 15 months 40 (1.6) 45 (1.8) 97 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Adherence Ribociclib + ET N=2525 n (%) ET only N=2442 n (%) 15 to < 18 months 33 (1.3) 44 (1.8) 18 to < 21 months 45 (1.8) 56 (2.3) 21 to < 24 months 33 (1.3) 35 (1.4) 24 to < 27 months 25 (1.0) 28 (1.1) 27 to < 30 months 285 (11.3) 259 (10.6) 30 to < 33 months 124 (4.9) 126 (5.2) 33 to < 36 months 341 (13.5) 290 (11.9) ≥ 36 months 1287 (51.0) 1209 (49.5) Duration of exposure (mo) Mean 32.8 31.9 SD 12.83 13.66 Minimum 0 0 Median 36.2 35.9 Maximum 54 54 Patient years 6904.3 6487.3 Source: [SCS Add. Study O12301C Table 1-2] The Applicant’s Position: The duration and extent of study treatment exposure was considered adequate to assess the ribociclib safety profile in this patient population with HR-positive, HER2-negative, eBC. At the final iDFS analysis, the median duration of exposure was 36.2 months (range: 0 to 54) for ribociclib + ET treatment vs. 35.9 months (0 to 54) for ET only treatment. A total of 1228 patients (48.6%) had 33 months or longer of ribociclib exposure. A total of 1628 patients (64.5%) had 33 months or longer of study treatment exposure in the ribociclib + ET group, which includes the last dosing visit of the 3-year ribociclib regimen. The total exposure to study treatment was 6904.3 patient-years for the ribociclib + ET treatment group (N=2525) and 6487.3 patient-years for the ET only treatment group (N=2442). Importantly, the difference since IA3 was +1018.4 patient-years in the ribociclib + ET group. By each drug component, ribociclib exposure was 5352.1 patient-years (N=2525); NSAI exposure was 6879.1 patient-years in the ribociclib + ET group vs. 6467.5 patient-years in the ET only group (N=4967). The median relative dose intensity (RDI) for ribociclib was 94.0% (range: 14 to 132), and the median RDI for NSAI in both the ribociclib + ET and ET only groups was 100%, indicating the addition of ribociclib continued to not affect the tolerability of NSAI/ET. Generally, ribociclib dose reduction/interruption occurred early during study treatment administration. Dose adjustments (interruptions and reductions) of ribociclib were allowed for safety concerns per guidelines presented in the study protocol. Dose reductions of ribociclib occurred in 26.7% of patients and were primary attributable to AEs (22.8%). Dose interruptions of ribociclib occurred in 86.1% of patients and were also primarily attributable to AEs (66.2%). Dose interruptions for NSAI/AI occurred in 44.5% of patients in the ribociclib + ET arm, and in 98 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 35.7% of patients in the ET only arm. Overall, the primary reasons for dose adjustments were AEs. Discontinuation of ribociclib (reported for 78.3% of patients) was primarily due to completion of ribociclib treatment (42.8%), followed by AE (19.5%). Generally, ribociclib discontinuation due to AEs also occurred early during study treatment administration [SCS Add. Study O12301C- Section 1.2.1]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. As of the July 21, 2023 data cut-off, 82% of participants had completed >24 months of ribociclib + ET and approximately half had completed a full 36 months of treatment. The dose of ribociclib used in the NATALEE trial (400 mg daily) is lower than the dose in the metastatic setting (600 mg daily), and ribociclib was better tolerated in the adjuvant setting than in prior metastatic trials. In spite of a lower starting dose, dose modification of ribociclib, however, remained common. In total, 86% had treatment interruption, mostly for adverse reactions, more than one-quarter of participants required ribociclib dose reduction, and one in five patients discontinued due to an AE. On trial, discontinuations due to AE occurred in the first few months of treatment, and many of these were based upon laboratory abnormalities. Outside of a clinical trial, these early adverse reactions and need for one or more treatment interruptions may result in decreased patient adherence to ribociclib given that the treatment is self-administered to patients with no evidence of disease. The adverse reactions of ribociclib and ET are largely non-overlapping, and thus despite the increased toxicity resulting from addition of CDK 4/6 inhibitor to endocrine therapy, interruptions of endocrine therapy were only 9% more common in the ribociclib + ET arm, indicating that addition of ribociclib did not significantly compromise ability to deliver the known effective adjuvant endocrine therapy. AI-induced musculoskeletal symptoms (AIIMS) are among the most common tolerability issues that result in interruption or discontinuation of AIs in clinical practice. Based on FDA’s analysis of musculoskeletal pain as a grouped term, these AEs occurred in 56% (1.5% grade 3) of those on ribociclib + ET versus 58% (1.8% grade 3) on ET only, and therefore were not increased with the addition of ribociclib to AI. Relevant characteristics of the safety population: Data: Table 22: Overview of clinical studies with safety data Key feature Study O12301C Controlled study Yes Phase III Study design // endpoints Open-label, multicenter, randomized, active-controlled vs. standard-of-care // Efficacy, PK, safety, tolerability, exploratory. Population Salient demographic data 99 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Key feature Study O12301C North America/Western Europe/Oceania1 region=3032 patients Premenopausal women and men=2193 patients (based on eCRF stratum) Yes, had prior chemotherapy=4309 patients (based on eCRF stratum) Age: median=52.0 y (range: 24 to 90); ECOG PS score 0=83.1% Salient diagnostic data AJCC Stage II (40.3%) or Stage III (59.5%) Predominant histology: invasive ductal carcinoma NOS=73.0%. Prior mastectomy=65.7%. At diagnosis: G1=9.0%, G2=57.3%, G3=20.7%; N0=28.1%, N1=41.0%, N2=12.3%, N3=6.2%; Ki67 at diagnosis: median score=20.0; categories: ≤ 14%=20.0%, > 20%=36.8%. Surgical specimen: G1=8.4%, G2=56.8%, G3=27.0%; N0=15.7%, N1=41.3%, N2=27.8%, N3=15.0%; Ki67 of surgical specimen: median score=15.0; categories: ≤ 14%=22.0%, > 20%=18.1%. Treatment duration (fixed-term as adjuvant treatment) Ribociclib (36 mo) plus ET (at least 60 mo) ET only: at least 60 mo No. of patients (N) treated No. (n) by treatment combination 4968 Ribociclib (400 mg) plus ET: 2524 (female=2514; male=10, 0.4%) ET only: 2444 (female=2435; male=9, 0.4%) Relevant entry criteria (key only) Age, sex Disease/stage ≥ 18 years: females with known menopausal status; males HR-positive, HER2-negative, Stage II or Stage III eBC, irrespective of nodal status Inclusion criteria May have received any standard neoadjuvant and/or adjuvant ET upon ICF signing: randomization should have occurred within 12 mo of initial start date of ET. Of note: ovarian suppression or short-term ET (fertility preservation) was not considered neoadjuvant/adjuvant ET. If tamoxifen or toremifene received: washout as 5 half-lives (35 d) prior to randomization. By centralized 12-lead ECG: Screening QTcF < 450 ms; resting heart rate ≥ 50 to ≤ 90 bpm. Exclusion criteria Clinically significant, uncontrolled HD, and/or cardiac repolarization abnormality, included: history of documented MI, angina pectoris, symptomatic pericarditis, coronary artery bypass graft within 6 mo of study entry; documented cardiomyopathy; LVEF < 50% (by optional MUGA or ECHO); long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome; clinically significant cardiac arrhythmia, complete left bundle branch block, high-grade AV block; or uncontrolled arterial HTN with systolic BP > 160 mm Hg. Status // milestone Ongoing // First-patient-first-visit (FPFV): 07-Dec-2018; DCO: 11-Jan-2023 At enrollment, population was controlled to ~40% Stage II. 1Only patients from Australia were enrolled within the Oceania geographical region. Source: [SCS Study O12301C Table 1-2] The FDA’s Assessment: Only 16% of the NATALEE study population was enrolled from the United States. Therefore, it is important to assess whether the results of the trial can be generalized to a U.S. population. The median age of 52 with a range of 24 to 90 is representative of the demographics of HR+, HER2-negative breast cancer in the U.S. The patient population includes robust representation of patients with stage II (~40%) and stage III (~60%) disease, as well as a range of menopausal status; however, as noted earlier in the review, the NATALEE population was much higher risk than the broader US population with HR+, HER2-negative early breast cancer as 87% of participants had received (neo)adjuvant chemotherapy and only 12% had N0 disease. There were only 19 male patients enrolled in NATALEE, which is a limitation for the assessment of efficacy and safety/tolerability by sex, but their inclusion is important given 100 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. the rarity of the condition and the presently inadequate access to investigational agents and limited evidence base for male breast cancer. Despite typically having a higher stage at presentation and a greater risk of recurrence or death after early breast cancer in the U.S. population, Black or African-American patients are significantly under-represented in NATALEE. Only 1.7% of participants (n=86, of whom 41 were randomized to receive ribociclib + ET) were Black or African-American. As a result, the NATALEE trial contains only 118 patient-years of experience with ribociclib + ET in Black patients with early breast cancer compared to 5116 patient-years of experience with the combination in white patients. Sixty percent of participants had tumors that were stage III, 88% were N1-N3, 87% had received (neo)adjuvant chemotherapy, and very few were grade 1, which reflects a substantially higher risk population than most patients in the U.S. with HR+, HER2- negative early breast cancers. The benefit-risk assessment of adjuvant ribociclib based on the NATALEE trial should therefore not be extrapolated to a more typical lower-risk US population of patients with early-stage HR+, HER2-negative breast cancer. As noted in Table 22 above, patients with a variety of cardiac conditions were excluded from NATALEE. These conditions are not rare in the U.S., especially in the older adults who represent the majority of patients with HR+, HER2-negative breast cancer. Clinicians should counsel patients with pre-existing cardiac conditions regarding the limitations of the NATALEE safety data and consider whether treatment with ribociclib is appropriate and whether more routine monitoring of ECGs beyond 4 weeks is warranted. In addition, the majority of patients in NATALEE (83%) were ECOG performance status 0, and 17% were ECOG 1. Patients with ECOG ≥2 were excluded from the trial. The safety of ribociclib in the adjuvant setting for patients with poorer performance status or other comorbid conditions may differ. Adequacy of the safety database: The Applicant’s Position: Novartis considers the body of evidence based on Study O12301C as substantial to assess the ribociclib safety profile in patients with HR-positive, HER2-negative, eBC in the context of the known and established safety profile at 600 mg in the aBC setting (pooled aBC dataset = 1065 patients exposed to ribociclib with an estimated exposure of 2081 patient-years) [Study A2301 SCS Add.-Table 1-8]. The key safety data in support of this application are from the primary and final analysis of Study O12301C. In this large study (N=5101, FAS; N=4968; Safety set), ribociclib 400 mg in combination with standard adjuvant ET (AI; anastrozole or letrozole) is compared with standard of care adjuvant ET alone. The population enrolled in this study reflects the target population of adult patients (including pre- and postmenopausal women plus men) with HR-positive, HER2- negative, Stage II or Stage III eBC who are at risk of recurrence. Based on the Safety set, this study population consists of patients with anatomic Stage II (40.3%) or Stage III (59.4%) disease as per AJCC staging (eighth ed.) who had completed surgery, followed by chemotherapy, and/or radiotherapy with curative intent [CO Study O12301-Sections 5.1.1 and 5.1.2]. 101 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. As of the 21-Jul-2023 cut-off date, 1091 patients (42.8%) in the ribociclib + ET group have completed the 3-year ribociclib treatment duration per protocol, with 69.4% having completed at least 2 years of ribociclib treatment, based on all patients randomized to the ribociclib + ET group (FAS). The safety follow-up in Study O12301C in terms of patient-years of exposure was 6904.3 patient-years for the ribociclib + ET group vs. 6487.3 patient-years for the ET only group, or an additional 1018.4 patient-years since IA3 [SCS Add. Study O12301C-Section 1.2.1]. These data show that the level of safety follow-up completed in the study thus far is adequate to detect any signals that are related to the safety profile of ribociclib, including those that are not dose-dependent and/or rare events, and is unlikely to change substantially with longer follow-up [CO Study O12301-Section 6.3.1.1]. The FDA’s Assessment: FDA agrees that the NATALEE trial is adequate to characterize the benefits and risks of ribociclib to endocrine therapy in adults with high-risk stage II and III HR+, HER2- negative breast cancer, but notes that the majority of stage II disease was based upon tumor size as only 12% of participants had N0 disease. The size of the safety population is typical for an adjuvant breast cancer trial; however, the sample size may not be adequate to detect rare adverse events in the adjuvant setting. The majority of known adverse reactions related to ribociclib occurred on active treatment and resolved with treatment discontinuation, and therefore the duration of follow-up, which includes the full treatment period in the majority of patients as of the 90-day safety update, is acceptable to characterize adverse reactions with the following caveat. Given that patients with HR+, HER2-negative early breast cancer are being treated with curative intent, with a life expectancy measured in years to decades, the limited period of follow-up is not informative about the risk of late post-treatment adverse events, including secondary malignancy. 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments Issues Regarding Data Integrity and Submission Quality The Applicant’s Position: No meaningful concerns are anticipated in the quality and integrity of the submitted datasets and individual case narratives; these were sufficiently complete to allow for a thorough review of safety. Furthermore, no data integrity concerns were reported following completion of site inspections; data in the CRFs and adverse event databases were consistent. The FDA’s Assessment: FDA agrees with the Applicant’s assessment. An audit of randomly selected case report forms by the clinical safety reviewer did not identify any data integrity concerns. FDA inspected three U.S. and two foreign clinical trial sites for NATALEE. Per the inspectors, the NATALEE trial appears to have been conducted adequately, and the data generated by the clinical investigator sites appear acceptable in support of this sNDA. The overall assessment was that no action was indicated. Results of the inspections are discussed in further detail above in Section 4.1. Full details are available in the FDA OSI review. 102 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Categorization of Adverse Event The Applicant’s Position: The safety evaluations were conducted on the overall Safety set (N=4968) for Study O12301C. The safety of ribociclib in combination with ET (plus goserelin in premenopausal women plus men), was evaluated on the basis of the following: • Frequency, type, severity, and causal relationship of AEs to study treatment: AEs were graded according to the CTCAE v4.03 for all studies used in this safety assessment. • Frequency of deaths, serious adverse events (SAEs), and other clinically significant AEs (including AEs leading to discontinuation and AEs requiring dose interruption and/or reduction) • Frequency and type of AEs in key demographic subgroups (including sex, race, menopausal status at baseline, age group (< 65 years vs. ≥ 65 years) at baseline) and by Baseline disease characteristics • Changes in laboratory variables, with particular attention to grade 3/4 laboratory abnormalities • Electrocardiogram (ECG) changes Based on its clinical relevance, the on-treatment period was redefined taking the 36-month treatment period for ribociclib into account, to include a maximum of 36 months plus 30 days in either study group. Adverse events were coded using MedDRA version 25.1 [Study O12301C Primary Analysis CSR], [SCS Study O12301C] and MedDRA version 26.0 [Study O12301C EA&SU], [SCS Add. Study O12301C]. The FDA’s Assessment: FDA agrees with Applicant’s description of AE categorization and the clinical relevance of the approach to analysis of ribociclib safety in the adjuvant setting. The definition of the on-treatment death period of 36 months of investigational product (IP) administration plus 30 days after last dose of treatment is appropriate given the study drug half-life of <2 days. Routine Clinical Tests The Applicant’s Position: Safety assessments included the regular monitoring of hematology, blood biochemistry, and coagulation (at Screening) performed at local laboratories. Laboratory data summaries included all assessments available from samples collected no later than 30 days after the last study treatment administration date. Laboratory values converted to the International System of Units (SI) were analyzed using the CTCAE grading, and notable abnormal values were summarized for both hematology and blood biochemistry. The calculation of CTCAE grades was based on observed laboratory values only: clinical assessments were not considered. The severity grade of 0 was assigned for all non- missing values if a value was within normal laboratory limits for that parameter; grade 5 was not used. For laboratory tests where grades were not defined by CTCAE, results were categorized as 103 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. a low/normal/high classification(s) based on the normal laboratory range. The grading and criteria to define all laboratory toxicity grades were assigned programmatically by the coding dictionary. Safety assessments included the monitoring of vital signs, including height (Screening only) and weight, body temperature, heart rate, and BP at the site during the in-person visit(s); and 12-lead ECG performed at the local and/or central laboratories. ECG data were read both locally and centrally. The analyses were based on central ECG assessments as all local data were read centrally. Heart rate, QT interval, and QTcF were assessed [SCS Study O12301-Section 1.1.3.6 and 1.1.3.7]. The FDA’s Assessment: FDA agrees with Applicant’s description and approach to analysis of routine clinical tests. 8.2.4 Results Deaths Data: Table 23: On-treatment deaths in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Category Preferred term Ribociclib + ET N=2525 n (%) ET Only N=2442 n (%) No. pts who died on treatment 20 (0.8) 9 (0.4) Primary reason: disease recurrence/progression 9 (0.4) 4 (0.2) Primary reason: adverse event 11 (0.4) 4 (0.2) Primary reason: other 0 1 (< 0.1) Death 0 1 (< 0.1) SAEs with fatal outcome 11 (0.4) 4 (0.2) Brain oedema 1 (< 0.1) 0 COVID-19 3 (0.1) 1 (< 0.1) COVID-19 pneumonia 3 (0.1) 0 Cardiac arrest 1 (< 0.1) 0 Cardiac failure congestive 0 1 (< 0.1) Cardiopulmonary failure 1 (< 0.1) 0 Epilepsy 1 (< 0.1) 0 Ischaemic cardiomyopathy 0 1 (< 0.1) Myocardial infarction 0 1 (< 0.1) Pulmonary embolism 2 (0.1) 0 Respiratory failure 0 1 (< 0.1) Road traffic accident 1 (< 0.1) 0 Sepsis 0 1 (< 0.1) Treatment-related SAEs with fatal outcome 1 (< 0.1) 0 On-treatment deaths are defined as occurring on or after treatment start date and up to 30 days after 36 months of treatment or earlier treatment discontinuation. MedDRA Version 26.0 has been used for reporting. 111 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 357 (14.1) 252 (10.0) 44 (1.7) 11 (0.4) 256 (10.5) 192 (7.9) 26 (1.1) 4 (0.2) COVID-19 20 (0.8) 13 (0.5) 0 3 (0.1) 13 (0.5) 9 (0.4) 0 1 (< 0.1) Pneumonia 14 (0.6) 12 (0.5) 0 0 9 (0.4) 7 (0.3) 0 0 Pulmonary embolism 15 (0.6) 11 (0.4) 1 (< 0.1) 2 (0.1) 5 (0.2) 5 (0.2) 0 0 Dyspnoea 12 (0.5) 9 (0.4) 0 0 5 (0.2) 3 (0.1) 0 0 Alanine aminotransferase increased 9 (0.4) 1 (< 0.1) 7 (0.3) 0 0 0 0 0 Breast cellulitis 9 (0.4) 9 (0.4) 0 0 3 (0.1) 3 (0.1) 0 0 COVID-19 pneumonia 9 (0.4) 5 (0.2) 0 3 (0.1) 5 (0.2) 4 (0.2) 1 (< 0.1) 0 Humerus fracture 8 (0.3) 7 (0.3) 0 0 4 (0.2) 3 (0.1) 0 0 Cellulitis 7 (0.3) 7 (0.3) 0 0 6 (0.2) 6 (0.2) 0 0 Cholelithiasis 7 (0.3) 6 (0.2) 1 (< 0.1) 0 5 (0.2) 5 (0.2) 0 0 Pyrexia 7 (0.3) 2 (0.1) 0 0 1 (< 0.1) 1 (< 0.1) 0 0 Atrial fibrillation 7 (0.3) 5 (0.2) 1 (< 0.1) 0 8 (0.3) 7 (0.3) 0 0 Drug-induced liver injury 6 (0.2) 2 (0.1) 3 (0.1) 0 0 0 0 0 Urinary tract infection 6 (0.2) 6 (0.2) 0 0 3 (0.1) 3 (0.1) 0 0 Aspartate aminotransferase increased 5 (0.2) 2 (0.1) 3 (0.1) 0 0 0 0 0 Diarrhoea 5 (0.2) 3 (0.1) 0 0 0 0 0 0 Hepatotoxicity 5 (0.2) 3 (0.1) 2 (0.1) 0 0 0 0 0 Papillary thyroid cancer 5 (0.2) 5 (0.2) 0 0 2 (0.1) 2 (0.1) 0 0 Postoperative wound infection 5 (0.2) 5 (0.2) 0 0 2 (0.1) 2 (0.1) 0 0 Appendicitis 4 (0.2) 3 (0.1) 1 (< 0.1) 0 2 (0.1) 2 (0. 1) 0 0 Cerebrovascular accident 5 (0.2) 2 (0.1) 0 0 1 (< 0.1) 0 1 (< 0.1) 0 Acute myocardial infarction 4 (0.2) 1 (< 0.1) 3 (0.1) 0 0 0 0 0 Mastitis 4 (0.2) 2 (0.1) 0 0 2 (0.1) 2 (0.1) 0 0 Osteoarthritis 4 (0.2) 4 (0.2) 0 0 4 (0.2) 4 (0.2) 0 0 Pneumonia viral 4 (0.2) 0 0 0 3 (0.1) 1 (< 0.1) 0 0 Suspected COVID-19 4 (0.2) 0 0 0 1 (< 0.1) 0 0 0 Syncope 4 (0.2) 4 (0.2) 0 0 2 (0.1) 2 (0.1) 0 0 112 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Erysipelas 4 (0.2) 2 (0.1) 0 0 3 (0.1) 2 (0.1) 0 0 Source: [SCS Add. Study O12301C-Table 2-8] The Applicant’s Position: Incidence of SAEs was 14.1% in the ribociclib + ET group vs. 10.5% in the ET only group. The most frequently reported SAEs by PT (in at least 10 patients) in the ribociclib + ET group were COVID-19 (0.8%), pneumonia (0.6%), pulmonary embolism (0.6%), and dyspnea (0.5%). COVID-19 (0.5%) was the only SAEs reported in 10 or more patients in the ET only group. Considering the low rates of individual PTs, no pattern in the reported SAEs was identified in either treatment group [CO Study O12301-Section 5.2.2]. The FDA’s Assessment: Detailed narratives and case report forms for NATALEE participants with grade ≥3 SAEs on the ribociclib plus endocrine therapy arm have been reviewed, and the incidence of SAEs has been verified by FDA. FDA generally agrees with the Applicant’s assessment of SAEs. SAEs occurred in 14% of patients on ribociclib + ET compared to 10% on ET only. Most SAEs were grade 3. Grade ≥4 SAEs occurred in 2.1% of participants randomized to receive ribociclib versus 1.3% of the control group. As reflected in the USPI and discussed in further detail in Section 8.2.5.3 under hepatobiliary AESIs, hepatic SAEs (increased AST or ALT, hepatotoxicity, or drug- induced liver injury) were among the most common SAEs and occurred exclusively in patients who received ribociclib. These were also the most common grade 4 SAEs. Given the very high incidence of neutropenia with ribociclib and the prolonged exposure to ribociclib in the adjuvant setting, infections were expected to be among the most common SAEs in NATALEE. As discussed in Section 8.2.5.1 on the neutropenia AESI, the risk of serious infections was low in both arms, but there was a consistent slight increase in infectious SAEs with the addition of ribociclib to endocrine therapy compared to endocrine therapy alone. The majority of these were respiratory or cutaneous. COVID-19 and COVID-19 pneumonia, including fatal cases, were more common in patients on the ribociclib + ET arm. COVID-19 has been discussed in further detail above in Section 8.2.4 on on-treatment deaths. In addition to these confirmed cases of COVID-19 and COVID-19 pneumonia, there were additional SAEs that suggested a small increase in risk of SAEs due to potentially undiagnosed COVID-19 or other respiratory infections, including pneumonia (0.6% vs 0.4%), viral pneumonia (0.2% vs 0.1%), and suspected COVID-19 (0.2% vs <0.1%). The incidence of oral herpes was also noted to be increased (1.5% vs 0.5%). As described above, grade 3/4 lymphopenia was more common in patients receiving ribociclib in combination with ET (19.1% vs 6.3%) and may have contributed to an increased risk of viral infection. 113 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Most of the remaining infectious SAEs were local/cutaneous infections. While rare overall, these local/cutaneous infections including breast cellulitis (0.4% vs 0.1%), mastitis (0.2% vs 0.1%), postoperative wound infection (0.2% versus 0.1%), and erysipelas (0.2% vs 0.1%) were similarly slightly more common in patients who received ribociclib. An FDA analysis of thrombosis overall as a grouped term found an approximate doubling of the incidence of all-grade AEs with ribociclib + ET (1.7%) compared to ET alone (0.9%). Most of these AEs were grade 1-2 in severity, but the incidence of the rare, more severe, AEs related to thrombosis was similarly doubled: 15 patients (0.6%) had a grade ≥ 3 thrombosis AE on the ribociclib + ET arm compared with 8 (0.3%) on ET alone. This includes one patient with grade 4 AE and 2 patients with fatal thrombosis-related AEs on the ribociclib + ET arm compared with none on the ET only arm. Thromboembolic SAEs including pulmonary emboli (0.6% vs 0.2%), myocardial infarction (0.2% vs 0.1%), and cerebrovascular accidents (0.2% vs 0%) were also reported slightly more commonly in the ribociclib + ET only group. Narratives for the two patients with grade 5 AEs, both pulmonary emboli, on the ribociclib + ET arm are discussed in further detail above in Section 8.2.4. These hepatic and thromboembolic SAEs may be observed more commonly in the postmarketing setting as patients who would have been excluded from NATALEE due to comorbid conditions are treated with ribociclib for early breast cancer. Adverse events in these system organ classes will continue to be monitored in the postmarket setting and the ribociclib USPI updated for safety as appropriate. Dropouts and/or Discontinuations Due to Adverse Effects Data: Table 26: Adverse events leading to discontinuation by preferred term and worst toxicity grade, irrespective of causality, with at least 0.2% / either group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 524 (20.8) 201 (8.0) 36 (1.4) 2 (0.1) 134 (5.5) 38 (1.6) 5 (0.2) 3 (0.1) Alanine aminotransferase increased 180 (7.1) 84 (3.3) 19 (0.8) 0 2 (0.1) 1 (< 0.1) 0 0 Aspartate aminotransferase increased 71 (2.8) 28 (1.1) 7 (0.3) 0 0 0 0 0 Arthralgia 37 (1.5) 4 (0.2) 0 0 49 (2.0) 9 (0.4) 0 0 Fatigue 18 (0.7) 3 (0.1) 0 0 1 (< 0.1) 0 0 0 Neutropenia 19 (0.8) 15 (0.6) 2 (0.1) 0 0 0 0 0 114 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Neutrophil count decreased 7 (0.3) 7 (0.3) 0 0 0 0 0 0 Nausea 13 (0.5) 1 (< 0.1) 0 0 1 (< 0.1) 0 0 0 Hepatotoxicity 7 (0.3) 4 (0.2) 2 (0.1) 0 0 0 0 0 Rash 7 (0.3) 2 (0.1) 0 0 2 (0.1) 0 0 0 Asthenia 11 (0.4) 5 (0.2) 0 0 0 0 0 0 Blood magnesium decreased 7 (0.3) 0 0 0 0 0 0 0 Headache 7 (0.3) 1 (< 0.1) 0 0 3 (0.1) 0 0 0 Blood creatinine increased 8 (0.3) 1 (< 0.1) 0 0 0 0 0 0 COVID-19 8 (0.3) 2 (0.1) 2 (0.1) 1 (< 0.1) 1 (< 0.1) 0 1 (< 0.1) 0 Diarrhoea 7 (0.3) 2 (0.1) 0 0 2 (0.1) 0 0 0 Electrocardiogram QT prolonged 7 (0.3) 2 (0.1) 0 0 0 0 0 0 Hypomagnesaemia 6 (0.2) 0 0 0 0 0 0 0 Alopecia 5 (0.2) 0 0 0 0 0 0 0 Pneumonitis 5 (0.2) 0 0 0 0 0 0 0 Pulmonary embolism 4 (0.2) 3 (0.1) 1 (< 0.1) 0 1 (< 0.1) 1 (< 0.1) 0 0 Anxiety 4 (0.2) 1 (< 0.1) 0 0 1 (< 0.1) 0 0 0 Hyperkalaemia 4 (0.2) 1 (< 0.1) 0 0 0 0 0 0 Hypertransaminasaemia 4 (0.2) 1 (< 0.1) 0 0 0 0 0 0 Papillary thyroid cancer 4 (0.2) 4 (0.2) 0 0 0 0 0 0 Gamma-glutamyltransferase increased 3 (0.1) 2 (0.1) 0 0 0 0 0 0 Hypercalcaemia 5 (0.2) 0 0 0 0 0 0 0 Myalgia 2 (0.1) 1 (< 0.1) 0 0 5 (0.2) 2 (0.1) 0 0 Source: [SCS Add. Study O12301C-Table 2-9] The Applicant’s Position: Overall, AEs leading to discontinuation of study treatment were observed at a higher frequency (relative difference between treatment groups) in the ribociclib + ET group (20.8%) vs. the ET only group (5.5%) [SCS Add. Study O12301C-Table 2-9]. The discontinuation rate was relatively low for each individual event, indicating these events were manageable. The median 115 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. relative dose intensity (RDI) for ribociclib was 94.0% (range: 14 to 132), and the median RDI for NSAI in both the ribociclib + ET and ET only groups was 100%, indicating the addition of ribociclib continued to not affect the tolerability of NSAI/ET. The most frequently reported AEs (in ≥ 10 patients) leading to study treatment drug discontinuation in the ribociclib group plus ET group were increased ALT (7.1%), increased AST (2.8%), arthralgia (1.5%), neutropenia (0.8%), fatigue (0.7%), and nausea (0.5%,). The most frequent AE leading to study treatment discontinuation in the ET only group was arthralgia (2.0%). Overall, the proportion of grade-3 and grade-4 AEs leading to discontinuation continued to be higher with ribociclib + ET (8.0% and 1.4%, respectively) vs. ET only (1.6% and 0.2%, respectively). When required, most ribociclib discontinuations occurred early during study treatment, with a median of approximately 4 months [CO Study O12301-Section 5.2.2]. The FDA’s Assessment: FDA has analyzed AEs leading to discontinuation of study drug and generally agrees with the Applicant’s assessment. As discussed earlier, the toxicities of ribociclib and ET are largely non-overlapping, and co-administration of ribociclib with ET had a limited effect on the delivery of standard adjuvant ET. Adverse events leading to treatment discontinuation were increased almost fourfold with the addition of ribociclib to ET (20.8% vs 5.5%). The most common AEs that led to discontinuation in the ribociclib group were increased transaminases, which most commonly occur in the first two to three months of treatment and are a known AESI with ribociclib for which there is an existing warning in the USPI. Hepatotoxicity as an AESI associated with ribociclib is discussed in further detail in Section 8.2.5.3. While neutropenia is also common and tended to occur early in treatment, it was well- managed with treatment interruption or dose reduction, as discussed below, and required ribociclib discontinuation in <1% of patients. As noted in the section above on SAEs, serious infections were uncommon and predominantly respiratory or cutaneous. Neutropenia as an AESI is discussed in further detail in Section 8.2.5.1. The only on-study deaths due to infections in the ribociclib + ET arm were COVID-19 or COVID-19 pneumonia and not associated with treatment-emergent neutropenia. These deaths are reviewed in further detail above in Section 8.2.4. Dose Interruption/Reduction Due to Adverse Effects Data: Table 27: Adverse events leading to study drug interruption by preferred term and worst toxicity grade, irrespective of causality, with incidence at least 2% / either group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred Term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 1858 (73.6) 1226 (48.6) 87 (3.4) 0 199 (8.1) 67 (2.7) 8 (0.3) 0 116 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred Term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Neutropenia 683 (27.0) 637 (25.2) 30 (1.2) 0 1 (< 0.1) 0 1 (< 0.1) 0 Neutrophil count decreased 441 (17.5) 411 (16.3) 17 (0.7) 0 2 (0.1) 1 (< 0.1) 1 (< 0.1) 0 Alanine aminotransferase increased 255 (10.1) 116 (4.6) 16 (0.6) 0 7 (0.3) 2 (0.1) 1 (< 0.1) 0 COVID-19 228 (9.0) 8 (0.3) 2 (0.1) 0 20 (0.8) 3 (0.1) 0 0 Aspartate aminotransferase increased 171 (6.8) 56 (2.2) 8 (0.3) 0 7 (0.3) 4 (0.2) 0 0 Hypomagnesaemia 127 (5.0) 0 1 (< 0.1) 0 0 0 0 0 SARS-CoV-2 test positive 115 (4.6) 0 0 0 8 (0.3) 0 0 0 Leukopenia 81 (3.2) 45 (1.8) 0 0 0 0 0 0 Hyperkalaemia 81 (3.2) 3 (0.1) 0 0 0 0 0 0 Hypocalcaemia 81 (3.2) 1 (< 0.1) 0 0 0 0 0 0 Hypokalaemia 70 (2.8) 4 (0.2) 0 0 0 0 0 0 White blood cell count decreased 70 (2.8) 43 (1.7) 1 (< 0.1) 0 0 0 0 0 Blood magnesium decreased 63 (2.5) 1 (< 0.1) 0 0 0 0 0 0 Pyrexia 73 (2.9) 3 (0.1) 0 0 8 (0.3) 0 0 0 Arthralgia 42 (1.7) 6 (0.2) 0 0 54 (2.2) 15 (0.6) 0 0 Source: [SCS Add. Study O12301C-Table 2-10] Table 28: Adverse events leading to study drug dose reduction by preferred term and worst toxicity grade, irrespective of causality with incidence at least 0.2% / either group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 586 (23.2) 338 (13.4) 36 (1.4) 0 0 0 0 0 Neutropenia 215 (8.5) 157 (6.2) 23 (0.9) 0 0 0 0 0 117 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Neutrophil count decreased 141 (5.6) 114 (4.5) 13 (0.5) 0 0 0 0 0 Alanine aminotransferase increased 49 (1.9) 21 (0.8) 0 0 0 0 0 0 Fatigue 26 (1.0) 4 (0.2) 0 0 0 0 0 0 White blood cell count decreased 26 (1.0) 6 (0.2) 0 0 0 0 0 0 Leukopenia 17 (0.7) 7 (0.3) 0 0 0 0 0 0 Aspartate aminotransferase increased 16 (0.6) 3 (0.1) 0 0 0 0 0 0 Nausea 11 (0.4) 2 (0.1) 0 0 0 0 0 0 Asthenia 10 (0.4) 2 (0.1) 0 0 0 0 0 0 Alopecia 6 (0.2) 0 0 0 0 0 0 0 Rash 6 (0.2) 1 (< 0.1) 0 0 0 0 0 0 Gamma-glutamyltransferase increased 5 (0.2) 2 (0.1) 0 0 0 0 0 0 Stomatitis 4 (0.2) 0 0 0 0 0 0 0 Diarrhoea 4 (0.2) 2 (0.1) 0 0 0 0 0 0 Headache 4 (0.2) 3 (0.1) 0 0 0 0 0 0 Arthralgia 4 (0.2) 0 0 0 0 0 0 0 Source: [SCS Add. Study O12301C Table 2-11] The Applicant’s Position: AEs leading to study treatment interruption were observed more frequently in the ribociclib + ET group compared to the ET only group (73.6% vs 8.1%, respectively). Despite the higher frequency of AEs leading to dose interruptions in the ribociclib + ET group, the discontinuation rate was relatively low for each individual event, indicating these events were manageable. In addition, the median RDI of ribociclib was 94.0%, and importantly there was no impact on the ET dose maintenance, which is supported by RDI of 100% for ET in both treatment arms. The most frequent AEs (overall: ≥ 10%) leading to interruption with ribociclib + ET were neutropenia (all grades: 27.0% vs. < 0.1%), followed by neutrophil count decreased (17.5% vs. 0.1%) and increased ALT (10.1% vs. 0.3%) [SCS Add. Study O12301C-Table 2-10]. All remaining AEs leading to study drug interruption were < 10%. The most frequent grade 3/4 AEs leading to study drug interruption in the ribociclib + ET group were also neutropenia and neutrophil count decreased [SCS Add. Study O12301C-Table 2-1 0]. The most frequently reported AEs (with incidences ≥ 2%) that required dose reduction in the ribociclib + ET group were neutropenia (8.5%) and neutrophil count decreased (5.6%). The most frequently reported grade 3 and grade 4 AEs that required ribociclib dose reduction were 118 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. neutropenia (grade 3: 6.2%; grade 4: 0.9%) and neutrophil count decreased (grade 3: 4.5%; grade 4: 0.5%) [SCS Add. Study O12301C-Table 2-11]. Neutropenia AEs (PT) leading to dose interruption were frequent in the ribociclib + ET group (27.0%), but the corresponding frequency of neutropenia AEs (PT) leading to discontinuation was only 0.8%. Importantly, the majority of AEs were effectively resolved with ribociclib dose interruptions and/or reductions [CO Study O12301C-Section 5.2.2]. The FDA’s Assessment: FDA has analyzed AEs leading to study drug interruption and dose reductions and generally agrees with the Applicant’s assessment. Approximately three-quarters of patients on the ribociclib + ET arm required temporary treatment interruption due to an adverse event, most of which were abnormal laboratory values. This is markedly increased over the ET only arm where only 8% of patients required treatment interruption. Combining laboratory abnormalities of neutrophil counts decreased and reported AEs of neutropenia, neutropenia accounted for the majority of ribociclib interruptions/dose reductions. Neutropenia tended to occur in the first few cycles of treatment and was effectively managed for most patients via interruption. About one in seven participants on ribociclib required a dose reduction to 200 mg/day due to grade 3/4 neutropenia. Both permanent discontinuation due to neutropenia (<1%) and clinical complications of neutropenia were rare and are discussed in further detail below. As noted above, while both infections of all grades, as well as SAEs related to infections, were more common in participants receiving ribociclib + ET, infections other than SARS-CoV-2 occurred rarely overall in NATALEE. In addition to myelosuppression, the other common causes of study drug interruption were also mostly laboratory-related: elevated ALT or AST, SARS-CoV2 test positive or COVID- 19, and electrolyte abnormalities (increased or decreased potassium, calcium, or magnesium). A small number of patients also had treatment interruption due to fatigue, arthralgia, and pyrexia. Ribociclib dose reductions were required in almost 1 in 4 participants on the ribociclib + ET arm and occurred for similar reasons to treatment interruption. More than half of the dose reductions were due to neutropenia/neutrophil count decreased. Other than myelosuppression, the next most common reason for dose reductions was abnormal liver function tests (ALT, AST, or GGT), which resulted in ribociclib discontinuation in approximately 3% of patients. The remaining causes of dose reduction occurred in ≤1% of patients on the ribociclib + ET arm with constitutional symptoms (fatigue, asthenia) and GI symptoms (stomatitis, nausea, and diarrhea) being most common. Significant Adverse Events The Applicant’s Position: The significant AEs reported are described in other sections of this document, “Serious Adverse Events” and “Treatment Emergent Adverse events and Adverse Reactions”. The FDA’s Assessment: 119 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. FDA generally agrees with the Applicant’s assessment with the addition of the concern regarding an increased incidence of severe/fatal COVID-19 and COVID-19 pneumonia. This appears to have been mitigated later in the trial with availability of COVID-19 vaccination and therapeutics, as well as likely immunity related to prior infections. This risk is discussed in further detail earlier in Section 8.2.4 in the section about on-treatment deaths. Treatment Emergent Adverse Events and Adverse Reactions Data: Table 29: Common adverse events with grade ≥ 3 events at incidence ≥ 1.0% in either group, by preferred term in Study O12301C (Safety set) Final iDFS Analysis (21-Jul-2023 data cut-off) AE Ribociclib + ET only N=2525 N=2442 Ribociclib + ET only N=2525 N=2442 All grades n (%) All grades n (%) Grade ≥ 3 n (%) Grade ≥ 3 n (%) Total no. patients with at least 1 TEAE 2474 (98.0) 2145 (87.8) 1607 (63.6) 469 (19.2) Neutropenia 1047 (41.5) 73 (3.0) 707 (28.0) 14 (0.6) Neutrophil count decreased 609 (24.1) 41 (1.7) 448 (17.7) 8 (0.3) Alanine aminotransferase increased 492 (19.5) 136 (5.6) 192 (7.6) 17 (0.7) Aspartate aminotransferase increased 426 (16.9) 139 (5.7) 118 (4.7) 13 (0.5) White blood cell count decreased 246 (9.7) 38 (1.6) 94 (3.7) 6 (0.2) Leukopenia 337 (13.3) 50 (2.0) 94 (3.7) 2 (0.1) Hypertension 212 (8.4) 185 (7.6) 54 (2.1) 59 (2.4) Gamma-glutamyltransferase increased 119 (4.7) 67 (2.7) 26 (1.0) 22 (0.9) Lipase increased 58 (2.3) 33 (1.4) 25 (1.0) 12 (0.5) Arthralgia 942 (37.3) 1058 (43.3) 25 (1.0) 31 (1.3) Grade ≥ 3 AEs are sorted by decreasing order of frequency in the ribociclib + ET column. Source: [CO Study O12301C-Table 5-1] The Applicant’s Position: Most frequent AEs by Preferred term Overall, AEs were observed at a higher frequency (relative difference between treatment groups) in the ribociclib + ET group vs. ET only group of +10.2%. AEs observed at a higher frequency (with a ≥ 10% relative difference between treatment groups in overall decreasing order of frequency with ribociclib + ET) included: neutropenia (+38.5%), decreased neutrophil count (+22.4%), nausea (+15.5%), increased ALT (+13.9%), leukopenia (+11.3%), alopecia (+10.5%), and increased AST (+11.2%). In the ET only group, no PT met this criterion. Arthralgia was reported in a greater proportion (6% relative difference) of ET only-treated patients, compared with ribociclib + ET-treated patients [SCS Add. Study O12301C-Section 2.2.2]. Severity of AEs The majority of the most frequent (≥ 1.0%/either group) grade ≥ 3 AEs were consistent with the known safety profile of ribociclib, predominantly pertaining to the known risk of myelosuppression, occurring usually within the first few cycles of therapy, and the incidence did 120 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. not increase over time. The clinical impact of grade ≥ 3 TEAEs on patients in the ribociclib + ET group was limited, as the majority of events were asymptomatic laboratory abnormalities and completely resolved with appropriate management as per protocol [CO Study O12301C CO- Section 5.2.1.2] Adverse drug reactions The screening, methodology, and selection process used to identify ADRs for the target population are described in [SCS Study O12301C-Section 1.1.3.5] and [SCS Study O12301C- Appendix 2]. No new ADRs were identified based on the Novartis comprehensive medical evaluation of data from Study O12301C. In addition, the ribociclib ADR profile in patients with HR-positive, HER2-negative eBC is compared favorably with the established safety profile of Kisqali in patients with aBC [SCS Study O12301C-Section 2.9], (Kisqali USPI 2022, Kisqali SmPC 2023). This is due to a considerable number of pre-existing ADRs that did not qualify as ADRs in the eBC setting and several pre-existing ADRs that were downgraded in their frequency category for this patient population. For further details, see [SCS Study O12301C-Section 2.9]. These data are considered robust based on the adequate overall sample size of Study O12301C (N=4968; Safety set) and study design, including the control arm [CO Study O12301-Section 5.5]. No new ADRs or changes in the frequency categories of ADRs identified based on the primary analysis were identified in the target population based on the Novartis comprehensive medical evaluation of data from Study O12301C for the final iDFS analysis. The FDA’s Assessment: FDA’s analysis of common and grade 3/4 AEs generally agrees with the Applicant’s analysis/assessment except regarding COVID-19. As SARS-CoV-2 did not yet exist at the time the ribociclib trials were conducted in the metastatic setting, COVID-19 represents a new ADR. The incidence of SARS-CoV-2 infection and COVID-19 illness, including severe or fatal cases, was increased in patients who received ribociclib, as discussed above in Section 8.2.4. Addition of a Warning and Precaution related to COVID-19 was discussed by the review team, but given that the risk of severe illness appears to have diminished over the course of the trial, likely due to the availability of vaccines and COVID-19 therapeutics, as well as immunity related to prior infection, it was not added. If an increase in severe or fatal COVID-19 is observed in the postmarket setting, the USPI will be updated accordingly. As discussed above and in Section 8.2.5, the most common overall and grade ≥3 treatment- emergent AEs were laboratory findings, in particular myelosuppression and liver function abnormalities, most of which were asymptomatic. Laboratory Findings Data: Table 30: New or worsening postbaseline hematology and clinical chemistry abnormalities, with incidence at least 10% / either group in Study O12301C (Safety set) 121 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Safety endpoint (hyper / hypo grade) Ribociclib + ET N=2525 ET only N=2442 Grade 1/2 Grade 3 Grade 4 Grade 1/2 Grade 3 Grade 4 n (%) n (%) n (%) n (%) n (%) n (%) Hematology abnormalities Hemoglobin (hypo) 1178 (46.7) 14 (0.6) 0 619 (25.3) 8 (0.3) 0 Leukocytes (hypo) 1714 (67.9) 688 (27.2) 5 (0.2) 1089 (44.6) 12 (0.5) 2 (0.1) Lymphocytes (hypo) 1980 (78.4) 413 (16.4) 67 (2.7) 1998 (81.8) 98 (4.0) 55 (2.3) Neutrophils (hypo) 1225 (48.5) 1083 (42.9) 55 (2.2) 818 (33.5) 35 (1.4) 6 (0.2) Platelets (hypo) 705 (27.9) 9 (0.4) 1 (< 0.1) 312 (12.8) 7 (0.3) 1 (< 0.1) Clinical chemistry abnormalities ALT (hyper) 926 (36.7) 167 (6.6) 38 (1.5) 837 (34.3) 24 (1.0) 1 (< 0.1) ALP (hyper) 884 (35.0) 5 (0.2) 0 884 (36.2) 5 (0.2) 0 Amylase (hyper) 363 (14.4) 24 (1.0) 8 (0.3) 328 (13.4) 29 (1.2) 4 (0.2) AST (hyper) 978 (38.7) 113 (4.5) 20 (0.8) 780 (31.9) 26 (1.1) 0 Calcium corrected (hyper) 247 (9.8) 5 (0.2) 3 (0.1) 356 (14.6) 9 (0.4) 6 (0.2) Calcium corrected (hypo) 517 (20.5) 6 (0.2) 16 (0.6) 386 (15.8) 9 (0.4) 29 (1.2) Creatinine (hyper) 815 (32.3) 7 (0.3) 0 278 (11.4) 0 0 Direct bilirubin (hyper) 456 (18.1) 26 (1.0) 8 (0.3) 426 (17.4) 14 (0.6) 1 (< 0.1) GGT (hyper) 865 (34.3) 90 (3.6) 8 (0.3) 760 (31.1) 83 (3.4) 6 (0.2) Glucose (hyper) 1478 (58.5) 48 (1.9) 12 (0.5) 1396 (57.2) 36 (1.5) 12 (0.5) Lipase (hyper) 407 (16.1) 67 (2.7) 12 (0.5) 400 (16.4) 69 (2.8) 9 (0.4) Magnesium (hypo) 379 (15.0) 4 (0.2) 3 (0.1) 371 (15.2) 0 1 (< 0.1) Potassium (hyper) 355 (14.1) 16 (0.6) 1 (< 0.1) 378 (15.5) 15 (0.6) 4 (0.2) Potassium (hypo) 261 (10.3) 16 (0.6) 7 (0.3) 208 (8.5) 22 (0.9) 14 (0.6) Sodium (hyper) 276 (10.9) 3 (0.1) 1 (< 0.1) 291 (11.9) 2 (0.1) 0 Sodium (hypo) 270 (10.7) 26 (1.0) 6 (0.2) 230 (9.4) 17 (0.7) 7 (0.3) Urate (hyper) 771 (30.5) 0 38 (1.5) 701 (28.7) 0 43 (1.8) Source: [SCS Add. Study O12301C-Table 3-1 and 3-2] The Applicant’s Position: Most hematology abnormalities were of low-grade, with the exception of neutrophil counts. The most common worst-post-baseline grade 1 / 2 hematological abnormalities in the ribociclib + ET group (≥ 10.0% difference relative to ET only group) were: decreased leukocytes (+23.3%), decreased hemoglobin (+21.3%), decreased platelets (+15.1%), and decreased neutrophils (+15.0%). Grade 3 hematological abnormalities in the ribociclib + ET group (≥ 10.0% difference relative to ET only group) were: decreased neutrophils (+41.5%), decreased leukocytes (+26.8%), and decreased lymphocytes (+12.4%). The highest number of patients (in both treatment groups) with grade-4 hematological abnormalities were decreased lymphocytes (2.7% of ribociclib + ET patients and 2.3% of ET only patients) [Study O12301C EA&SU-Section 4.4.1]. Most clinical chemistry abnormalities were of low-grade. Grade 1 / 2 increased creatinine (+20.9%) were the only clinical chemistry parameter reported in a higher proportion of patients (difference ≥ 10%) who received ribociclib + ET, compared with patients who received ET only. The frequency of remaining post-baseline biochemical abnormalities was similar by group. 122 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. There were no grade 3 clinical chemistry abnormalities in ribociclib + ET group with a ≥ 10% difference relative to ET only group. The most common grade 4 clinical chemistry abnormalities (with incidences ≥ 1.0%) reported in ribociclib + ET group were increased ALT (1.5% vs. < 0.1%) and increased urate (1.5% vs. 1.8%) [Study O12301C EA&SU-Section 3.1 and 3.2]. The FDA’s Assessment: FDA has analyzed laboratory abnormalities and generally concurs with the Applicant’s analysis and assessment of clinical chemistry and hematology abnormalities. The most common laboratory abnormalities were related to myelosuppression and abnormal liver function tests. The incidence and severity of neutropenia was markedly increased in patients who received ribociclib. While grade 1-2 neutropenia was reported in half of patients receiving ribociclib + ET compared to a third of patients receiving ET only, the most striking difference was in the incidence of higher grades of neutropenia. In the ribociclib + ET arm, 45% of patients had grade ≥3 neutropenia compared to 2% of those in the ET arm. Neutropenia as an AESI is discussed in further detail in Section 8.2.5.1. Grade 1-2 anemia (47% vs 25%) and thrombocytopenia (28% vs 13%) were approximately twice as common in patients who received ribociclib + ET compared to those who received ET only. Grade ≥ 3 anemia and thrombocytopenia were more common with addition of ribociclib but occurred at <1% incidence in both treatment groups. Transaminases were elevated more often in patients on ribociclib + ET. All-grade increases in ALT (ribociclib + ET 44.8% vs ET only 35.3%) and AST (44% vs 33%), as well as grade ≥3 increases in ALT (8.1% vs 1%) and AST (5.3% vs 1.1%) were more common in patients receiving ribociclib. Liver function abnormalities and hepatotoxicity are discussed in further detail as an AESI in Section 8.2.5.3. Patients who received ribociclib in addition to ET were more likely to have all-grade increased creatinine (32.5% vs 11.4%). While almost all of these were low-grade, grade 3 increased creatinine was also more common with ribociclib (0.3% vs 0%). FDA therefore analyzed acute kidney injury (AKI) as a grouped term (consisting of PT terms: acute kidney injury, GFR decreased, renal failure, renal disorder, renal impairment, oliguria, creatinine renal clearance decreased, and azotemia). While uncommon overall, this analysis found that AKI occurred more often in patients who received ribociclib + ET (2.5% vs 0.9%). As with laboratory abnormalities, most of these AKI group term AEs were grade 1/2. Grade ≥3 AKI AEs occurred in 4 patients (0.2%) of those on ribociclib compared with none of those on ET alone. This will continue to be monitored in the postmarket setting and the USPI Warnings & Precautions updated as appropriate if more severe renal dysfunction becomes apparent with wider use. Electrolyte abnormalities (magnesium, potassium, and calcium, both increased and decreased) were more common in patients who received ribociclib, but most were grade 1/2. Grade 3/4 electrolyte abnormalities occurred in <1% of patients. To further understand this issue, FDA performed an analysis using grouped terms to assess multiple gastrointestinal (GI) AEs. This found an increased risk of all-grade stomatitis (8% vs 123 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 1.3%), nausea (23% vs 8%), vomiting (8% vs 4%), and diarrhea (15% vs 6%). It is likely that most of the observed electrolyte abnormalities are related to poor oral intake and GI losses, though it is possible that the increased incidence of renal dysfunction may also be playing a role. Given the potential for electrolyte abnormalities, whether due to GI toxicity or renal dysfunction, to increase the risk of QT prolongation, which is a known AESI for ribociclib, chemistries should be monitored regularly per the USPI and electrolytes corrected as needed. Vital Signs The Applicant’s Position: No meaningful differences between the treatments groups were observed for vital signs, i.e. systolic or diastolic BP, heart rate, and body temperature. In general, median change from baseline to the lowest postbaseline median value or the highest postbaseline median value was not appreciably different by group for any vital sign [SCS Study O12301-Section 4.1]. The FDA’s Assessment: FDA agrees with the Applicant’s assessment of vital signs. Electrocardiograms (ECGs) The Applicant’s Position: Notable ECG values are discussed in detail in Section 8.2.5.2. Based on ECG, change in heart rate by treatment group was similar by group. Heart rate data were not analyzed from local ECGs. Overall clinical interpretation of centrally assessed ECG results at baseline compared with worse on-treatment did not identify a pattern. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. See detailed discussion of QTcF findings in the following section and as an AESI in Section 8.2.5.2. 124 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Data: Table 31: Clinically notable ECG values by treatment group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off QT parameter Ribociclib + ET N=2525 ET only N=2442 Overall N=4967 n/m (%) n/m (%) n/m (%) QTcF New value > 450 and ≤ 480 ms 240/2477 (9.7) 66/2365 (2.8) 306/4842 (6.3) New value > 480 and ≤ 500 ms 7/2493 (0.3) 4/2378 (0.2) 11/4871 (0.2) New value > 480 ms 10/2493 (0.4) 4/2378 (0.2) 14/4871 (0.3) New value > 500 ms 3/2493 (0.1) 1/2378 (< 0.1) 4/4871 (0.1) Increase from baseline > 30 and ≤ 60 ms 462/2493 (18.5) 167/2378 (7.0) 629/4871 (12.9) Increase from baseline > 60 ms 19/2493 (0.8) 2/2378 (0.1) 21/4871 (0.4) Central assessments only. Patients are counted based on any notable ECG postbaseline value. Baseline is defined as the last assessment on or before start of study treatment. For any replicate/triplicate ECGs per timepoint, the average of these measurements would be calculated for baseline. n=Number of patients who meet the designated criterion. m=Number of patients at risk for a specific category. For new abnormality postbaseline, this is the number of patients with both baseline and postbaseline evaluations, and baseline not meeting the criteria. For abnormal change from baseline, it is the number of patients with both baseline and postbaseline evaluations. N=Total number of patients in the treatment group in this analysis set. Source: [SCS Add. Study O12301C-Table 2-24] The Applicant’s Position: Based on central ECG assessment, clinically notable QTcF value of > 480 ms was infrequent in both groups: in the ribociclib + ET group (10 patients, 0.4%) vs. the ET only group (4 patients, 0.2%), which included 3 patients (0.1%) with a QTcF > 500 ms in the ribociclib + ET group vs. one patient (<0.1%) in the ET only group. An increase of QTcF > 60 ms from baseline was observed in 19 patients (0.8%) in the ribociclib + ET group, and in 2 patients (0.1%) in the ET only group. Of note, overall, increase in QTcF > 60 ms from baseline or QTcF >480 ms did not result in clinically relevant abnormalities and were not associated with cardiac signs or symptoms. These ECG changes were reversible with dose interruption, and the majority occurred within the first 4 weeks of treatment. There were no reported cases of sudden death or Torsades de Pointes [CO Study O12301-Section 5.3.2]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of QT interval prolongation except as noted in the discussion below. FDA’s QT-IRT committee independently confirmed the QT results based upon central assessment provided by the Applicant in Table 31. Adding ribociclib to ET clearly increases QT interval compared to ET only. In total, based upon centrally-assessed ECGs, 481 (19%) of patients in the ribociclib + ET group had an increase in QT interval >30 ms compared with 169 (7%) of patients in the ET only group. Increases in QT interval >60 ms, while increased with the addition of ribociclib, remained uncommon overall, however, reported in 19 (0.8%) of patients on ribociclib + ET 126 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. therefore assess a patient’s individual risk, based upon baseline QT interval, comorbidities, concomitant medications, and other risk factors for QT prolongation, and discuss the limitations of available data to inform shared decision-making on further ECG monitoring in patients at higher risk of developing QT prolongation. QT prolongation as an AESI is discussed is further detail in Section 8.2.5.2. Immunogenicity The Applicant’s Position: Not applicable as this was not assessed nor expected. The FDA’s Assessment: Not applicable. 8.2.5 Analysis of Submission-Specific Safety Issues Study O12301C was properly designed to actively monitor, capture, and adequately characterize the current safety topics of interest with ribociclib in this target population in the adjuvant eBC setting. Analyses of the Safety set from Study O12301C did not reveal any new safety signal. The current safety topics of interest with ribociclib in adults with HR-positive, HER2-negative eBC reveal a predictable and manageable safety profile with a 400 mg starting dose of ribociclib in combination with ET. Three categories of events are discussed here (neutropenia, QT interval prolongation, and hepatobiliary toxicity); these are well characterized clinical issues associated with the use of ribociclib which, in general, can be effectively managed in the clinical setting (with dose interruption and/or dose modification). Analysis results for the remaining AESIs are provided in [SCS Study O12301C-Section 2.6]. 8.2.5.1 Neutropenia The Applicant’s Position: Neutropenia is an important identified risk for ribociclib. This common adverse effect associated with CDK4/6 inhibition is concentration dependent, transient, and reversible. Neutropenia associated with ribociclib therapy can be clinically managed through dose modification and interruption. Neutropenia AESI were among the most common toxicities reported (overall: 62.5% vs. 4.6%). Events were limited to (in decreasing frequency for ribociclib + ET) neutropenia (41.5%), decreased neutrophil count (24.1%), febrile neutropenia (0.3%), and granulocytopenia (0.2%). Events of Neutropenia AESI represented the vast majority of grade ≥ 3 AEs in Study O12301C. These events had limited clinical impact, as the majority of events were asymptomatic laboratory abnormalities and completely resolved with appropriate management as per protocol. In the ribociclib + ET group, Neutropenia AESIs were often severe (grade ≥3: 44.3%) and resulted in dose interruption (43.3%). However, AEs leading to dose adjustment (14.2% vs. 0) 127 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. and specifically AEs leading to discontinuation (1.1% vs. 0) due to neutropenia events were infrequent (ribociclib + ET vs. ET only). Although there was a high incidence of grade ≥ 3 neutropenia AESIs, this did not translate into a clinically significant increase in risk of severe infections in patients treated with ribociclib; grade ≥ 3 infections occurred in 5.5% and 3.2% in the ribociclib + ET and the ET only treatment arms respectively. Febrile neutropenia was limited to 7 patients (0.3%) in the ribociclib + ET group: 4 patients (0.2%) required dose interruption; 2 patients (0.1%) required dose reduction and/or discontinuation of study treatment, and 1 patient (< 0.1%) had an SAE. There were no cases of febrile neutropenia in the ET only group, and there were no fatalities related to neutropenia. Based on neutrophil counts, neutropenia events were generally observed early over the course of treatment with ribociclib and their incidences did not increase over time. Management guidelines for neutropenia remain the same as in the approved label for patients with aBC [CO Study O12301-Section 5.3.1] The FDA’s Assessment: FDA has analyzed neutropenia as an abnormal laboratory value and a grouped term AE (including PT terms neutrophil count decreased and neutropenia) and generally agrees with the Applicant’s assessment. As discussed earlier, taking into consideration both decreased neutrophils on laboratory values as well as reported adverse events of neutropenia of any grade, the majority of patients receiving ribociclib on NATALEE experienced a low neutrophil count. Neutropenia with ribociclib is concentration-dependent, and the incidence of grade ≥3 neutropenia in early breast cancer is significantly lower than that observed in the trials in metastatic breast cancer, presumably due to the lower dose of ribociclib used in the NATALEE trial. Even with the dose of ribociclib used in the NATALEE trial, which is 200 mg lower than that used in the metastatic setting, nearly half of the patients on the ribociclib + ET arm had at least one episode of grade ≥3 neutropenia. However, despite the high incidence of neutropenia, including grade ≥3 neutropenia, it was able to be managed on study for most patients with temporary interruption of the CDK inhibitor. About 1 in seven patients required a dose reduction for neutropenia, but permanent discontinuation due to neutropenia was required in only 1% of patients. Clinically meaningful complications of neutropenia occurred more often in those receiving ribociclib but were infrequent overall; grade ≥3 infections were 2.3% more common and febrile neutropenia was 0.3% more common in patients on ribociclib + ET compared to those on ET alone. There were no deaths reported to have been associated with neutropenia on ribociclib. The incidence and severity of neutropenia generally did not increase with time for patients over the course of the 36-month treatment, suggesting that neutropenia management guidelines used in the NATALEE trial and reflected in the USPI are appropriate to mitigate the risk. The Applicant’s proposed labeling has been modified to reflect both the laboratory abnormalities and adverse events of neutropenia as this better characterizes the overall incidence and ensures that clinicians monitor absolute neutrophil count (ANC) closely and modify treatment as necessary. 128 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. While neutropenia with adjuvant ribociclib is very common and often high-grade, with the recommended monitoring and treatment interruption, dose reduction, or discontinuation as described in the USPI, the risk of serious infections attributable to neutropenia in this curative intent population who will be receiving 3 years of treatment appears to be low. There was an increased risk of SARS-CoV-2 infection and COVID-19/COVID-19 pneumonia, including fatal cases that occurred during the on-treatment period, in patients receiving ribociclib + ET. This AE did not appear to be related to treatment-emergent neutropenia and is discussed in further detail in Section 8.2.4. 8.2.5.2 QT interval prolongation QT prolongation is an important identified risk for ribociclib. As previously known, ribociclib prolongs the QT interval in a concentration-dependent manner. This risk is minimized by the specific dose modification guidance and ECG and serum electrolyte monitoring plan in the current label, which is considered adequate. A comprehensive clinical safety assessment of QT prolongation is included within this dossier in a specialty safety report [QT/QTc Safety Analysis Report Study O12301C]. Per the study inclusion criteria, patients were required to have baseline QTcF < 450 ms with no significant uncontrolled cardiac disorder. Frequency of events in the QT interval prolongation AESI were as follows in the ribociclib + ET group compared with the ET only group: all grades: 5.3% vs. 1.4%; grade ≥3: 1.0% vs 0.6%. Among the AESI grouping term, the most frequent AE by PT term was ECG QT prolonged (all grades: 4.3%, ribociclib + ET; 0.7%, ET only). Following in frequency, syncope presented infrequently and similarly by group (0.7% vs. 0.6%). There was one AE (cardiac arrest) leading to death in the ribociclib + ET group. This event occurred >30 days off ribociclib and was considered not related by the Investigator. The patient had no reported ECG/QT/QTcF abnormalities. Overall, events within the QT prolongation AESI were uncommon and with limited clinical impact rarely requiring dose adjustment, interruption, or discontinuation (0.1%; 1.1%; 0.4% respectively) in the ribociclib + ET group. Notable ECG values Based on central ECG assessment, clinically notable QTcF value of > 480 ms was infrequent in both groups: in the ribociclib + ET group (10 patients, 0.4%) vs. the ET only group (4 patients, 0.2%), which included 3 patients (0.1%) with a QTcF > 500 ms in the ribociclib + ET group vs. one patient (<0.1%) in the ET only group. An increase of QTcF > 60 ms from baseline was observed in 19 patients (0.8%) in the ribociclib + ET group, and in 2 patients (0.1%) in the ET only group. Of note, overall, increase in QTcF > 60 ms from baseline or QTcF >480 ms did not result in clinically relevant abnormalities and were not associated with cardiac signs or symptoms. These ECG changes were reversible with dose interruption, and the majority occurred within the first 4 weeks of treatment. There were no reported cases of sudden death or Torsades de Pointes. Time to event analyses: Median time-to-onset of ECG QT prolongation grade ≥2 events was 0.5 months (range: 0.5 to 1.5), which correlates to approximately Cycle 1 Day 15 per protocol- 129 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. scheduled monitoring in the ribociclib + ET group, compared with 1.4 months (range: 0.9 to 2.8), or approximately Cycle 2 Day 15 per protocol-scheduled monitoring in the ET only group. Of note, the majority of notable QTcF values were observed on Cycle 1 Day 15. Median time-to-onset of ECG QT prolongation grade ≥3 events was 1.4 months (range: 0.5 to 1.5) in the ribociclib + ET group, compared with 1.9 months (range: 1.9 to 1.9) in the ET only group. Of note, there was minimal change in notable QTcF values at Cycle 2 Day 1 compared to baseline (mean change from baseline at Cycle 2 Day 1 was 0.5 ms) in the ribociclib + ET group. This minimal QTcF prolongation is expected due to the 7 days off of dose, where the concentration of ribociclib is expected to be low, based on the 3-weeks on/1-week off ribociclib dosing schedule. This is further supported by the fact that no first occurrences of notable ECG values have been observed at this timepoint in ribociclib + ET group. Management recommendations: As described above, ECG prolongation events were of low incidence (1.0% grade ≥ 3 QT ECG prolonged AESI; 0.4% QT interval > 480 ms) without associated cardiac signs or symptoms in ribociclib + ET group. The mean QTcF change (ΔQTcF) from baseline was 9.5 ms at Cycle 1 Day 15 2 hours postdose, which corresponds to steady state ribociclib concentration. The mean change from baseline was 0.5 ms at Cycle 2 Day 1 predose ECG, which corresponds to the lowest ribociclib concentration, as expected, following the 7 days off dose based on the 3-weeks on/1-week off dosing schedule. In view of these data from Study O12301C, Novartis proposes ECG monitoring for patients with eBC at baseline before initiating treatment, and approximately Cycle 1 Day 14 (steady-state ribociclib concentration), with additional ECGs as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended. Consistent with the proposal for patients with eBC, Novartis also proposes to revise the existing risk minimization measures for management of risk of QT interval prolongation in patients with aBC (ie, to remove the requirement for ECG monitoring at the beginning of the second cycle/Cycle 2 Day 1), based on the low incidence of QT prolongation events at Cycle 2 Day 1, which corresponds to the low concentration of ribociclib and minimal change in QTc interval from baseline (ΔQTcF), median time to first occurrence of Grade 2/3/4 QT prolongation of 2.1 weeks which approximates Cycle 1 Day 15, and no clinical evidence among patients with notable ECG at Cycle 1 Day 15 and Cycle 2 Day 1 that mandating Cycle 2 Day 1 QTcF monitoring for all patients would have provided additional benefit to support managing the risk of QT prolongation in patients with aBC [SCS Add. Study O12301C-Appendix 4]. Other risk mitigation measures for QT prolongation including dose modification guidance, baseline threshold of QTcF <450 ms, monitoring of electrolytes, and assessment of relevant medical history and concomitant medications are included in the proposed label. More details are provided in [QT/QTc Safety Analysis Report Study O12301C] included in this submission. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment except as noted below. The median time to grade ≥2 QT prolongation, a QTc of 481-500 ms, was 0.5 months (range: 0.5 to 1.5), which corresponds with the cycle 1 day 15 ECG. Although there were cases of QT prolongation beyond Cycle 1, there were no patients with a first occurrence of 134 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. With appropriate patient selection, including baseline QTcF <450 ms and assessment of risk based upon personal/family history, as well as risk mitigation, including avoidance of other QT prolonging medications, monitoring/correction of electrolyte abnormalities, and dose modification as needed, FDA concurs that routine ECG monitoring for all patients on Cycle 2 Day 1 is not required. The Cycle 1 Day 15 ECG, which occurs at steady state concentration, may be used by clinicians in combination with the above elements of the history and laboratories to identify the subset of patients on ribociclib for whom additional ECG monitoring beyond Cycle 1 is necessary. Patients with QT prolongation observed on the Cycle 1 Day 15 ECG, as well as patients at increased risk of QT prolongation or arrhythmia based upon medical history or concomitant medications, should have continued ECG monitoring beyond Cycle 1. The USPI will be updated to reflect this modified recommendation. While there was no difference in the incidence or severity of tachycardia between the two groups, FDA noted that palpitations were reported more commonly in patients on the ribociclib + ET arm (3.4%) compared to those on the ET only arm (1.1%). To evaluate for arrhythmias that may have occurred without QT prolongation or with QT prolongation that was not captured on ECG, FDA also analyzed arrhythmia as a grouped term (consisting of atrial fibrillation, electrocardiogram QT prolonged, Wolff-Parkinson-White syndrome, supraventricular tachycardia, sinus bradycardia, sinus arrhythmia, electrocardiogram repolarization abnormality, extrasystoles, arrhythmia, supraventricular extrasystoles, atrioventricular block first degree, ventricular extrasystoles, arrhythmia supraventricular, sinus tachycardia, atrial flutter, atrial tachycardia, electrocardiogram P wave abnormal, bundle branch block right, atrioventricular block, tachyarrhythmia, electrocardiogram PR prolongation, ventricular tachycardia, long QT syndrome, TdP, and bundle branch block left) and found an increased incidence of all-grade AEs in the ribociclib + ET group (6% vs 3.3%). While the majority of these were grade 1/2, the incidence of grade ≥ 3 AEs in this grouped term was also doubled with ribociclib use (0.6% vs 0.3%). As discussed earlier in Section 8.2.4, electrolyte abnormalities were more common in patients on ribociclib + ET, and while most were grade 1/2, it is possible that this contributed. It is important to note that patients with significant cardiac history were excluded from NATALEE (as well as trials in the metastatic setting) but may be exposed to ribociclib in the postmarket setting. In addition, nearly one in five patients on the NATALEE trial received at least one dose of a prohibited concomitant medication, including many medications prohibited due to increased risk of QT prolongation. As discussed above in the narratives in this section, although adverse cardiac events potentially related to concomitant medication use occurred on the NATALEE trial, they appear to have been rare. Attention to reports of arrythmia AEs, especially TdP, ventricular arrhythmias, or sudden cardiac death, will be especially important for postmarketing pharmacovigilance given the broader introduction of ribociclib in a curative intent setting. No cases of TdP have been 135 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. reported to date. If clinically significant QT prolongation is identified in patients with early breast cancer in the postmarket setting, consideration of a labeling change to add back routine ECG monitoring in Cycle 2, but at Day 15 rather than Day 1, given the 3 week on, 1 week off dosing regimen, is recommended. 8.2.5.3 Hepatobiliary toxicity Hepatobiliary toxicity is an important identified risk for ribociclib. The majority of hepatobiliary AESIs were laboratory findings of elevated ALT/AST concentrations, which tended to occur early during treatment and were manageable with protocol dose management guidance specific for hepatotoxicity. Hepatobiliary AESIs were one of the most common grade ≥ 3 AEs in Study O12301C, and the most common reason for treatment discontinuation but were effectively manageable with dose adjustments, and were reversible. In Study O12301C, the proportion of patients with hepatobiliary toxicity grouped AEs was greater in the ribociclib + ET group vs. the ET only group (26.4% vs. 11.2%); likewise the proportions of patients with grade ≥3 events were 8.6% and 1.7%, respectively. The most frequently reported events in this AESI category included: ALT increased (19.5% vs. 5.6%) and AST increased (16.9% vs. 5.7%) [SCS Add. Study O12301C-Table 2-19]. Importantly, these 2 PTs were amongst the most common [SCS Add. Study O12301C-Table 2-3] and more severe events [SCS Add. Study O12301C-Table 2-4] that were assessed with causal relationship to study treatment by the Investigator [SCS Add. Study O12301C-Table 2-5] in the ribociclib + ET group. All remaining PTs in the hepatobiliary toxicity grouped AEs were reported at < 5.0% in either group. No noteworthy differences were observed since IA3. No additional patients with DILI or confirmed Hy’s Law were identified since the primary analysis/IA3 [SCS Add. Study O12301C- Section 2.6.7]. • Within the Hepatobiliary toxicity AESI, DILI was reported for 9 patients (0.4%) and of these, 5 were grade ≥ 3. Of these 9, 8 patients’ events resolved as of DCO [Study O12301C Primary Analysis CSR-Listing 16.2.7-1.1]. All 9 patients with DILI are discussed in [Study O12301C Primary Analysis CSR-Section 14.3.3], and were in the ribociclib + ET group. • There were 8 clinically confirmed Hy’s Law cases, including 4 of the 9 patients with DILI. All 8 patients were in the ribociclib + ET treatment group (n=2524). Importantly, most (6 out of 8 patients) completely recovered after discontinuation of ribociclib; 2 patients had improvement in lab values after ribociclib discontinuation, albeit mild lab abnormalities were still as of DCO (1 patient, grade 2 elevated TBL; 1 patient, grade-1 elevated AST/ALT and grade-2 elevated TBL) [Study O12301C SCS-Section 2.6.6]. When assessing Hepatobiliary toxicity AESI as grade ≥ 3 AEs, SAEs, AEs leading to discontinuation, dose adjustment, and/or dose interruption, increased ALT (7.6%, 0.4%, 7.1%, 1.9%, and 10.1%, respectively) and increased AST (4.7%, 0.2%, 2.8%, 0.6%, and 6.8%, 136 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. respectively) were often the most frequent events in the ribociclib + ET group [SCS Add. Study O12301C-Appendix 1-Table 14.3.1-6.2]. There were no on-treatment deaths in the Hepatobiliary toxicity AESI [SCS Add. Study O12301C-Table 2-19]. Time-to-event analyses: Median time-to-first occurrence of grade ≥ 3 elevated ALT/AST was 2.8 months (range: 0.36 to 33.15) in the ribociclib + ET group, compared with 12.5 months (range: 0.46 to 33.28) in the ET only group [SCS Study O12301C-Appendix 1-Table 14.4-4.1], [SCS Study O12301C- Figure 2-6]. The estimated median duration of grade 3 or higher AST or ALT elevations (recovering to ≤ grade 2) was 0.7 months (95% CI: 0.7, 0.9) in the ribociclib + ET group and 2.2 months (95% CI: 1.2, 2.8) in the ET only group [Study O12301C Primary Analysis CSR- Table 14.3-6.2] Management recommendations: Hepatobiliary toxicity has been reported during treatment with ribociclib and therefore, should be closely monitored. Management guidelines remain the same as in the approved label for patients with aBC. The FDA’s Assessment: FDA has analyzed hepatobiliary AEs and laboratory abnormalities and generally agrees with the Applicant’s assessment with the following additional comments. Hepatobiliary AEs were much more common with addition of ribociclib to ET. In FDA’s analysis of liver function test AEs (as a grouped term consisting of elevation in one or more of: AST, ALT, GGT, alkaline phosphatase, and blood bilirubin), 26.4% of participants on the ribociclib + ET arm had a liver function test abnormality, of which 8.6% were grade ≥3. This is a significant increase compared to the ET only arm where only 11.2% had a liver function abnormality, of which 1.7% each were grade ≥3. Most were increases in transaminases. An FDA analysis of hepatotoxicity AEs (a grouped term consisting of PT of hepatotoxicity, drug-induced liver injury (DILI), autoimmune hepatitis, and hepatic cytolysis) was also performed and similarly identified an increased incidence of all-grade (1.4% vs 0.5%) as well as grade ≥3 hepatotoxicity AEs (0.7% vs <0.1%) in the ribociclib + ET arm compared to the ET only arm. The median time to first occurrence of grade 3/4 elevated transaminases was 2.8 months on the ribociclib + ET arm, although cases of grade 3/4 transaminase elevation occurred as early as 0.4 months and as late as 33 months into treatment. Hepatobiliary SAEs were rare overall but clearly increased for those receiving ribociclib (1.0% vs 0.2%). Liver function test abnormalities, most commonly elevated transaminases, resulted in treatment interruption of ribociclib in 12.4% of patients, dose reduction in 2.6% patients, and permanent discontinuation in 8.9% of patients. With these treatment modifications according to the protocol, the median duration of grade 3/4 elevated transaminases in the ribociclib + ET arm was 0.7 months, and there were no on-study deaths attributed to hepatobiliary toxicity, indicating that instructions in the agreed upon USPI regarding liver function abnormalities appear adequate to monitor and mitigate this 143 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Day 84, her AST was grade 3, ALT was grade 4, alkaline phosphatase was grade 1, and total bilirubin was normal. Ribociclib was interrupted on Day 85 (last dose was taken on Day 77) and never restarted. On Study Day 90, AST and ALT were grade 4, alkaline phosphatase was grade 1, and total bilirubin was grade 1. Letrozole was interrupted from Study Day 91 to 118. By Study Day 140, AST, ALT, and alkaline phosphatase were grade 1 and total bilirubin was normal, and on Study Day 252, AST and ALT were resolved, total bilirubin was normal, and alkaline phosphatase remained grade 1. These results remained the same through Study Day 1000. No biopsies, viral serologies, or autoimmune testing was reported. The Investigator, Applicant, and FDA all agree DILI was due to ribociclib, and this case satisfied clinical criteria for Hy’s Law. 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability The Applicant’s Position: Patient-reported outcomes have been discussed in Section 8.1.2. The FDA’s Assessment: Refer to the section discussing patient-reported outcomes in Section 8.1.2. 8.2.7 Safety Analyses by Demographic Subgroups The Applicant’s Position: The comprehensive discussion of intrinsic factors by demographic characteristics (sex and menopausal status, age and age categories, race and race categories, ethnicity, American Joint Committee on Cancer (AJCC) Anatomic Stage groups) and by special populations (baseline hepatic function, baseline renal function) in Study O12301C is described based on the primary iDFS analysis data cut-off. No clinically relevant differences were observed by group for TEAEs, AESI groupings, and/or on-treatment deaths, except for the following intrinsic factors: Adverse events by sex and menopausal status No trends in TEAEs by SOC were observed by menopausal status. When considering male patients, overall trends in TEAE data were no different; albeit the number of male patients was few. In the ribociclib + ET group, events belonging to the Renal toxicity AESI were numerically lower in premenopausal women (2.8%), compared with postmenopausal women (7.9%). This pattern was also observed in the ET only group (0.8% and 2.9%, respectively). Of note, there were fewer premenopausal women (0.2%) who presented AKI, compared with postmenopausal women (0.4%). This pattern was observed in the ET only group (0 vs. 0.2%, respectively). No other trends in AESI by menopausal status were observed. For male patients only, no trends in AESI groupings by sex were observed. However, as the number of male patients was low, i.e. 19 patients, these data should be interpreted with caution. No male patient presented AKI. In the ribociclib + ET group, on-treatment deaths were 0.5% in 144 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. premenopausal women, compared with 0.7% in postmenopausal women. This pattern was also observed in the ET only group (0.2% and 0.5%, respectively). There was 1 premenopausal woman (0.1%) who died due to COVID-19 pneumonia, compared with 5 postmenopausal women with COVID-19 events. This pattern was not observed in the ET only group. There was 1 on-treatment death due to AE (road traffic accident) in male patients (ribociclib + ET: 10.0%) [SCS Study O12301C-Section 5]. Adverse events by age In general, no trends in TEAEs as SOCs by age, i.e., younger than 45 years, ≥ 45 years to 54 years, ≥ 55 years to 64 years vs. the older subgroup, were observed. When assessing these data as the elderly subgroup, blood and lymphatic system disorders SOC was more frequent overall and in the ribociclib + ET group (57.1% and 11.1%, respectively), compared with patients younger than 75 years (47.0% and 8.5%). No trends in TEAEs by SOC were observed when patients were younger than median age vs. median age and older. Of note, median age was 52.0 years of age. No trends in AESI by age, younger than 65 years vs. the older subgroup, were observed. When assessing these data as the elderly subgroup, Anemia AESI was more frequent overall and in the ribociclib + ET group (25.0% and 7.9%, respectively), compared with patients younger than 75 years (7.9% and 2.9%, respectively). In general, overall Renal toxicity AESI was more frequent in elderly patients irrespective of study treatment (12.5% vs. 11.1%), but more frequent in patients younger than 75 years in the ribociclib + ET group (5.6% vs. 1.8%). There was no trend in on-treatment deaths in patients 65 years of age and younger (0.5%), compared with the older subgroup (0.8%). When assessing these data by primary reason for death, there was no trend. There was no on-treatment death in the elderly. On-treatment deaths when primary reason was AE in patients younger than the median age was 0.1% vs. those who were ≥ median age at 0.4%. In the ribociclib + ET group, patients who were younger than the median age had on-treatment deaths due to AE at 0.2% vs. those who were ≥ median age at 0.5%. The most frequent of these belonged to infections and infestations SOC (younger than median age, 0.1%; older than median age, 0.4%) and were COVID-19 events [SCS Study O12301C-Section 5]. Adverse events by race Overall, events related to ET presented less frequently in patients who were Asian (51.8% vs. 57.5%), compared to not Asian (64.2% vs. 62.1%). Several categories of TEAEs presented more frequently in patients who were Asian vs. not Asian. These were grade ≥ 3 AEs, leading to dose reduction, interruption, and those requiring additional therapy (Asian: 76.5%, 29.7%, 86.2%, 85.0%, respectively; not Asian: 60.3%, 18.7%, 70.3%, 74.5%, respectively) in the ribociclib + ET group. However, this trend was not observed in the ET only group (Asian: 13.7%, NA, 5.1%, 70.3%, respectively; Not Asian: 18.5%, NA, 7.5%, 63.0%, respectively). Trends were observed of less frequent TEAEs of several SOCs (blood and lymphatic system disorders; general disorders and administration site conditions; hepatobiliary disorders; 145 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. musculoskeletal and connective tissue disorders; reproductive system and breast disorders; vascular disorders) in Asian patients (27.1%, 42.1%, 1.8%, 48.8%, 6.2%, 19.7%), compared to not Asian (49.5%, 53.0%, 5.2%, 60.0%, 13.8%, 32.5%) in the ribociclib + ET group. However, this trend was only observed when events belonging to the blood and lymphatic system disorders; and general disorders and administration site conditions in patients in the ET only group (Asian: 2.9%, 23.0%, respectively; not Asian: 9.5%, 36.1%, respectively). Conversely, there were more frequent TEAEs within 1 SOC (investigations) in Asian patients (all grades, 82.4%; grade-3, 48.8%; grade-4, 2.9%), compared to combining patients into the category of not Asian (all grades: 61.2%; grade-3, 19.3%; grade-4, 2.1%) in the ribociclib + ET group. The trend was not observed when events belonged to investigations in the ET only group (Asian: all grades, 34.8%; grade-3, 1.9%; grade-4, 0.3% and not Asian: all grades, 30.4%; grade- 3, 2.4%; grade-4, 0.3%) [SCS Study O12301C-Section 5]. Overall, events in the Neutropenia AESI were more frequent in Asian patients (79.1% vs. 6.4%) and predominantly decreased neutrophil count, compared to not Asian (59.4% vs. 4.3%). Events belonging to the Reproductive toxicity AESI were only mastitis (0.6% vs. 0.3%) in Asian patients. This pattern was not observed in patients not Asian. For some races, the number of patients was low and data should be interpreted with caution. When patients were American Indian or Alaskan native (n=7), Infections AESI was highest (100% vs. 66.7%): 5 of these 7 patients had COVID-19, grade 1 / 2. Similarly in Black or African American patients (n=84), events in the Infections AESI (48.8% vs. 23.3%) were most frequently COVID-19 (14.6% vs. 9.3%). In general, trends in on-treatment deaths by race were not observed. There was no on- treatment death due to AE in American Indian or Alaskan native or Asian patients. There was no on-treatment death due to AE in Black or African American patients. All remaining on-treatment deaths due to AE were White patients (overall: 0.4%; 0.5% vs. 0.2%). The primary reason for all on-treatment deaths in Asian patients (overall: 0.5%) was disease recurrence (0.3% vs. 0.6%). Conversely, on-treatment deaths due to disease recurrence included not Asian patients (overall: 0.2%), but also were due to AE (overall: 0.3%) irrespective of treatment group (0.5% vs. 0.2%) [SCS Study O12301C-Section 5]. Adverse events by ethnicity Events in the skin and subcutaneous tissues disorders SOC were more frequent in patients with unknown ethnicity (43.9%), compared with the other 2 ethnic categories (Hispanic/Latino: 28.0%; non-Hispanic/non-Latino: 36.4%) in the ribociclib + ET group. However, this pattern was not observed in the ET only group (15.2%, 18.9%, 25.0%, respectively). No other trends by ethnicity were observed. No trends in AESI by ethnicity were observed. There was 1 patient (0.2%) with on-treatment death (disease recurrence) whose ethnicity was Hispanic/Latino. In non-Hispanic/non-Latino patients, on-treatment deaths due to AE (0.5% vs. 0.2%) were generally comparable to on-treatment deaths due to disease recurrence (0.3% vs. 0.2%). There was 0 on-treatment deaths in patients of unknown ethnicity [SCS Study O12301C-Section 5] [SCS Study O12301C-Section 5]. The FDA’s Assessment: 149 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. after the last dose of ribociclib, letrozole, and goserelin. On , an ultrasound T2 scan was normal. There were no infections during the pregnancy. Neonate delivery date was . The known safety information is as of (MfCtrNo NVSC2022FR246991). As part of current good pharmacovigilance practices (GVP), Novartis performs due diligence as follow-up and will continue to collect additional information on the neonate case [SCS Study O12301-Section 5.3] The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. The Applicant’s proposed indication includes pre- and perimenopausal females. Because ribociclib is to be co- administered with an AI, and AIs are not efficacious in the setting of functioning ovaries, all females who are not in confirmed menopause require concurrent ovarian suppression, which is clinician-administered in a health care setting. The USPI reflects this, and the need for concurrent ovarian suppression is well-known to US oncologists, thus the rate of pregnancy is expected to be low; however, clinicians should emphasize that adequate contraception is required with ribociclib use for those of childbearing potential. The risk of fetal harm to humans exposed to ribociclib in pregnancy is poorly characterized. Pediatrics and Assessment of Effects on Growth The Applicant’s Position: Refer to Section 10. The FDA’s Assessment: The NATALEE trial was limited to adults age ≥18 and thus provides no new information regarding pediatrics and assessment of effects on growth. The status of agreed iPSP is summarized in Section 10. Overdose, Drug Abuse Potential, Withdrawal, and Rebound The Applicant’s Position: Overdose: No new information about overdose has been generated in support of this dossier; recommendations are described in the approved prescribing information. In Study O12301C, a grade-3 SAE of overdose was reported in 1 patient (< 0.1%) who received ribociclib + ET. This elderly patient took 3 tablets of ribociclib daily from Day 1 to Day 21, which was 600 mg instead of 400 mg, as per protocol. Concomitant AE at the time was grade 1 tremor. The last dose of 600 mg was taken on Day 21 and then 1 week off drug (second cycle was delayed due to the neutropenia). Ribociclib was interrupted on Day 28 to Day 34 due to grade 3 neutropenia (onset: Day 13). The patient recovered on Day 34 and 400 mg ribociclib dosing was restarted the next day. The patient was re-educated on the proper dosing regimen. (b) (6) (b) (6) (b) (6) 150 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Drug abuse: No new information about abuse/dependence potential has been generated in support of this dossier. There is no known potential for abuse of ribociclib and no abuse studies have been performed. Withdrawal and rebound: No new information about withdrawal and rebound has been generated in support of this dossier. No studies have been conducted to assess withdrawal and rebound effects. Based on the product profile, no withdrawal effect is expected [SCS Study O12301C-Section 5.4 to 5.6]. The FDA’s Assessment: FDA concurs that the current submission provides limited information regarding “overdose” and no new information regarding withdrawal or rebound. The review team noted that 245 (10%) of patients on the ribociclib + ET arm had a protocol deviation related to dosing. In NATALEE, a protocol deviation related to dosing was defined as any of the following: a participant did not adhere or exceeded the prescribed daily dose of ribociclib for >3 days, or exceeded the planned duration of ribociclib for >3 days, or received a single dose of ribociclib ≥900 mg, or had an off- period of <7 days in a cycle. The most common dosing protocol deviation was exceeding the planned duration of ribociclib. The mean number of extra days on ribociclib was 2.7 days. In response to an information request from the Agency, the Applicant submitted an analysis demonstrating that the incidence and severity of AEs in participants with dosing-related protocol deviations were similar to that in the overall safety population. In particular, the incidence of grade ≥3 AEs (62.4% vs 62.6%, respectively) and the incidence of AESIs were not significantly increased. The Applicant was queried about the reasons for the frequency of observed dosing-related protocol deviations on the NATALEE trial, to determine whether the USPI should be modified to provide clearer instructions on dosing in the postmarket setting. Per the Applicant, on study, dosing instructions was provided to all participants, and all were issued a medication diary to be completed for each visit by both the patient and study site staff. Patients were instructed to return the diary as well as unused medication at each visit for assessment of compliance by study staff. A drug accountability log was maintained and reviewed by the trial monitor at site visits and study completion. There was no systematic capture of details regarding the reasons for dosing-related protocol deviations, and thus the reason for the dosing errors remains uncertain. It is possible that these errors will be more common in the postmarket setting where medication diaries are seldom used, and compliance is rarely formally assessed. Given that the drug is usually dispensed monthly in clinical practice, however, the harm of likely potential dosing errors by the patient is expected to be limited. The highest dose of ribociclib to which a patient is reported to have been exposed in NATALEE was 600 mg/day, which was an error on the patient’s part, and was corrected back to the prescribed dose of 400 mg/day. As 600 mg/day is the approved dose in combination with ET in the metastatic setting, this does not provide any new information regarding “overdose.” 151 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The lower dose of ribociclib (400 mg/day) used in the NATALEE trial and being approved in the adjuvant setting provides a margin of safety to patients with early breast cancer who may inadvertently exceed the intended adjuvant daily dose or number of days of treatment per cycle. 8.2.10 Safety in the Postmarket Setting Safety Concerns Identified Through Postmarket Experience The Applicant’s Position: Routine signal detection activities included regular review by qualified medical personnel of worldwide literature searches, frequency analyses in external and internal safety databases, registries containing safety data, blinded review of safety data reported from ongoing clinical studies, as well as postmarketing reports in the Novartis Safety Database. Cumulatively, since the time of the first marketing authorization approval of Kisqali in 2017, the established comprehensive safety monitoring identified 2 new safety signals (Interstitial Lung Disease/Pneumonitis and Toxic Epidermal Necrolysis) that eventually were added as postmarketing ADRs in the Kisqali prescribing information with appropriate communication within the Warning and precaution section. Considering the implemented risk minimization measures, there was no impact on the individual and the benefit-risk assessment of ribociclib. With the estimated cumulative exposure of approximately PTY (Kisqali PSUR 13 Mar 2022 to 12 Mar 2023-Section 5.2), the evaluation and detailed analysis of the known ribociclib- associated safety concerns in Kisqali PSURs did not reveal any evidence of increased reporting rates or increased severity of the AEs supporting the adequacy of established risk minimization activities in the currently approved indication. As demonstrated in Kisqali PSUR (Kisqali PSUR 13 Mar 2022 to 12 Mar 2023), based on the cumulative review of available safety data from all sources, the benefit-risk assessment remained favorable and unchanged [SCS Study O12301C- Section 6]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of safety based upon the postmarket experience. The updated USPI accurately characterizes the risks of ribociclib, and the benefit-risk assessment remains favorable for the intended use population. The safety of ribociclib will continue to be monitored in the postmarket setting. Given the safety signal for ILD identified in the postmarket use of ribociclib in the metastatic setting, there was concern for an increased risk of ILD in the adjuvant setting where most patients with stage II/III breast cancer will receive adjuvant radiotherapy to the breast/chest wall and/or regional lymph nodes. FDA therefore analyzed interstitial lung disease (ILD) in the NATALEE trial as a grouped term (consisting of PT terms of interstitial lung disease, pulmonary fibrosis, pneumonitis, and radiation pneumonitis). There were 30 (1.2%) patients who received ribociclib + ET with an ILD AE compared to 18 (0.7%) of those receiving ET only. All cases were grade 1 or 2 except for one patient (b) (4) 152 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. (<0.1%) in the ET only group with grade 3 ILD. Therefore, while there was a 0.5% increase in risk of all-grade ILD with ribociclib in NATALEE, the risk is low overall, and cases do not appear to be more severe with ribociclib use. Although FDA’s analysis of rash as a grouped term identified an increased incidence with ribociclib + ET compared to ET only (13% vs 5%), most of these were grade 1/2. Grade ≥3 rash was rare and equal (0.2%) in both arms. There were no cases of toxic epidermal necrolysis reported with ribociclib in the NATALEE trial. Expectations on Safety in the Postmarket Setting The Applicant’s Position: Overall frequency and severity of AEs, especially dose dependent toxicities, is less in Study O12301C compared with data at the 600 mg dose in the aBC setting. The safety follow-up in Study O12301C in terms of patient-years of exposure was 6904.3 patient-years for the ribociclib + ET group vs. 6487.3 patient-years for the ET only group, or an additional 1018.4 patient-years since IA3. These data show that the level of safety follow-up completed in the study thus far is adequate to detect any signals that are related to the safety profile of ribociclib, including those that are not dose-dependent and/or rare events, and is unlikely to change substantially with longer follow-up. Furthermore, the long-term safety of ribociclib is well established based on treatment in the advanced/metastatic BC population (1065 patients exposed to ribociclib in the pool of the three pivotal trials in aBC, with an estimated exposure of 2081 PTY [Study A2301 SCS Add.-Table 1- 8]) and a higher starting dose of ribociclib (600 mg), with results showing no change to the safety profile of the drug over time compared with the primary analyses. As of 12-Mar-2023, 10,289 subjects/patients have received ribociclib in clinical trials, and the cumulative post- authorization patient exposure since the first launch of ribociclib is estimated to be approximately PTY. Evaluation of the cumulative safety data from clinical trials and post-marketing sources did not reveal any new safety signal related to the long-term use of ribociclib. With longer follow-up and more patients completing ribociclib treatment in the eBC setting, no new safety signals were identified and overall, the safety profile remains unchanged, indicating stability of safety findings [CO Study O12301-Section 6.3.1]. Therefore, the safety in patients with eBC is not expected to significantly change in post-marketing setting. The FDA’s Assessment: FDA disagrees with the Applicant’s statement that “the safety in patients with eBC is not expected to significantly change in post-marketing setting.” Granting an indication in early breast cancer results in both a marked increase in the number of patients eligible to receive treatment, as well as a heightened scrutiny and level of concern for AEs given that many patients, even those at high risk, may be cured by existing local and systemic adjuvant therapy. In addition, despite modernized eligibility criteria, clinical trials enroll a population with more favorable performance status and fewer comorbidities/concomitant medications compared to the general population. We therefore cannot conclude that the (b) (4) 153 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. safety in patients with eBC will not change in the postmarket setting when a much larger and more diverse group of patients will be exposed to ribociclib. The Applicant and the FDA will continue to monitor safety in the postmarket setting and update the USPI as needed. As noted, there was an increased risk for overall and severe COVID-19 in patients who received ribociclib, although this risk diminished over the course of the study. This will also continue to be monitored in the postmarket setting. 8.2.11 Integrated Assessment of Safety Data: Table 32: Summary of deaths and adverse event categories in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET [N=2525] ET only [N=2442] Category All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All deaths1 83 (3.3) NA NA NA 89 (3.6) NA NA NA On-treatment deaths2 20 (0.8) NA NA NA 9 (0.4) NA NA NA AEs 2474 (98.0) 1463 (57.9) 133 (5.3) 11 (0.4) 2145 (87.8) 425 (17.4) 40 (1.6) 4 (0.2) Suspected to be drug- related 2368 (93.8) 1284 (50.9) 101 (4.0) 1 (< 0.1) 1566 (64.1) 97 (4.0) 6 (0.2) 0 SAEs 357 (14.1) 252 (10.0) 44 (1.7) 11 (0.4) 256 (10.5) 192 (7.9) 26 (1.1) 4 (0.2) Suspected to be drug- related 68 (2.7) 39 (1.5) 17 (0.7) 1 (< 0.1) 13 (0.5) 9 (0.4) 0 0 AEs leading to discontinuation 524 (20.8) 201 (8.0) 36 (1.4) 2 (0.1) 134 (5.5) 38 (1.6) 5 (0.2) 3 (0.1) Suspected to be drug- related 435 (17.2) 165 (6.5) 26 (1.0) 0 94 (3.8) 18 (0.7) 0 0 AEs requiring dose interruption 1858 (73.6) 1226 (48.6) 87 (3.4) 0 199 (8.1) 67 (2.7) 8 (0.3) 0 Suspected to be drug- related 1635 (64.8) 1156 (45.8) 70 (2.8) 0 99 (4.1) 27 (1.1) 3 (0.1) 0 AEs requiring dose adjustment 586 (23.2) 338 (13.4) 36 (1.4) 0 NA NA NA NA Suspected to be drug- related 561 (22.2) 330 (13.1) 36 (1.4) 0 NA NA NA NA AEs requiring additional therapy 1962 (77.7) 499 (19.8) 61 (2.4) 2 (0.1) 1627 (66.6) 297 (12.2) 28 (1.1) 1 (< 0.1) Suspected to be drug- related 1225 (48.5) 240 (9.5) 32 (1.3) 0 696 (28.5) 58 (2.4) 3 (0.1) 0 AEs of special interest 2183 (86.5) 1291 (51.1) 114 (4.5) 7 (0.3) 1179 (48.3) 168 (6.9) 15 (0.6) 2 (0.1) 154 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET [N=2525] ET only [N=2442] Category All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Suspected to be drug- related 1886 (74.7) 1188 (47.0) 100 (4.0) 0 203 (8.3) 17 (0.7) 2 (0.1) 0 1 All deaths including those not considered on-treatment deaths. Includes deaths with cause other than AE. Deaths due to disease progression or other are listed in the All Grades column. 2 On treatment deaths are defined as occurring on or after treatment start date and up to 30 days after 36 months of treatment or earlier treatment discontinuation. Includes deaths with cause other than AE. Deaths due to disease progression or other are listed in the All Grades co lumn. Suspected to be drug related refers to any component of study treatment. Additional therapy includes all non- drug therapy and concomitant medications. Discontinuation refers to discontinuation of any treatment component. n=number of patients. Patients are counted once per category at worst toxicity grade in the main category rows, and once per category per toxicity in the related rows. Source: SCS Add. Study O12301-Table 2-1 The Applicant’s Position: A predictable and manageable safety profile was observed with ribociclib in the eBC setting at the 400 mg starting dose in combination with standard of care NSAI/AI. No new safety signals or safety concerns were identified based on the thorough review of the safety data from Study O12301C. Ribociclib-related AEs are well characterized and are readily identifiable with routine laboratory work or physical examination, are manageable with appropriate intervention (standard medical care and/or through the use of ribociclib dose reduction, temporary treatment interruption or permanent discontinuation), and are generally reversible upon treatment adjustment. The majority of ribociclib discontinuations due to AEs occurred early on in the course of treatment, indicating that if patients tolerate the first few months of treatment, they are likely to tolerate for the duration of the treatment. With the lower starting dose of ribociclib at 400 mg, a lower overall incidence and severity of toxicities was observed compared with that observed at 600 mg in the aBC setting; this is specifically relevant for dose-dependent toxicities including QT interval prolongation and neutropenia. On-treatment death was reported for 20 patients (0.8%) in the ribociclib + ET group vs. 9 patients (0.4%) in the ET only group within 36 months of treatment plus 30 days of safety follow-up. The main causes of on-treatment deaths in the ribociclib + ET group and ET only group, respectively, were disease recurrence/progression: 9 patients (0.4%) vs. 4 patients (0.2%); and deaths due to COVID-19: 6 patients (0.2%) vs. 1 patient (< 0.1%). Of the 20 total patients who died in the ribociclib + ET group, 8 died within the defined on-treatment period, but >30 days after ending treatment with ribociclib [CO Study O12301-Section 5.7]. Key safety topics Neutropenia, hepatobiliary toxicity, and QT interval prolongation are known safety concerns that continue to be considered as important identified risks for ribociclib. All appear to be 155 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. manageable with appropriate monitoring, and reversible upon recommended dose modification guidance for ribociclib. Although these remain important identified risks for ribociclib, the frequency and severity of neutropenia and QT prolongation events and severity of hepatobiliary toxicity events is lower with ribociclib 400 mg in the eBC setting compared with ribociclib 600 mg in the aBC setting. The data at the final iDFS analysis support previous observations that these events happen early on treatment with ribociclib and their incidence does not increase over time. Neutropenia Neutropenia was the most common AE leading to study treatment dose adjustment or dose interruption in the ribociclib + ET group (reported for 12.6% and 42.8% of patients based on the AESI pooled event category). However, neutropenia AESIs leading to discontinuation were infrequent (1.3%; 32 patients) in the ribociclib + ET group. Neutropenia events were generally observed early over the course of treatment with ribociclib, with a median time of 1.0 month to first occurrence of grade ≥3 neutropenia and estimated median duration of grade ≥ 3 neutropenia (that recovered to grade ≤ 2) of 0.3 months in the ribociclib + ET group. The incidence of grade ≥ 3 neutropenia in Study O12301C (based on the AESI pooled event category) was 43.8% in the ribociclib + ET group (vs. 0.8% in the ET only group). Although there was a high incidence of grade ≥ 3 neutropenia, it did not translate into a clinically significant increase in risk of severe infections in patients treated with ribociclib. Febrile neutropenia events were reported uncommonly, with only two patients discontinuing study treatment due to febrile neutropenia; there were no fatal neutropenia events in either group. As expected, due to the concentration-dependent effect of ribociclib on ANC level, the incidence of grade ≥3 neutropenia in Study O12301C (43.8%; AESI grouping) with ribociclib 400 mg is lower than the incidence of grade 3/4 neutropenia (62.5%; AESI grouping) for pooled data from Studies A2301, E2301 (NSAI/AI subgroup), and F2301 in advanced/metastatic breast cancer with ribociclib 600 mg. Management guidelines for neutropenia remain the same as in the approved label for patients with aBC. QTc interval prolongation Based on the totality of data, the overall low incidence and types of QT interval prolongation AESI, the change from baseline in QTcF interval, and notable ECG values had a limited impact on patients in Study O12301C. In Study O12301C, the risk difference between the ribociclib + ET and ET only groups for QT prolongation (AESI) grade ≥3 events was 0.5% (95% CI: 0.0, 0.9). Electrocardiogram QT prolongation events (PT) occurred predominantly within the initial 2 cycles of treatment with ribociclib with the majority events detected around the middle of the first cycle, when the drug is expected to reach its steady state. Of note, no first occurrences of notable QTcF values (> 480 ms) were observed at the beginning of the second cycle of treatment after the scheduled 7-day washout period. No associated cardiac signs or symptoms were 156 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. observed at the time of QT prolongation events. Overall, events within the QT prolongation AESI were uncommon and with limited clinical impact rarely requiring dose adjustment, interruption, or discontinuation (0.1%; 0.8%; 0.2% respectively) in the ribociclib + ET group. As expected with the lower starting dose of ribociclib 400 mg in combination with ET in patients with eBC in Study O12301C, less overall incidence of QT prolongation events and considerably lower incidence of notable ECG values were observed compared to that with ribociclib 600 mg in aBC (pooled dataset). As a result of the evaluation of the safety data related to the QT interval prolongation, Novartis is proposing to update the ribociclib label in regard to ECG monitoring recommendations for patients with eBC. As described above, ECG prolongation events were of low incidence (1.0% grade ≥ 3 QT ECG prolonged AESI; 0.4% QT interval > 480 ms) without associated cardiac signs or symptoms in ribociclib + ET group. The mean QTcF change (ΔQTcF) from baseline was 9.5 ms at Cycle 1 Day 15 2 hours postdose, which corresponds to steady-state ribociclib concentration. The mean change from baseline was 0.5 ms at Cycle 2 Day 1 predose ECG, which corresponds to the lowest ribociclib concentration, as expected, following the 7 days off dose based on the 3-weeks on/1-week off dosing schedule [QT/QTc Safety Analysis Report Study O12301C]. In view of these data from Study O12301C, Novartis proposes ECG monitoring for patients with eBC at baseline before initiating treatment, and approximately Cycle 1 Day 14 (steady-state ribociclib concentration), with additional ECGs as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended. Other risk mitigation measures for QT prolongation including dose modification guidance, baseline threshold of QTcF <450 ms, monitoring of electrolytes, and assessment of relevant medical history and concomitant medications are included in the proposed label. Hepatobiliary toxicity Hepatobiliary AESIs, which tended to occur early on treatment, were manageable with protocol dose management guidance specific for hepatotoxicity, and reversible upon ribociclib dose modifications. The majority of Hepatobiliary AESI were increased ALT/AST, which were one of the most common grade ≥ 3 AEs in Study O12301C, and the most common reason for treatment discontinuation due to AE. Hepatobiliary toxicity (primarily LFT increases) has been reported during treatment with ribociclib, predominantly within the initial 3 months of treatment, and should be closely monitored. There was an 8.3% incidence of grade ≥3 Hepatobiliary toxicity AESIs in the ribociclib pus ET group, and with dose interruptions reported in 12.0% of patients, and adjustments reported in 2.5%. A total of 225 patients (8.9%) discontinued treatment due to these events in the ribociclib + ET group. The risk difference between the ribociclib + ET and ET only groups for grade ≥3 AESIs was 6.8% (95% CI: 5.6, 7.9). Within Hepatobiliary toxicity AESI, DILI was reported for 9 patients (0.4%) and of these, 5 were grade ≥ 3. Of these 8 patients’ events resolved as of DCO. There were 8 clinically confirmed 157 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Hy’s Law cases, including 4 of the 9 patients with DILI. All 8 patients were in the ribociclib + ET treatment group (n=2524). Importantly, most (6 out of 8 patients) completely recovered after discontinuation of ribociclib, and two patients were recovering as of the DCO. Of note, there were fewer grade ≥ 3 hepatobiliary toxicity AESIs for Study O12301C compared with the pooled dataset in the aBC setting at 600 mg [CO Study O12301-Section 6.3.1]. Hepatobiliary toxicity has been reported during treatment with ribociclib and therefore, should be closely monitored. Management guidelines remain the same as in the approved label for patients with aBC. Subpopulations No additional safety concerns were raised; subgroup analyses typically demonstrated patterns of events consistent with those reported for the overall population. The FDA’s Assessment: FDA generally agrees with the Applicant’s Integrated Assessment of Safety. Many ribociclib AEs are known to be concentration-dependent, and the lower dose of ribociclib used in NATALEE (400 mg/day) compared with that approved in the metastatic setting (600 mg/day) generally resulted in decreased incidence and severity of AEs in the adjuvant setting, including AESIs. Addition of ribociclib to ET nonetheless resulted in increased toxicity, including high-grade toxicity, compared to ET alone. Patients receiving ribociclib were more likely to experience a grade ≥3 AE (63.6% vs 19.2%) and more likely to experience a grade ≥3 SAE (12.1% vs 9.2%). On-treatment deaths, defined as deaths while on or within 30 days of the last dose of ribociclib, were uncommon and evenly divided between disease progressions/recurrences and AEs. While deaths during the on-treatment period were increased in the ribociclib + ET group (n=20, 0.8%) compared to those who received ET only (n=9, 0.4%) with COVID- 19/COVID-19 pneumonia the most common causes of on-treatment death, deaths overall on study were numerically lower in the ribociclib + ET group. This reflects a decrease in deaths due to disease recurrence, as well as due to COVID-19, over time. As of the 90-day safety update, 4.1% of patients on the ET only arm had died compared to 3.6% on the ET + ribociclib arm. The OS HR was <1. There were no additional on-treatment deaths reported at the 90-day safety update. Despite the lower dose of 400 mg/day used in this adjuvant trial, toxicity-related treatment interruptions were much more common in patients on ribociclib + ET (73.8% vs 8.1% on ET only), most often due to laboratory abnormalities, and nearly one-quarter of patients (23.8%) required ribociclib dose reduction to 200 mg/day. While many AEs were successfully managed with a combination of treatment interruptions and dose reductions, patients on ribociclib were also more likely to discontinue due to an AE (20.8% vs 5.5%), with nearly one in five patients ultimately discontinuing the CDK 4/6 inhibitor due to a laboratory abnormality or AE. 159 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. ribociclib has been adequately controlled to be below the recommended limit for all indications. At the time of the 90-day safety update, there were no additional on-treatment deaths or new safety signals identified, the HR for OS remained < 1, and the incidence of AESIs was almost identical to that at the time of the final iDFS analysis. Based on the available safety data, the benefits of ribociclib in iDFS in this population of patients with high-risk Stage II and III HR-positive, HER2-negative early breast cancer outweigh the risks identified in the NATALEE trial. These benefits should not be extrapolated to the broader US population of patients with early-stage HR+, HER- breast cancer, most of whom are at considerably lower risk than patients enrolled to NATALEE. Clinical trials also represent idealized conditions and exclude many patients with comorbid conditions. Therefore, it will be important to continue to monitor this product in adjuvant use in the postmarket setting where safety may differ. 160 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 8.3 Statistical Issues The FDA’s Assessment: There were no major statistical issues with this application. The NATALEE trial met its primary objective of INV-assessed iDFS, showing a statistically significant improvement in iDFS with the treatment of ribociclib + ET compared to ET at IA3. However, at IA3, there was a large amount of censoring for iDFS as only 20% of patients had completed 3 years of adjuvant ribociclib. Thus, there was a concern for a potentially diminishing iDFS effect with longer follow-up, therefore FDA requested that the Applicant continue NATALEE until the final iDFS analysis. At the final iDFS analysis (DCO: July 21, 2023), 43% of patients had completed 3 years of adjuvant ribociclib. The iDFS hazard ratio was 0.75 (95% CI: 0.63, 0.89) which was consistent with the results at IA3. The final iDFS results were also consistent across various sensitivity analyses and exploratory subgroup analyses. The study was not designed to formally test any secondary endpoints including OS. At the time of final iDFS analysis, the number of deaths observed was less than what was originally projected. Overall, results of OS at the time of final iDFS and at the 90-day safety update support that there appears to be no detriment in OS at this time. A PMC will be issued for the applicant to provide all additional overall survival analyses as prespecified in the protocol and SAP, including OS at the time of end of trial. 8.4 Conclusions and Recommendations The FDA’s Assessment: Overall the benefit/risk is favorable for ribociclib for the adjuvant treatment of adults with high-risk, stage II and III HR+, HER2-negative breast cancer, based on the results of the NATALEE trial. At the final analysis of iDFS, addition of ribociclib to ET resulted in a 25% relative risk reduction, corresponding to a 3.1% absolute improvement in iDFS. This represents a number needed to treat of 32 to prevent one iDFS event. This magnitude of improvement is considered clinically meaningful as all recurrences result in morbidity, and distant metastatic disease is presently incurable. The majority of deaths, as well as recurrences, due to HR-positive, HER2-negative breast cancer occur in years 5 and beyond. The number of deaths on study was fortunately much lower than projected on both arms, and OS remains immature at this time, but the point estimate for the OS HR is <1. While patients with both high-risk stage II and III disease were adequately represented in the study to support the indication, only 12% of patients had node-negative tumors. In FDA’s analysis, patients with N0 disease had an iDFS HR that was comparable to that of the overall ITT population, and therefore these patients were included in the indication. Importantly, the patients in the NATALEE trial represented a considerably higher risk group than the average US population of adults with HR-positive, HER2-negative breast cancer; <10% had grade 1 tumors, 87% had received prior (neo-)adjuvant chemotherapy, and 88% had N1-N3 disease. The results of the NATALEE trial should therefore not be 161 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. extrapolated to the broader US population of patients with HR-positive, HER2-negative breast cancer, most of whom are at much lower risk of recurrence. The AE profile was similar to that observed in prior trials in the metastatic setting, but the incidence and severity of most AEs was lower, likely due to the lower dose of ribociclib used in the adjuvant setting, as well as a healthier adjuvant population. Neutropenia, hepatotoxicity, and QT prolongation remain the most important identified AESIs with ribociclib. With appropriate monitoring and timely treatment interruption, as well as dose reduction or drug discontinuation for those patients who require it based upon treatment modification guidelines used in the NATALEE trial and reflected in the agreed upon USPI, these risks can be sufficiently mitigated. There was an increased incidence and severity of COVID-19 infections noted in patients receiving ribociclib, including an increased incidence of on-treatment death due to COVID- 19, with deaths confined almost entirely to patients with no prior documented vaccination. The severity of COVID-19 infections appears to have fallen over time; there were no deaths due to COVID-19 reported after early 2022, which likely represents an increasing level of population immunity due to vaccines and prior infections, as well as availability of COVID- 19 therapeutics. This safety signal will continue to be monitored in the postmarket setting. The overall determination of risk-benefit is favorable and supports regular approval. 8.4.1 Approach to Substantial Evidence of Effectiveness 1. Verbatim indication: 209092: KISQALI is indicated in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 209935: KISQALI FEMARA Co-Pack is indicated for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 2. SEE was established with a. Adequate and well-controlled clinical investigation(s): i. ☐ Two or more adequate and well-controlled clinical investigations, OR ii. ☐ One adequate and well-controlled clinical investigation with highly persuasive results that is considered to be the scientific equivalent of two clinical investigations OR b. ☒ One adequate and well-controlled clinical investigation and confirmatory evidence1,2,3 OR 163 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 9 Advisory Committee Meeting and Other External Consultations The FDA’s Assessment: Not applicable. 164 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 10 Pediatrics The Applicant’s Position: Novartis submitted an iPSP waiver for pediatric studies in eBC to IND 117796 on October 12, 2023, [SN 0974] and a revised version on November 10, 2023. The Agency provided email confirmation on November 17, 2023 that the November 10, 2023 submission of the iPSP waivers for early breast cancer are considered agreed iPSPs. The FDA’s Assessment: FDA agrees with the Applicant’s position. 171 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 12 Risk Evaluation and Mitigation Strategies (REMS) The FDA’s Assessment: Not applicable. 173 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 33: FDA – PMC/PMR Checklist for Trial Diversity and U.S. Population Representativeness The following were evaluated and considered as part of FDA’s review: Is a PMC/PMR needed? x The patients enrolled in the clinical trial are representative of the racial, ethnic, and age diversity of the U.S. population for the proposed indication. _x_ Yes __ No x Does the FDA review indicate uncertainties in the safety and/or efficacy findings by demographic factors (e.g. race, ethnicity, sex, age, etc.) to warrant further investigation as part of a PMR/PMC? __ Yes _x_ No x Other considerations (e.g.: PK/PD), if applicable: __ Yes _x_ No L 179 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 19 Appendices 19.1 References The Applicant’s References: [Arimidex USPI (2018)] Arimidex (anastrozole) 1 mg tablet - US Prescribing Information (USPI). ANI Pharmaceuticals, Inc. Last updated 13-Dec-2018. [Aromasin USPI (2021)] Aromasin (exemestane) 25 mg tablet - US Prescribing Information (USPI). Pharmacia & Upjohn Company LLC, New York, NY, USA. Last updated November 2021. [Bria E, Carlini P, Cuppone F, et al (2010)] Early recurrence risk: aromatase inhibitors versus tamoxifen. Expert Rev Anticancer Ther; 10(8):1239-53. [Clarke M, Collins R, Darby S, et al (2005)] Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet; 365(9472):1687-717. [Eggemann H, Ignatov A, Smith BJ, et al (2013)] Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Res Treat; 137(2):465- 70. [Femara USPI 2020] Femara (letrozole) 2.5 mg tablets - US Prescribing Information (USPI). Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. Last updated May 2020. [GLOBOCAN (2020)] World Health Organization. International Agency for Research on Cancer. Breast cancer fact sheet. (Online) Accessed 15-Nov-2022. [Gomis RR, Gawrzak S (2017)] Tumor cell dormancy. Mol Oncol; 11(1):62-78. [Kisqali USPI (2022)] Kisqali (ribociclib) tablets, for oral use. US Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Revised 10/2022. [Kisqali SmPC (2023)] Kisqali 200 mg film-coated tablets. Summary of product characteristics. Novartis Europharm Limited, Dublin, Ireland. Updated 31-Mar-2023. [Lynparza USPI (2023)] Lynparza ( olaparib) 100/150 mg tablets - US Prescribing Information (USPI). AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA. Last updated November 2023. [National Comprehensive Cancer Network (2019)] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Breast Cancer Risk Reduction. Version 1.2019-December 11, 2018. [Pan H, Gray R, Braybrooke J, et al (2017)] 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med; 377(19)1836-46. 181 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Investigator Study No. Cente r No. Amount Disclosed Category of Disclosure Dr 2301C >$25,000 Research Grant Dr 2301C >$25,000 Honorarium Dr 2301C >$25,000 Research Grant Dr 2301C >$25,000 Honorarium Dr 2301C $28,820 Speaker Grant Dr 2301C >$50,000 Equity Ownership Dr 2301C >$50,000 Equity Ownership Dr 2301C $40,000 Support on electronic platform development Dr 2301C $50,000 Project Support Any bias resulting from these arrangements is minimized by independent data monitoring by Novartis and CRO (TRIO) and multiple investigators used in the study. Covered Clinical Study (Name and/or Number):* CLEE011O12301C Was a list of clinical investigators provided: Yes No (Request list from Applicant) Total number of investigators identified: 4538 Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0 Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 17 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0 Significant payments of other sorts: 15 Proprietary interest in the product tested held by investigator: 0 Significant equity interest held by investigator in study: 2 Sponsor of covered study: 0 Is an attachment provided with details of the disclosable financial interests/arrangements: Yes No (Request details from Applicant) Is a description of the steps taken to minimize potential bias provided: Yes No (Request information from Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) NA Is an attachment provided with the reason: Yes No (Request explanation from Applicant) The table above should be filled by the applicant, and confirmed/edited by the FDA. The FDA’s Assessment: The financial disclosure information was reviewed with no concerns identified. 19.3 Nonclinical Pharmacology/Toxicology The Applicant’s Position: No new information is provided in the current submission. The FDA’s Assessment: (b) (6) (b) (6) 187 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Covariate Category N BW# <50kg 8 50-60kg 24 60-70kg 34 70-80kg 26 80-90kg 19 >=90kg 12 Menopausal status Premenopausal women and men 42 Postmenopausal women 81 Anatomic stage group Stage group II 68 Stage group III 55 #: Subjects with missing records were excluded from the summary. Source: [SCP Study O12301C-Table 6-1] Table 36: Summary of steady-state ribociclib PK parameters across populations and studies Stud y Popul ation Riboci clib Dose (mg) Dose regimen Cmax (ng/m L) geo- mean (Geo- CV% ) Tmax (hr) media n (min, max) AUC0- 24h (ng∙hr/ mL) geo- mean (Geo- CV%) Ctrou gh (ng/m L) geo- mean (Geo- CV%) CL/Fss (L/hr) (Geo- CV%) PopPK simulated data[a] Updat ed O123 01C popP K model eBC 400 Multiple doses (C1D15) with NSAI 952 (39.5) 3.79 (24.4) 10388 (41.0) 263 (52.8) 38.4 (95%CI: 35.5 – 41.9) Data are presented as geometric mean (CV% geo mean) for all parameters except for Tmax which is presented as median (range). Formulation of ribociclib used in the studies was capsule unless specified. [a] population PK parameters are presented as population mean (95%CI) Source: [SCP Study O12301C-Table 3-2] Table 37: Simulated C1D1 and steady-state ribociclib PK parameters at the dose of 400 mg QD in HR-positive, HER2-negative eBC patients in Study O12301C 188 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Statistic C1D1 Steady-state Ctrough (Cmin) (ng/mL) Geometric mean (CV%) 108 (50.7) 263 (52.8) Arithmetic mean (90% CI) 121 (115, 128) 297 (281, 313) 5th percentile (90% CI) 48.9 (48.9, 48.9) 118 (118, 118) 95th percentile (90% CI) 227 (227, 227) 583 (583. 583) Cmax (ng/mL) Geometric mean (CV%) 671 (51.9) 952 (39.5) Arithmetic mean (90% CI) 751 (705, 796) 1023 (974, 1073) 5th percentile (90% CI) 298 (298, 298) 514 (514, 514) 95th percentile (90% CI) 1423 (1423, 1423) 1767 (1767, 1767) AUC0-24 (hr∙ng/mL) Geometric mean (CV%) 5296 (39.5) 10388 (41.0) Arithmetic mean (90% CI) 5691 (5429, 5953) 11224 (10706, 11724) 5th percentile (90% CI) 2863 (2863, 2863) 5510 (5510, 5510) 95th percentile (90% CI) 9752 (9752, 9752) 19702 (19702, 19702) Tmax (hr) Geometric mean (CV%) 3.79 (24.4) 3.79 (24.4) Arithmetic mean (90% CI) 3.90 (3.77, 4.04) 3.90 (3.77, 4.04) 5th percentile (90% CI) 2.57 (2.57, 2.57) 2.57 (2.57, 2.57) 95th percentile (90% CI) 5.71 (5.71, 5.71) 5.71 (5.71, 5.71) Source: [SCP Study O12301C-Table 2-2] 189 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Figure 5: Prediction-corrected visual predictive check (VPC) of the updated popPK model compared with observed PK concentrations in Study O12301C Dots represent the observed concentrations in the PK-iDFS dataset. Upper and lower borders of the blue area represent the 90% CI of the 5th and 95th percentiles of the simulations, while the red area represents the 90% CI of the median. Similarly, the upper and lower dashed line represent the 5th and 95th percentile of the observations, while the solid line represents the median of the observations. Source: [SCP Study O12301C-Figure 6-2] The FDA’s Assessment: The Applicant’s population PK analysis is acceptable. Overall, the final population PK model is adequate to characterize the PK profile of ribociclib in patients with early breast cancer as indicated in the Applicant’s diagnostic plots. The FDA reviewer repeated and verified the Applicant’s analysis with no significant discordance identified. The proposed labeling statements related to PK parameters in Section 12.3 are acceptable. 200 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. baseline QTcF) + combination + population + combination log(concentration/median concentration + 1). Horizontal dotted lines are the reference lines at 30 ms and 60 ms. Source: SCP Study O12301C Appendix 1-Figure 3-1.2 The FDA’s Assessment: The Applicant’s E-R analyses for ribociclib and neutropenia are considered acceptable for the purpose of exploring the relationship between ribociclib exposure and neutropenia in patients with early breast cancer. 19.4.2.5 ER Review Issues The FDA’s Assessment: No substantive issue. 19.4.2.6 Reviewer’s Independent Analysis The FDA’s Assessment: Reviewer’s independent analysis was not performed. 19.4.2.7 Overall benefit-risk evaluation based on E-R analyses The Applicant’s Position: Efficacy in patients with eBC was demonstrated by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Due to limited sample size of patients with iDFS events, exposure-efficacy relationship cannot be characterized. The PK-QT modeling confirmed the exposure-QTcF relationship in eBC patients, and patient population is a significant covariate where eBC patients showed less QTcF response than aBC patients. In Study O12301C, the ribociclib Ctrough values of eBC patients with vs. without Grade ≥ 3 neutropenia largely overlap with no apparent difference, which might be due to limited sample size and variability of Ctrough. Both neutropenia and QTcF prolongation, the adverse events related to ribociclib PK exposure, are lower in eBC patients in Study O12301C at the dose of 400 mg than in aBC patients at the dose of 600 mg, supporting improved tolerability of 400 mg dose in eBC patients Collectively, the exposure response analyses and the safety and efficacy result of NATALEE support the use of ribociclib 400 mg in combination with ET (letrozole or anastrozole) in patients with HR-positive, HER2-negative eBC [CO Study O12301-Section 3.2 and 3.3]. The FDA’s Assessment: Refer to other clinical pharmacology sections of the Assessment Aid for the FDA review. 19.4.3 Physiologically based Pharmacokinetic Modeling Review The FDA’s Assessment: 205 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Source: PBPK Report DMPK R2300859, Table 6-1. Data analysis: For DDI predictions, the AUC and Cmax ratios were defined as the geometric mean and 90% confidence interval (CI). Prediction error (PE) was calculated as PE = (predicted value -observed value)/observed value × 100. 3. Results 3.1 Predictive performance of ribociclib PBPK model for DDI in healthy subjects Using the updated ribociclib PBPK model and the “adapted healthy volunteer” population model, the predicted DDI effect of ribociclib, as a CYP3A perpetrator and CYP3A victim agreed with the observed data in healthy subjects. The DDI effect of the strong CYP3A4 inhibitor ritonavir and the strong CYP3A inducer rifampicin on the PK of ribociclib was reasonably described (PE <±35%). Furthermore, the ribociclib model recovered the interaction effect of ribociclib, as a strong inhibitor of CYP3A4, on the PK of the CYP3A substrate midazolam (PE<±12%) (Table 40). 210 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. HV 600 SD 61.1 (44.4) 16 A2117 HV 600 SD 49.8 (60) 24 A2111(DiC, fasting) HV 600 SD 42 (32.3) 23 A2111(Tablet, fasting) HV 600 SD 67.1 (51.4) 24 A2101 HV 600 SD 61.1 (44.4) 16 A2117 Late cancer3 400 QD 35.3 (59.2) 4 X2101 Metastatic breast cancer 400 QD 24.4 (51.8) 17 A2207 Late cancer3 600 QD 25.5 (65.7) 53 X2101 Metastatic breast cancer 600 QD 21.0 (50.0) 13 A2207 Late cancer3 600 QD 26.5 (53.2) 20 X2107 Early breast cancer 400 QD Population PK Early breast cancer 600 QD Population PK (M3/7 model) Metastatic breast cancer 600 QD Population PK (M3/7 model) %CV, percent coefficient of variance; CP, cancer population; DiC: drug in capsule; HV, healthy volunteer; N, number of subjects; QD, once a day; SD, single dose 1 The PBPK simulated trials consisted of 10 trials of 10 subjects (n=100) with an age range of 20-55 years, and 100% female. The population model used was the “adapted healthy volunteer (HV)” or “metastatic breast cancer patient (CP)” population model. 2 CL/F value calculated by dose (400 mg) divided by geometric mean AUC0-24h 400 mg QD (10600 ng.h/mL, A2106-Table 11-13). 3 “Late cancer” refers to patients with advanced solid tumor or lymphomas. Source: Reviewer modified from Table 6-2 of PBPK Report DMPK R2300859. The Reviewer did not consider the proposed “metastatic breast cancer patient” population model sufficiently justified based on the following reasons: • Currently, there is no consensus on the clinical effect of cancer on CYP3A abundance. The default cancer population model (Simcyp V22) assumes no alterations on CYP3A abundance in patients with cancer compared to healthy subjects, based on analysis of literature data by the software’s developer (data not shown). Additionally, research from Cheeti et al. (2013) suggested that CYP3A activity is not altered in patients with cancer based on PBPK modeling of midazolam exposure. This finding is supported by Baker et al. (2004), which examined CYP3A activity in 134 patients with cancer and found no significant changes related to age, sex, or body size. In contrast, CYP3A downregulation has been reported in patients with cancer during an acute inflammatory response (Coutant et al., 2015). This alteration (30% reduction in hepatic and intestinal CYP3A4 abundance) has been investigated in a PBPK study demonstrating a better prediction of exposure to sensitive CYP3A4 substrates (midazolam and simvastatin) in patients with cancer (Schwenger et al., 2018). (b) (4) 212 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 3.3 Model Application: Prediction of the effect of CYP3A modulators on the PK of ribociclib PBPK simulations were conducted to predict the DDI effect of moderate (erythromycin) and strong CYP3A inhibitors (ritonavir) and moderate (efavirenz) and strong CYP3A inducers (rifampicin) on the PK of ribociclib in early and metastatic breast cancer patients (Table 43 and Table 44). A slightly dose and time-dependent (i.e., single dose vs steady state) interaction effect on the PK of ribociclib was predicted with CYP3A inhibitors due to autoinhibition effect of ribociclib on CYP3A4. Following administration of the strong CYP3A4 inhibitor ritonavir (100 mg BID, for 14 days) with a single dose of 400 mg ribociclib, the model predicted similar increase in ribociclib exposure (predicted AUCinf and Cmax ratios of 3.1- and 1.4-fold, respectively) as observed in the clinical DDI study in healthy subjects (observed AUCinf and Cmax ratios of 3.2 and 1.7, respectively). Administering ribociclib 400 mg QD for 8 days in the presence of ritonavir, a lower DDI effect was predicted with AUCtau and Cmax ratios of 1.84 and 1.47, respectively. The predicted Cmax and AUCtau of ribociclib in presence of ritonavir was 1322 ng/mL and 19401 ng.h/mL. Following administration of ribociclib 200 mg QD in the presence of ritonavir, a slightly higher DDI effect compared to ribociclib 400 mg QD was predicted due to less autoinhibition of CYP3A4. The predicted AUCtau and Cmax ratios are 2.51 and 1.76, respectively. Consequently, the predicted ribociclib exposure at 200 mg QD in the presence of ritonavir (AUCtau=9695 ng.h/mL) was comparable to the predicted exposure at 400 mg QD without inhibitor (AUCtau=10523 ng.h/mL) (Table 43). Also, the predicted exposure of ribociclib at 400 mg QD dose in presence of ritonavir (AUCtau and Cmax of 19401 ng.h/mL and 1322 ng/mL, respectively) is lower than its reported exposure at the 600 mg QD dose (standard dose for metastatic breast cancer therapy) in patients with late cancer (AUCtau and Cmax of 23800 ng.h/mL and 1820 ng/mL, Study X2101). Therefore, for patients with early breast cancer, a dose reduction from 400 mg QD to 200 mg QD in the presence of a strong CYP3A inhibitor is justified. Administering ribociclib 600 mg QD for 8 days in the presence of ritonavir, the predicted AUCtau and Cmax ratios were 1.56 and 1.33, respectively (Table 43). The predicted ribociclib exposure at 400 mg QD in the presence of ritonavir (AUCtau=19401 ng.h/mL) was comparable to the predicted exposure at 600 mg QD without inhibitor (AUCtau=18696 ng.h/mL). Therefore, for patients with metastatic breast cancer, a dose reduction from 600 mg QD to 400 mg QD in the presence of a strong CYP3A inhibitor is justified and in agreement with conclusions from the original submission (FDA Multidiscipline Review Ribociclib, 2017). No clinically meaningful interaction was predicted with the coadministration of the moderate CYP3A4 inhibitor erythromycin (500 mg BID, for 8 days) with ribociclib 400 mg QD (predicted AUCtau and Cmax ratios of 1.23 and 1.13, respectively) and ribociclib 600 mg QD (predicted AUCtau and Cmax ratios of 1.13 and 1.08, respectively) (Table 43). 213 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 43: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inhibitors Source: Table 6-6 of PBPK Report. Following administration of the strong CYP3A4 inducer rifampin (600 mg QD, for 13 days) with a single 600 mg dose of ribociclib, the model predicted a comparable decrease in ribociclib AUCinf (77%) as observed in the clinical DDI study in healthy subjects (decrease in AUCinf by 89%). A similar decrease in ribociclib AUCtau (around 83-80%) was predicted following administration of ribociclib 400 mg QD or 600 mg QD at steady state (Table 44). Therefore, concomitant use of ribociclib with strong CYP3A4 inducers should be avoided. Following administration of the moderate CYP3A4 inducer efavirenz (600 mg BID, for 14 days) with ribociclib 400 mg QD or 600 mg QD dose, a moderate interaction effect was predicted. The predicted decreases in AUCtau and Cmax of ribociclib were 74% and 55%, respectively, for 400 mg QD and 71% and 52%, respectively, for 600 mg QD. These 214 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. decrease in ribociclib exposure in the presence of efavirenz was comparable to the predictions for a single 400 mg or 600 mg dose of ribociclib (AUCinf decreased by 69%. Table 44: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inducers Source: Table 6-7 of PBPK Report. 4. Conclusions A previously developed ribociclib PBPK model was updated in a newer version of the modeling software (Simcyp version V22) and used to support the revised labeling regarding DDI effects (USPI section 12.3). The Applicant proposed updating the DDI results with moderate CYP3A modulators using the updated PBPK model of ribociclib and their modified versions of the healthy volunteer (‘adapted healthy volunteer’) and cancer (‘metastatic breast cancer patient’) population models. The reviewer identified limitations in the ‘metastatic breast cancer patient’ population model and concluded that it was 215 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. inadequate to be used to support the proposed labeling edits. Consequently, predictions using the updated ribociclib model and the ‘adapted healthy volunteer’ population model were used in the USPI section 12.3. PBPK analyses were adequate to predict the interaction effect of a strong CYP3A inhibitor (ritonavir) and a moderate CYP3A inhibitor (erythromycin) on ribociclib exposure at steady state. The model predicted that coadministration of ritonavir may increase ribociclib AUCtau by 1.8-fold and 1.6-fold, respectively, for 400 mg QD and 600 mg QD doses of ribociclib, respectively. Coadministration of erythromycin is not expected to meaningfully change ribociclib exposure. PBPK analyses were adequate to predict the interaction effect of a moderate CYP3A inducer (efavirenz) on ribociclib exposure at steady state. The model predicted that coadministration of efavirenz may decrease ribociclib AUCtau by around 70% for 400 mg QD and 600 mg QD doses. 5. References Baker SD, van Schaik RHN, Rivory LP, et al (2004). Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res. 10: 8341-8350. Cheeti S, Budha NR, Rajan S, et al. (2013). A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer. Biopharm Drug Dispos. 34: 141-154. Coutant DE, Kulanthaivel P, Turner PK, et al. (2015). Understanding Disease-Drug Interactions in Cancer Patients: Implications for Dosing within the Therapeutic Window. Clin Pharmacol Ther. 98: 76-78. Cubitt HE, Yeo KR, Howgate EM, et al (2011). Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model. Xenobiotica. 41:623-638. FDA Multi-discipline Review and Evaluation NDA 209092. KISQALI (ribociclib). 2017. Accessed at: https://www.accessdata.fda.gov/drugsatfda docs/nda/2017/209092orig1s000multidiscipline r.pdf KISQALI (ribociclib) 200 mg tablets, for oral use. US Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Revised 10/2022. 216 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Samant TS, Huth F, Umehara K, et al (2020). Ribociclib Drug-Drug Interactions: Clinical Evaluations and Physiologically-Based Pharmacokinetic Modeling to Guide Drug Labeling. Clin Pharm Ther. 108: 575-585. Schwenger E, Reddy VP, Moorthy G, et al (2018). Harnessing meta-analysis to refine an oncology patient population for physiology-based pharmacokinetic modeling of drugs. Clin Pharmacol Ther. 103:271-280. 19.5 Additional Safety Analyses Conducted by FDA The FDA’s Assessment: Not applicable.	custom-source	2025-02-12T15:46:47.097670	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/209092s018,209935s027MultidisciplineR.pdf', 'application_number': 209092, 'submission_type': 'SUPPL ', 'submission_number': 18}
80,224	NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 2 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 209935: KISQALI FEMARA CO-PACK is indicated for the adjuvant treatment of adults with hormone receptor (HR)- positive, human epidermal growth factor receptor 2 (HER2)- negative stage II and III early breast cancer at high risk of recurrence. Recommendation on Regulatory Action Regular Approval NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 3 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 9 1. Executive Summary ............................................................................................................... 12 1.1 Product Introduction ........................................................................................................... 12 1.2 Conclusions on the Substantial Evidence of Effectiveness ................................................ 12 1.3 Benefit-Risk Assessment (BRA) ........................................................................................ 16 1.4 Patient Experience Data ...................................................................................................... 19 2. Therapeutic Context .............................................................................................................. 20 2.1 Analysis of Condition ......................................................................................................... 20 2.2 Analysis of Current Treatment Options .............................................................................. 20 3. Regulatory Background ......................................................................................................... 26 3.1 U.S. Regulatory Actions and Marketing History ................................................................ 26 3.2 Summary of Presubmission/Submission Regulatory Activity ............................................ 26 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................................................... 30 4.1 Office of Scientific Investigations (OSI) ............................................................................ 30 4.2 Product Quality ................................................................................................................... 32 4.3 Clinical Microbiology ......................................................................................................... 32 4.4 Devices and Companion Diagnostic Issues ........................................................................ 32 5. Nonclinical Pharmacology/Toxicology ................................................................................. 33 5.1 Executive Summary ............................................................................................................ 33 6. Clinical Pharmacology .......................................................................................................... 36 6.1 Executive Summary ............................................................................................................ 36 6.2 Summary of Clinical Pharmacology Assessment .......................................................... 38 6.2.1 Pharmacology and Clinical Pharmacokinetics........................................................ 38 6.2.2 General Dosing and Therapeutic Individualization ................................................ 39 6.2.2.1 General Dosing ............................................................................................... 39 6.2.2.2 Therapeutic Individualization ......................................................................... 39 6.2.2.3 Outstanding Issues .......................................................................................... 40 6.3 Comprehensive Clinical Pharmacology Review ............................................................ 41 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 4 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 41 6.3.2 Clinical Pharmacology Questions ........................................................................... 41 7 Sources of Clinical Data ........................................................................................................ 46 7.1 Table of Clinical Studies ..................................................................................................... 46 8 Statistical and Clinical Evaluation ......................................................................................... 49 8.1 Review of Relevant Individual Trials Used to Support Efficacy ....................................... 49 8.1.1 Study CLEE011O12301C ........................................................................................ 49 8.1.2 Study Results ........................................................................................................... 60 8.1.3 Integrated Review of Effectiveness ......................................................................... 91 8.1.4 Assessment of Efficacy Across Trials ..................................................................... 91 8.1.5 Integrated Assessment of Effectiveness ................................................................... 92 8.2 Review of Safety ................................................................................................................ 95 8.2.1 Safety Review Approach ......................................................................................... 95 8.2.2 Review of the Safety Database ................................................................................ 96 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ......................................... 101 8.2.4 Results ................................................................................................................... 103 8.2.5 Analysis of Submission-Specific Safety Issues ..................................................... 126 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ... 143 8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 143 8.2.8 Specific Safety Studies/Clinical Trials .................................................................. 146 8.2.9 Additional Safety Explorations .............................................................................. 146 8.2.10 Safety in the Postmarket Setting .......................................................................... 151 8.2.11 Integrated Assessment of Safety .......................................................................... 153 8.3 Statistical Issues ................................................................................................................ 160 8.4 Conclusions and Recommendations ................................................................................. 160 8.4.1 Approach to Substantial Evidence of Effectiveness ............................................. 161 9 Advisory Committee Meeting and Other External Consultations ....................................... 163 10 Pediatrics ............................................................................................................................. 164 11 Labeling Recommendations ................................................................................................ 165 12 Risk Evaluation and Mitigation Strategies (REMS) ............................................................ 171 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 5 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 13 Postmarketing Requirements and Commitment .................................................................. 172 14 Division Director (DHOT) (NME ONLY) .......................................................................... 174 15 Division Director (OCP) ...................................................................................................... 175 16 Division Director (OB) ........................................................................................................ 176 17 Division Director (Clinical) ................................................................................................. 177 18 Office Director (or designated signatory authority) ............................................................ 178 19 Appendices .......................................................................................................................... 179 19.1 References ....................................................................................................................... 179 19.2 Financial Disclosure ........................................................................................................ 180 19.3 Nonclinical Pharmacology/Toxicology........................................................................ 181 19.4 OCP Appendices (Technical documents supporting OCP recommendations) ............ 182 19.4.1 Population PK Analysis ....................................................................................... 182 19.4.1.1 Executive Summary .......................................................................................... 182 19.4.1.2 PPK Assessment Summary ........................................................................... 182 19.4.1.3 PPK Review Issues ........................................................................................... 190 19.4.1.4 Reviewer’s Independent Analysis..................................................................... 190 19.4.2 Exposure-Response Analysis ............................................................................... 190 19.4.2.1 ER (efficacy) Executive Summary ................................................................... 190 19.4.2.2 ER (efficacy) Assessment Summary ................................................................ 190 19.4.2.3 ER (safety) Executive Summary ....................................................................... 192 19.4.2.4 ER (safety) Assessment Summary .................................................................... 192 19.4.2.5 ER Review Issues ............................................................................................. 200 19.4.2.6 Reviewer’s Independent Analysis..................................................................... 200 19.4.2.7 Overall benefit-risk evaluation based on E-R analyses .................................... 200 19.5 Additional Safety Analyses Conducted by FDA ......................................................... 216 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 6 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table of Tables Table 1: Summary of treatment armamentarium relevant to proposed indication other than chemotherapy ................................................................................................................................ 21 Table 2: -Induced Increase in MF in Duodenum of Male MutaTMMice ........................ 33 Table 3: -Induced Increase in MF in Duodenum of Female MutaTMMice ..................... 34 Table 4: -Induced Increase in MF in Livers of Male MutaTMMice ................................ 34 Table 5: Equivocal Increase in MF in Livers of Female MutaTMMice ......................................... 35 Table 6: Key Clinical Pharmacology Review Issues .................................................................... 36 Table 7: Listing of Clinical Trials Relevant to this NDA/BLA .................................................... 46 Table 8: Patient disposition (final iDFS analysis, 21-Jul-2023 data cut-off) by treatment arm (FAS)............................................................................................................................................. 61 Table 9: Protocol deviations (FAS) .............................................................................................. 63 Table 10: Demographic Characteristics ........................................................................................ 64 Table 11: Disease characteristics (FAS) ....................................................................................... 67 Table 12: Randomization by stratification factor (Full analysis set) ............................................ 72 Table 13: Log-rank test results for iDFS (FAS) ........................................................................... 74 Table 14: FDA – iDFS Censoring Reasons (final iDFS analysis) ................................................ 77 Table 15: FDA – Timing of Censoring for Patients Censored for Withdrawal of Consent ......... 77 Table 16: FDA – iDFS Sensitivity Analyses to Account for Imbalance in Patients Censored at Randomization for Withdrawal of Consent .................................................................................. 78 Table 17: Secondary efficacy results (Study O12301C) - final iDFS analysis (21-Jul-2023 data cut-off) .......................................................................................................................................... 78 Table 18: Applicant's OS Simulation ............................................................................................ 85 Table 19: FDA – Clinical Site Inspections ................................................................................... 86 Table 20: FDA – Final iDFS by Anatomic Stage and Nodal Status ............................................. 91 Table 21: Duration of exposure to study treatment by group in Study O12301C (Safety set) ..... 96 Table 22: Overview of clinical studies with safety data ............................................................... 98 Table 23: On-treatment deaths in Study O12301C (Safety set) ................................................. 103 Table 24: FDA – Analysis of Deaths by Study Period and Cause of Death ............................... 104 Table 25: Serious adverse events by preferred term and worst toxicity grade, irrespective of causality, with incidence at least 0.2% / either group in Study O12301C (Safety set) .............. 110 Table 26: Adverse events leading to discontinuation by preferred term and worst toxicity grade, irrespective of causality, with at least 0.2% / either group in Study O12301C (Safety set) ....... 113 (b) (4) (b) (4) (b) (4) NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 7 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 27: Adverse events leading to study drug interruption by preferred term and worst toxicity grade, irrespective of causality, with incidence at least 2% / either group in Study O12301C (Safety set) .................................................................................................................................. 115 Table 28: Adverse events leading to study drug dose reduction by preferred term and worst toxicity grade, irrespective of causality with incidence at least 0.2% / either group in Study O12301C (Safety set) .................................................................................................................. 116 Table 29: Common adverse events with grade ≥ 3 events at incidence ≥ 1.0% in either group, by preferred term in Study O12301C (Safety set) ........................................................................... 119 Table 30: New or worsening postbaseline hematology and clinical chemistry abnormalities, with incidence at least 10% / either group in Study O12301C (Safety set) ........................................ 120 Table 31: Clinically notable ECG values by treatment group in Study O12301C (Safety set) .. 124 Table 32: Summary of deaths and adverse event categories in Study O12301C (Safety set) .... 153 Table 33: FDA – PMC/PMR Checklist for Trial Diversity and U.S. Population Representativeness ...................................................................................................................... 173 Table 34: Summary of disclosable financial arrangements and interests ................................... 180 Table 35: Distribution of intrinsic factors in popPK dataset ...................................................... 186 Table 36: Summary of steady-state ribociclib PK parameters across populations and studies .. 187 Table 37: Simulated C1D1 and steady-state ribociclib PK parameters at the dose of 400 mg QD in HR-positive, HER2-negative eBC patients in Study O12301C ............................................. 187 Table 38: Estimated mean QTcF change from baseline from QTcF–ribociclib concentration model (PK-ECG set) ................................................................................................................... 198 Table 39: Input parameters for ribociclib PBPK model ............................................................. 204 Table 40: Predicted and observed DDI effect of ribociclib as a CYP3A perpetrator or CYP3A victim .......................................................................................................................................... 206 Table 41: PBPK predicted and observed PK parameters or plasma concentrations of ribociclib ..................................................................................................................................................... 206 Table 42: Comparison of ribociclib CL/F reported in clinical studies, estimated by Population PK analysis and predicted by PBPK analysis ................................................................................... 209 Table 43: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inhibitors ..................................................................................................................................... 213 Table 44: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inducers ....................................................................................................................................... 214 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 8 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table of Figures Figure 1: Study design .................................................................................................................. 50 Figure 2: Kaplan-Meier plot for iDFS (FAS) - final iDFS analysis (21-Jul-2023 data cut-off) ... 75 Figure 3: Forest plot of iDFS by stratum (final iDFS analysis, 21-Jul-2023 data cut-off (FAS) . 80 Figure 4: Forest plot of iDFS – subgroup analysis (final iDFS analysis, 21-Jul-2023 data cut-off (FAS)............................................................................................................................................. 80 Figure 5: Prediction-corrected visual predictive check (VPC) of the updated popPK model compared with observed PK concentrations in Study O12301C ................................................ 189 Figure 6: Kaplan-Meier plot of iDFS by quartiles of geometric mean of popPK-predicted Ctrough (ng/mL) on non-zero dosing days (PK-iDFS set) ......................................................... 192 Figure 7: Boxplot of evaluable ribociclib SS Ctrough (ng/mL) collected on C1D15 by occurrence of newly occurring grade 3 or worse neutropenia (PK-Neutropenia set) ................................... 195 Figure 8: Scatter plot of QTcF change from baseline versus ribociclib concentration with PK-QT model and 90% CI (PK-ECG set) ............................................................................................... 199 Figure 9: Predicted and observed plasma concentration-time profiles of ribociclib in healthy subjects and patients with late cancer ......................................................................................... 207 Figure 10: Predicted and observed plasma concentration-time profiles of ribociclib in patients with early breast cancer .............................................................................................................. 208 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 9 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reviewers of Multi-Disciplinary Review and Evaluation OPQ Team Qi (Charles) Liu, Rohit Kolhatkar, Ramesh Raghavachari RBPM Utkarsh Desai OPDP Courtney Leach, Rachael Conklin PLT Susan Redwood, Barbara Fuller OSI Suyoung Tina Chang, Phillip Kronstein OSE/DMEPA Tingting Gao, Alice Tu OSE/RPM Frances Fahnbulleh QT/IRT Consult Devi Kozeli, Yanyan Ji, Anantha Ram Nookala, Eliford N. Kitabi, Ferdouse Begum, Dalong Huang, Michael Y. Li, Christina E. Garnett Safety Team Stacie Woods, Oladimeji (Ladi) Akinboro, Abhilasha Nair OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion PLT=Patient Labeling Team OSI=Office of Scientific Investigations OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DRISK=Division of Risk Management RPBM = Regulatory Business Process Manager Regulatory Project Manager Sherry Hou Pharmacology/Toxicology Reviewer George Ching-Jey Chang Pharmacology/Toxicology Team Leader Tiffany Ricks Office of Clinical Pharmacology Reviewer Francis Green Office of Clinical Pharmacology Team Leader Hong Zhao Pharmacometrics Reviewer Huali Wu Pharmacometrics Team Leader Jingyu (Jerry) Yu PBPK Reviewer Manuela Grimstein PBPK Team Leader Yuching Yang Clinical Reviewers Tatiana Prowell (Safety) Jennifer Gao (Efficacy) Clinical Team Leader Jennifer Gao Safety Analyst Ilynn Bulatao Statistical Reviewer Haley Gittleman Statistical Team Leader Joyce Cheng Associate Director for Patient Outcomes Vishal Bhatnagar Associate Director for Labeling (ADL) William Pierce Cross-Disciplinary Team Leader Jennifer Gao Division Director (OCP) Nam Atiqur Rahman Supervisory Mathematical Statistician (OB) Mallorie Fiero Division Director (OOD) Laleh Amiri-Kordestani NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 10 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Glossary aBC advanced breast cancer ADR adverse drug reaction AE adverse event AI aromatase inhibitor ANC absolute neutrophil count BC breast cancer BCRP Breast cancer resistance protein (transporter) BSEP Bile salt export pump (transporter) CDK4/6 Cyclin-dependent kinase 4/6 CRF case report form CRO contract research organization CSR clinical study report DCO data cut-off DDFS distant disease-free survival DFS disease-free survival DRFS distant recurrence-free survival ECG electrocardiogram ECOG Eastern Cooperative Oncology Group eCRS electronic case retrieval strategy eCTD electronic common technical document EORTC European Organisation for Research and Treatment of Cancer ER estrogen receptor ET endocrine therapy ET only arm/group letrozole or anastrozole, plus goserelin (if applicable) FDA Food and Drug Administration GCP good clinical practice HER2 Human epidermal growth factor receptor 2 HR hormone receptor iDFS invasive disease-free survival ILD interstitial lung disease IRT interactive response technology IND Investigational New Drug MATE1 Multidrug and toxin extrusion protein 1 (transporter) MedDRA Medical Dictionary for Regulatory Activities NDA new drug application NSAI nonsteroidal aromatase inhibitor OCT2 Organic cation transporter 2 OS overall survival PARP Poly (ADP-ribose) polymerase PBPK physiologically-based pharmacokinetic (model) PD pharmacodynamics PFS progression-free survival NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 11 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. PgR progesterone receptor PI prescribing information popPK population pharmacokinetics PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PPS per protocol set PRO patient reported outcome PSUR periodic safety update report RFS recurrence-free survival RDI relative dose intensity SAE serious adverse event SAP statistical analysis plan SC Steering Committee SCE summary of clinical efficacy SCP summary of clinical pharmacology SCS summary of clinical safety SEER Surveillance, Epidemiology, and End Results SOC system organ class SPM second primary malignancies STEEP Standardized Definitions for Efficacy End Points (in Adjuvant Breast Cancer Trials) TTR time to response TEAE treatment emergent adverse event VPC visual predictive checks NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 13 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. disease recurrence or unacceptable toxicity occurred. Endocrine therapy was given per standard of care for a total duration of at least 60 months (5 years). The primary endpoint of NATALEE was invasive disease-free survival (iDFS) by investigator in the intent to treat (ITT) population. Final iDFS analysis was planned at 500 events with 93% power to detect a hazard ratio of 0.73 at a one-sided alpha of 0.025 using a stratified log-rank test. Three interim analyses (IA) for iDFS were planned: • IA1: for futility at 40% iDFS events • IA2: for efficacy superiority at 70% iDFS events • IA3: for efficacy superiority at 85% iDFS events Secondary endpoints included overall survival (OS), although the trial was not powered for OS, and OS was not formally tested. OS analysis was planned at iDFS IA2 and IA3 if the efficacy boundary were crossed, and at the final analysis of iDFS. A total of 2549 patients were randomized to the ribociclib + ET arm and 2552 patients were randomized to the ET only arm. The trial met its primary endpoint of iDFS at IA3 demonstrating a statistically significant improvement in iDFS (hazard ratio [HR] 0.748, 95% confidence interval [CI] 0.619-0.906). The 3-year iDFS was 90.4% (88.6-91.9) on the ribociclib + ET arm compared to 87.1% (85.3-88.8) on the ET only arm, for an absolute difference of 3.3%. However, at IA3, there was a large amount of censoring for iDFS, as only 20% of patients had completed 3 years of adjuvant ribociclib. Thus, there was a concern for possible diminishing iDFS effect with longer follow-up. Additionally, OS was immature with 134 total events (OS HR 0.759, 95% CI 0.539-1.068), and there were more treatment-emergent adverse events (TEAEs) and deaths on the ribociclib + ET arm compared to the ET only arm. Due to these concerns, FDA requested the Applicant continue NATALEE until the final iDFS analysis, and to conduct an additional OS analysis at the time of final iDFS analysis. The sNDA submission for 209092/S-018 was received on December 22, 2023. The Applicant used a priority review voucher (PRV). The sNDA submission for 209935/S-027 was received on March 11, 2024, and cross-references sNDA 209092/S-018. The sNDA submissions are based on final iDFS of the NATALEE trial, with a data-cutoff date of July 21, 2023. At the final iDFS analysis, the iDFS HR was 0.749 (95% CI 0.628-0.892). While the median iDFS was not estimable on either treatment arm, the 3-year iDFS rates were 90.7% (95% CI: 89.3, 91.8) in the ribociclib + ET arm and 87.6% (95% CI: 86.1, 88.9) in the ET only arm. The interim OS analysis at the time of final iDFS remained immature with 84 deaths (3%) on the ribociclib + ET arm and 88 deaths (3%) on the ET only arm; the OS HR was 0.89 (95% CI 0.66-1.20) with median OS not estimable. The overall safety data was consistent with the known adverse event (AE) profile of ribociclib + ET, but the incidence and severity of most AEs was lower, likely due to the lower dose of ribociclib used in the adjuvant setting, as well as a generally healthier adjuvant population. As of July 21, 2023 data-cut off, 43% patients had completed ≥3 years of ribociclib + ET and 69% had completed ≥2 years of ribociclib + ET. Deaths on treatment were uncommon overall but higher on the ribociclib + ET arm, with 20 deaths (0.8%) compared to 9 deaths (0.4%) on the ET only arm. Adverse events of special interest (AESI) were analyzed, including hepatobiliary toxicity, NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 20 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 2. Therapeutic Context 2.1 Analysis of Condition The Applicant’s Position: Breast cancer (BC) is the most frequently diagnosed cancer worldwide. Approximately 2.3 million new cases of BC and 685,000 deaths attributed to this disease were estimated to occur in 2020 worldwide. Breast cancer incidence varies between individuals of different ethnicities and in different geographic locations around the world, with age-standardized world incidence rates per 100,000 ranging from 26.2 for South-Central Asia to 95.5 for Australia and New Zealand (GLOBOCAN 2020). In the United States, BC is projected to be the most common cancer diagnosed in 2023 with an estimated incidence of 297,790 new cases and 43,170 deaths (SEER 2023). Across Europe, the estimated incidence of BC in 2020 was approximately 531,000, with 142,000 deaths (GLOBOCAN 2020). Breast cancer in men is uncommon, with a reported frequency of approximately 1% of all BC (Eggemann et al 2013). Almost all newly diagnosed BC cases are early BC (eBC), localized to the breast tissue and regional lymphatics, which are potentially curable with surgical resection and a variety of treatment modalities. Based on SEER Program data collected between the years 2010 and 2019, among all HR-positive, HER2-negative breast cancer cases in females, 94.8% of cases diagnosed were eBC, with 68.9% localized to the breast tissue and 25.9% within both the breast tissue and regional lymph nodes (SEER 2022). The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of breast cancer worldwide and in the U.S. HR+, HER2-negative breast cancer is the most common subtype, and early-stage disease is treated with curative intent. 2.2 Analysis of Current Treatment OptionsThe Applicant’s Position: Besides primary surgery, systemic management of patients with HR-positive, HER2-negative eBC consists of additional antineoplastic treatment modalities including adjuvant endocrine therapy/aromatase inhibitor (ET/AI: letrozole, anastrozole or exemestane) or tamoxifen, radiotherapy, and neoadjuvant and/or adjuvant chemotherapy, typically considered for patients at risk for recurrence. The need for and selection of systemic adjuvant therapies is based on each individual’s risk of recurrence and is guided by several clinical, pathological and genomic predictive and prognostic considerations. Specifically, patients considered to be at increased risk for recurrence include anatomic stage Group II and III disease with larger tumor size and/or metastases in multiple regional lymph nodes, high tumor grade, and high recurrence genomic score, or a combination of these. Adjuvant systemic treatments, including multiagent chemotherapy and hormonal therapy in patients with eBC decrease locoregional and distant recurrences, and have been shown to improve 15-year breast cancer mortality (Clarke et al 2005). Adjuvant ET/AI or tamoxifen, independent of chemotherapy, has been shown to reduce the risk of recurrence and BC deaths (Clarke et al 2005), and has therefore been incorporated into clinical NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 21 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. guidelines as a recommended treatment for pre- and postmenopausal women with HR-positive eBC (Senkus et al 2015, NCCN 2019). Based on limited data, adjuvant AI or tamoxifen is also considered to be the treatment of choice for men with HR-positive, HER2-negative eBC (Zagouri et al 2015). While the incorporation of adjuvant ET for the treatment of patients with HR-positive eBC has been shown to reduce the risk of recurrence and BC deaths (Clarke et al 2005), recurrences are still common, affecting approximately 30-60% of patients with Stage II and III disease (Bria et al 2010, Wangchinda, Ithimakin 2016, Gomis, Gawrzak 2017 Pan et al 2017). In a meta-analysis including more than 60,000 women with ER-positive eBC who were disease-free after 5 years of adjuvant ET, the cumulative 20-year risk of distant recurrence was 31% in those with 1-3 positive nodes (N1-3), and 52% in those with 4-9 positive nodes (N4-9). Additionally, the cumulative 20-year risk of distant recurrence in patients without nodal disease (N0) was 22%, indicating that these patients are also at risk for recurrence. The corresponding cumulative 20- year risks of death from BC based on nodal status (N0, N1-3, N4-9) were 15%, 28%, and 49%, respectively (Pan et al 2017). Although the risk of recurrence in patients with HR-positive, HER-2 negative eBC is highest during the first 5 years after diagnosis, among those who recur, more than half experience late recurrences (≥ 5 years from diagnosis) (Bria et al 2010, Wangchinda, Ithimakin 2016, Gomis, Gawrzak 2017, Pan et al 2017). Disease recurrence typically presents as distant metastasis, which is generally incurable and will eventually lead to death due to BC (Pan et al 2017). Thus, prevention of both early and late recurrences are equally important considerations when making adjuvant treatment recommendations for patients with HR-positive, HER2-negative eBC. Of note, Verzenio (abemaciclib), a CDK4/6 inhibitor in combination with ET (tamoxifen or an AI) is approved for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive, eBC at high risk of recurrence. These data, including the long-term persistent risk of disease recurrence despite adjuvant ET, highlight the need for new therapeutic strategies that are well tolerated and improve clinical outcomes in patients with HR-positive, HER2-negative Stage II and III eBC. Table 1: Summary of treatment armamentarium relevant to proposed indication other than chemotherapy Products Name Relevant Indication Year of Approval And Type of Approval Dosing/ Administration Efficacy Information Important Safety and Tolerability Issues Other Comments FDA Approved Treatments Non-steroidal aromatase inhibitors NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 22 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Letrozole (Femara) Letrozole is indicated for: - Adjuvant treatment of postmenopaus al women with hormone receptor positive early breast cancer. - Extended adjuvant treatment of postmenopaus al women with early breast cancer, who have received prior standard adjuvant tamoxifen therapy. 2004 Recommended dose: 2.5.mg once daily Femara tablets are taken orally without regard to meals vs. tamoxifen DFS: HR 0.79; 95% CI (0.68, 0.92); systemic DFS: HR 0.83; 95% CI (0.70, 0.97); time to distant metastasis: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06) The most common adverse drug reactions (≥ 20%) were hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholest erolemia, sweating increased, bone pain; and musculoskel etal Initial accelerated approvals for adjuvant (2005) and extended adjuvant (2004) treatment received that was converted to full approval in 2010. Anastrozole (Arimidex) Anastrozole is indicated as monotherapy for the adjuvant treatment of postmenopaus al women with hormone receptor positive early breast cancer 2002 One 1 mg tablet taken once daily vs. tamoxifen or in combination with tamoxifen DFS: HR: 0.87, 95% CI (0.78, 0.97), HR-positive subgroup: HR 0.83, 95% CI: (0.73, 0.94). Of note, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen and is therefore not recommended to be administered The most common adverse reactions (≥10%) were hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension , depression, nausea and vomiting, rash, osteoporosis , fractures, back pain, insomnia, headache, peripheral edema and lymphedema , regardless of causality. Priority review NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 23 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. in combination. Steroidal aromatase inhibitors Exemestane (Aromasin®) Exemestane is indicated as monotherapy for the adjuvant treatment of postmenopaus al women with ER-positive early breast cancer who have received 2 to 3 years of tamoxifen and are switched to Aromasin for completion of a total of 5 consecutive years for adjuvant hormonal therapy. 2005 Recommended Dose: One 25 mg tablet once daily after a meal vs tamoxifen DFS: HR: 0.69, 95% CI: (0.58, 0.82); HR-positive subpopulation DFS: HR: 0.65, 95% CI: (0.53, 0.79) Most common adverse reactions (≥ 10%) were hot flushes, fatigue, arthralgia, headache, insomnia, and increased sweating. Selective estrogen receptor modulator Tamoxifen (Soltamox) Tamoxifen is indicated as monotherapy for the adjuvant treatment of adult patients with early- stage ER- positive breast cancer. 2005 Recommended daily dose is 20 mg daily for 5- 10 years. The 10-year outcome data were reported in 1998 for 36,689 women in 55 randomized trials of another formulation of adjuvant tamoxifen using doses of 20 to 40 mg per day for 1 to 5+ years. Most common adverse reactions: hot flashes, mood disturbance, vaginal discharge, vaginal bleeding, nausea, and fluid retention. CDK 4/6 inhibitor NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 24 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Abemaciclib (Verzenio) Abemaciclib is indicated in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR- positive, HER2- negative, node-positive, early breast cancer at high risk of recurrence. 2023 Recommended starting dose in combination with fulvestrant or an aromatase inhibitor: 150 mg twice daily. Verzenio tablets are taken orally with or without food. vs ET alone Cohort 1 population: iDFS: HR: 0.653; 95% CI: (0.567, 0.753); 2-year IDFS rates of 85.5% (abemaciclib arm) versus 78.6% (control arm). Most common adverse reactions (≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocyto penia. Priority Review PARP inhibitor Olaparib (Lynparza) Olaparib in indicated as monotherapy for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2- negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. 2022 Recommended dose: 300 mg taken orally twice daily, with or without food for up to 1 year. vs placebo iDFS: HR 0.58; 95% CI: (0.46, 0.74); OS: HR 0.68; 95% CI: (0.50, 0.91). IDFS at 3 years was 86%; 95% CI: (82.8, 88.4) for patients receiving olaparib and 77%; 95% CI: (73.7, 80.1) for those receiving placebo. Most common adverse reactions (≥10%) were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocyto penia Priority Review NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 25 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Systemic treatment options other than chemotherapy are included. Source: Femara USPI 2020, Arimidex USPI 2018, Aromasin USPI 2021, Soltamox USPI 2019, Verzenio USPI 2023, Lynparza USPI 2023 The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of the current treatment options for patients with early-stage HR+, HER2-negative breast cancer in the U.S. FDA concurs with the Applicant’s assessment that additional treatment options are needed for this patient population, where treatment is given with curative intent. As noted by the Applicant, more than half of recurrences of HR+, HER2-negative breast cancer occur ≥5 years after diagnosis. Due to the limited follow-up of the NATALEE trial, there is no information available at this time on whether addition of ribociclib to ET impacts the risk of these late recurrences. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 26 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 3. Regulatory Background 3.1 U.S. Regulatory Actions and Marketing History The Applicant’s Position: Kisqali® (ribociclib) was initially approved on 13-Mar-2017 in the US for the treatment of HR- positive/HER2-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy, based on results from Study A2301. Ribociclib was approved on 10-Dec-2021 in the US for use in men in combination with aromatase inhibitor as initial endocrine based therapy or fulvestrant as initial endocrine based therapy or following disease progression on ET in HR-positive, HER2-negative advanced or metastatic breast cancer. Kisqali was also approved for an expanded indication on 18-Jul-2018 in the US based on results from Studies E2301 and F2301. In the US, Kisqali is indicated for the treatment of adult patients with HR-positive, HER2- negative advanced or metastatic breast cancer in combination with: • an aromatase inhibitor as initial endocrine-based therapy; or • fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men Kisqali is also available in the US as part of the Kisqali® Femara® Co-Pack (ribociclib tablets co- packaged with letrozole tablets), approved on 04-May-2017. The FDA’s Assessment: FDA generally agrees with the Applicant’s summary of the U.S. marketing history of ribociclib. 3.2 Summary of Presubmission/Submission Regulatory Activity The Applicant’s Position: A summary of the key interactions with the FDA are provided below: • September 10, 2018: The protocol for Study CLEE011O12301C (Study O12301C) was submitted to FDA for the adjuvant treatment of early breast cancer on September 10, 2018 (SN 0806). • October 18, 2018: The purpose of this Type B (EOPII) meeting was to seek FDA’s advice on key aspects of the study design of Study O12301. Preliminary comments were received on November 08, 2018 and the meeting was ultimately cancelled by Novartis on November 16, 2018 as FDA agreed with Novartis questions and gave clear advice on the design of the trial. • March 31, 2023: At the request of FDA, Novartis submitted topline data from the iDFS primary analysis (IA3). NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 32 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Overall, there was no evidence of discrepancy in iDFS events reported at the five inspected trial sites. There was no other evidence of underreporting of AEs at the five inspected trial sites. No significant discrepancies or notable findings were identified at Site 5057 and 5075. OSI concluded overall that the study appears to have been conducted adequately, and the data generated by the clinical investigator sites appear acceptable in support of this sNDA. FDA concurs with OSI’s assessment. The review team concluded that the issues identified during inspection do not meaningfully alter the finding of a favorable benefit-risk assessment or preclude regulatory approval. Refer to the FDA OSI review and FDA correspondence with the Applicant for full details. 4.2 Product Quality The FDA’s Assessment: The Office of Pharmaceutical Quality (OPQ), CDER recommends approval of these applications for 209092/S-018 and 209935/S-027. Refer to FDA Product Quality’s review for full details. 4.3 Clinical Microbiology The FDA’s Assessment: Not applicable. 4.4 Devices and Companion Diagnostic Issues The FDA’s Assessment: Not applicable. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 39 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 6.2.2 General Dosing and Therapeutic Individualization 6.2.2.1 General Dosing The Applicant’s Position: The pivotal Phase III study O12301C evaluated ribociclib 400 mg for eBC patients. Selection of the ribociclib dose and regimen (400 mg daily on Days 1 to 21 of a 28-day cycle) was based on previous PK-QTcF and ANC exposure-response modeling of data in patients with advanced cancer, exposure-efficacy analysis, and exploratory progression-free survival (PFS) analysis by dose reduction in patients with aBC. Results of Study O12301C demonstrated that the 400 mg ribociclib dose is safe and efficacious for use for eBC. Thus, the recommended dose of ribociclib for the adjuvant setting for eBC is 400 mg (two 200-mg film-coated tablets) of ribociclib once daily, Days 1 to 21 of each 28-day cycle for 3 years combined with 5 years of ET. The FDA’s Assessment: FDA generally agrees with the Applicant. The proposed recommended ribociclib dosage of 400 mg daily, on Days 1 to 21 of a 28-day cycle is acceptable for the indicated eBC patient population as it is supported by the efficacy and safety demonstrated in patients with eBC enrolled in the pivotal NATALEE trial. Refer to Section 6.3 for data and analyses supporting the proposed dosing regimen. 6.2.2.2 Therapeutic Individualization The Applicant’s Position: Specific populations: The recommendation for alternative dosing regimen for subpopulations based on intrinsic patient factors has no change since the prior approvals [Studies E2301/F2301]. Patients with hepatic impairment: In Study O12301C, no apparent increase in exposure was observed in patients with mild hepatic impairment, however, the sample size is limited (n=9). A total of 3 patients with moderate hepatic impairment were treated in the ribociclib arm of Study O12301C. Based on the data in eBC patients, the previously submitted hepatic impairment data in non-cancer subjects and advanced cancer patients, as well as post-marketing experience in aBC patients, no ribociclib dose adjustment is warranted for eBC patients with hepatic impairment [SCP Study O12301C-Section 5.2.1]. Patients with renal impairment: In Study O12301C, there was no apparent effect of mild renal impairment on ribociclib PK exposure. No apparent increase in exposure was observed in patients with moderate renal impairment, however, the sample size is limited (n=8). Based on the data in eBC patients and the previously submitted renal impairment data in aBC patients and non-cancer subjects, no dose reduction is required for eBC patients with mild or moderate renal impairment, and a lower starting dose of 200 mg is recommended in eBC patients with severe renal impairment [SCP Study O12301C-Section 5.2.2]. Drug-drug interactions: NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 40 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Effect of concomitant-medications on ribociclib: PBPK model-predicted ribociclib steady- state Cmax and AUC ratios with vs without coadministration of ritonavir were 1.47 and 1.84, respectively, in patients with eBC at the dose of 400 mg. Alternate concomitant medication with a low potential to inhibit CYP3A should be considered in eBC patients. If co-administration of ribociclib with a strong CYP3A inhibitor cannot be avoided, monitor for adverse reactions and consider reducing the dose to 200 mg, if necessary. Rifampicin (a strong CYP3A4 inducer) decreased ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single oral dose of 600 mg ribociclib, compared to ribociclib alone in Study A2101 [SCP Study A2301]. Concomitant use of ribociclib with strong CYP3A4 inducers should be avoided in patients with eBC [SCP Study O12301C-Section 5.3.1]. Effect of ribociclib on concomitant medications: Ribociclib dosed at 400 mg once daily is a moderate inhibitor of CYP3A4 and increased steady-state exposure of the CYP3A4 substrate midazolam by 280% (3.8-fold). Caution is recommended when ribociclib 400 mg is administered with CYP3A substrates with a narrow therapeutic index in patients with eBC. The dose of a sensitive CYP3A substrate with a narrow therapeutic index may need to be reduced. Based on in vitro inhibition data at the dose of 400 mg dose, ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations [SCP Study O12301C- Section 5.3.2]. The FDA’s Assessment: FDA agrees with the Applicant’s position that no therapeutic individualization of ribociclib is needed based upon intrinsic factors from the popPK modeling results including age, body weight, sex, or race. The impact of renal and hepatic impairment on the PK of ribociclib in patients with eBC was similar to that in patients with aBC. No new intrinsic factors were identified for dose adjustment. Refer to Section 6.3.2.3. For patients with eBC, the FDA agrees with dose reduction from 400 mg QD to 200 mg QD when co-administration of a strong CYP3A4 inhibitor, based on PBPK predictions. Co- administration of moderate CYP3A4 inhibitor is not expected to meaningfully change the exposure of ribociclib at steady state. A moderate effect is expected with co-administration of a moderate CYP3A4 inducer. For patients with aBC, PBPK predictions, using the updated model of ribociclib, are consistent with conclusions and DDI management strategies from the original NDA submission. Refer to section 19.4.3 for details about the PBPK modeling analysis. 6.2.2.3 Outstanding Issues The Applicant’s Position: There are no PMR/PMCs currently ongoing. The FDA’s Assessment: FDA concurs with the Applicant’s position. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 41 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 6.3 Comprehensive Clinical Pharmacology Review 6.3.1 General Pharmacology and Pharmacokinetic Characteristics The Applicant’s Position: Comprehensive PK data on ribociclib were provided in the prior submissions. In Study O12301C in patients with eBC, the population mean estimate of the apparent clearance of ribociclib in eBC patients was 38.4 L/hr at a 400 mg dose, based on population PK modeling. In Study A2207 in patients with aBC, the geometric mean Cmax and AUC0-24h were approximately 28% and 43% lower for the ribociclib 400 mg arm as compared to the ribociclib 600 mg arm. The observed geometric mean apparent clearance at steady-state was 24.4 L/hr at 400 mg and 21.0 L/hr at 600 mg in patients with aBC. The steady-state PK exposure in eBC patients in Study O12301C at 400 mg was lower than those in advanced cancer patients in Study X2101 at the dose of 600 mg (56% and 48% lower for AUC and Cmax, respectively), which can be attributed to lower dose as well as faster clearance due to PK nonlinearity and population effect potentially due to no detectable disease in eBC patients [CO Study O12301-Section 3.1.2]. The FDA’s Assessment: FDA generally agrees with the Applicant on the general clinical pharmacology characteristics of ribociclib. The updated popPK model adequately characterized the PK profile of ribociclib in patients with eBC who received the proposed recommended dosage. Refer to Section 19.4.1 for data and analyses related to popPK modelling. 6.3.2 Clinical Pharmacology Questions 6.3.2.1 Does the clinical pharmacology program provide supportive evidence of effectiveness? The Applicant’s Position: Yes. Collectively, the clinical pharmacology program supports the use of ribociclib 400 mg in combination with ET (letrozole or anastrozole) in patients with HR-positive, HER2-negative eBC. Selection of the ribociclib dose and regimen (400 mg daily on Days 1 to 21 of a 28-day cycle) is discussed in Section 6.2.2.1. The evidence of effectiveness of ribociclib was demonstrated in Study O12301C in patients ≥ 18 years of age with HR-positive, HER2-negative, Stage II or Stage III eBC by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Detailed efficacy results are provided in Section 8.1.2. Due to limited sample size of patients with iDFS events, exposure-efficacy relationship cannot be characterized [CO Study O12301C-Section 3.3]. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 42 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: FDA agrees that effectiveness of the proposed recommended dosage of ribociclib 400 mg daily for Days 1 to 21 days in a 28-day cycle with ET was demonstrated via the primary endpoint of iDFS in the NATALEE trial (See Section 8.1.5). The exposure-efficacy relationship is considered exploratory and could not be adequately characterized due to the limited PK data collected in the NATALEE trial. Refer to Section 19.4.2 for data and analyses regarding the exposure-response relationship between ribociclib exposure and iDFS from the NATALEE trial. 6.3.2.2 Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought? The Applicant’s Position: Yes. Based on the observed efficacy and safety data of Study O12301C, exposure-response analysis, and the historical data in patients with aBC, 400 mg ribociclib (once daily for 3 weeks on/1 week off in a 28-day cycle) is demonstrated to be a safe and effective dose in patients with eBC. Both neutropenia and QTcF prolongation, the adverse events related to ribociclib PK exposure, are lower in eBC patients in Study O12301C at the dose of 400 mg than in aBC patients at the dose of 600 mg, supporting improved tolerability of the 400 mg dose in eBC patients. The PK- QT modeling confirmed the exposure-QTcF relationship in eBC patients, and patient population is a significant covariate where eBC patients showed less QTcF response than aBC patients. Efficacy in patients with eBC was demonstrated by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Due to limited sample size of patients with a PK collection having an iDFS event, the exposure-efficacy relationship cannot be characterized [SCP Study O12301C-Section 5.5]. The FDA’s Assessment: FDA agrees that the recommended dosage of ribociclib 400 mg daily for Days 1 to 21 of a 28-day cycle is appropriate for the general population of adults with HR+, HER2-negative stage II and III eBC based on the primary endpoint of iDFS from the NATALEE trial. The following are the Applicant’s rationales for dosage selection for the NATALEE trial: • As extended duration of treatment is critical to prolong cell cycle arrest and drive more tumor cells into senescence/death, a 3-year duration of treatment was chosen at a dose of 400 mg to improve tolerability while maintaining efficacy. • There are sufficient safety data on long-term use of ribociclib (> 60 months) in the aBC setting to support the longer treatment duration in the NATALEE trial. • The 400 mg dose was selected based on consistent efficacy in post hoc exploratory analyses from the MONALEESA program, and a potentially improved safety NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 43 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. profile in terms of dose-dependent toxicities such as QTc prolongation and neutropenia as compared to the 600 mg dosage. Therefore, this dosage and treatment duration were chosen to optimize efficacy while improving tolerability in this patient population with no detectable disease. Both neutropenia and QTcF prolongation, which have a known concentration-dependent relationship, were less common in the NATALEE trial at the dosage of 400 mg than in trials in the advanced setting at the dosage of 600 mg, supporting improved tolerability of the 400 mg dosage in patients with eBC. The median relative dose intensity for eBC patients receiving 400 mg dosage plus ET (compared to aBC patients receiving the 600 mg dosage) was 94% (vs 87.5%), while dose reductions (due to AEs) was 23.1% (vs 45%), and discontinuations was 19.7% (vs 15%). In general, the lower recommended dosage in eBC demonstrated greater tolerability compared to patients with aBC receiving 600 mg dosage plus ET as reported in the most recent USPI. 6.3.2.3 Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors (e.g. race, ethnicity, age, performance status, genetic subpopulations, etc.)? The Applicant’s Position: Yes. The recommendation for alternative dosing regimen for subpopulation based on intrinsic patient factors has no change since the prior approvals [Studies E2301/F2301]. Intrinsic factors: No clinically relevant effects of age, body weight (BW), gender, or race on the systemic exposure of ribociclib in the adult population that would require a dose adjustment were identified based on the popPK analysis previously submitted [Study A2301], [Studies E2301/F2301] [SCP Study O12301C-Section 1.1.1.2.1]. No new information is submitted in this application. Details on patients with hepatic and renal impairment are provided in Section 6.2.2.2. The FDA’s Assessment: FDA agrees that no therapeutic individualization of ribociclib is needed based upon intrinsic factors from the popPK modeling results including age, body weight, sex, or race. Additionally, no new intrinsic factors were identified for dose adjustment in this application. There are limited data for hepatic impairment in the NATALEE trial: 9 patients with mild hepatic impairment and 3 patients with moderate hepatic impairment in which no PK data were available. Patients with severe hepatic impairment were excluded from the trial. Based upon data from the most recent USPI, moderate hepatic impairment increased ribociclib exposure (GMR) by 1.4 for Cmax and 1.3 for AUCinf, while severe hepatic NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 44 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. impairment increased ribociclib exposure by 1.3 for both Cmax and AUCinf. The Applicant is proposing no dose adjustments for patients with mild and moderate hepatic impairment, which is the same recommendation for patients with aBC. There are similar limited data for moderate renal impairment. In the NATALEE trial, 42 patients had mild renal impairment and 8 patients had moderate renal impairment. Patients with severe renal impairment were excluded from the NATALEE trial. Based upon data from the most recent USPI, severe renal impairment increased ribociclib exposure (GMR) by 2.7 for Cmax and 2.1 for AUCinf. The Applicant is proposing no dose adjustment for mild or moderate renal impairment, and a dose reduction to 200 mg QD (50% dose reduction) for patients with severe renal impairment. Despite these limitations, the Applicant’s proposed dosing for eBC patients with renal and hepatic impairment are acceptable. Based on the popPK model, the impact of renal and hepatic impairment on the PK of ribociclib in patients with eBC was similar to that in patients with aBC. Because the benefit-risk profile of these subpopulations has been established in patients with aBC receiving the higher 600 mg dosage, patients with eBC who have mild to moderate hepatic impairment or severe renal impairment receiving the lower recommended dose of 400 mg are not expected to experience unacceptably high ribociclib exposures leading to additional safety concerns. 6.3.2.4 Are there clinically relevant food-drug or drug-drug interactions, and what is the appropriate management strategy? The Applicant’s Position: No new information for food-drug interactions is provided in this submission. Details on patients with drug-drug interactions and the management strategy are provided in Section 6.2.2.2. The FDA’s Assessment: FDA agrees that no new information for food-drug interactions is pertinent to this submission. Assessment about DDI results and management strategy are presented in Section 6.2.2.2. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 46 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 7 Sources of Clinical Data 7.1 Table of Clinical Studies The Applicant’s Position: Table 7: Listing of Clinical Trials Relevant to this NDA/BLA Trial Identity NCT no. Trial Design Regimen/ schedule/ route Study Endpoints Treatment Duration/ Follow Up No. of patients enrolled Study Population No. of Centers and Countries Controlled Study to Support Efficacy and Safety CLEE011O 12301C NCT03 701334 A global, Phase III, multicenter, randomized, open- label trial to evaluate efficacy and safety of ribociclib with ET (investigational arm: ribociclib + ET) versus ET alone (control arm: ET only) as adjuvant treatment in patients with HR-positive, HER2-negative, eBC. Ribociclib 400 mg once daily on Days 1 to 21 of each 28- day cycle (up to 36 months of treatment) ET: letrozole 2.5 mg by mouth, once daily, given continuously or anastrozole 1 mg by mouth, once daily, given continuously (for premenopausal women and men, plus goserelin 3.6 mg subcutaneously, on Day 1 ±3 of each 28-day cycle (up to 60 months of treatment) Primary endpoint: - iDFS using STEEP criteria, as assessed by Investigator. Secondary endpoints: - RFS using STEEP criteria DDFS using STEEP criteria - Overall survival - Change from baseline in the physical functioning sub-scale score and global health status / QoL scale score as assessed by EORTC QLQ-C30. The final iDFS analysis was conducted after 40.3 months of median study follow-up, when patients were treated for a median duration of 36 months in both arms, with an additional 6.3 months of study follow- up from the primary analysis. Randomized to ribociclib + ET arm: 2549 patients Randomized to ET only arm: 2552 patients The study population consisted of female and male patients ≥18 years of age (and if female, with a known menopausal status at the time of randomizatio n) with histologically confirmed diagnosis of ER and/or PR-positive, HER2- negative eBC with Anatomic Stage Group A total of 393 centers across 20 countries NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 47 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. - Frequency and severity of AEs, laboratory and ECG abnormalities. - PK parameters such as Ctrough and other applicable parameters for ribociclib Exploratory endpoints: - LRRFS defined as time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, or death due to any cause. - Incidence of subsequent anti-neoplastic therapy and time to first subsequent anti- neoplastic therapy. - Number of patients hospitalized, total number of hospitalizations, and length of stay in hospitals, number of patients with Emergency Room and additional visits. III, IIB, or a subset of IIA cases, after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherap y (if indicated), and who were deemed eligible for adjuvant ET for at least a 60-month duration. Stage IIA patients with no nodal involvement had either tumor grade 3 or tumor grade 2 with high-risk genomic profile or Ki67 ≥20%. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 209092/S-018 (ribociclib) and NDA 209935/S-027 (ribociclib+letrozole copack) 48 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: For the sNDA, the Applicant submitted the results from the NATALEE trial in patients with high-risk Stage II or III HR+, HER2-negative early breast cancer comparing ribociclib + ET to ET only in the adjuvant setting. FDA generally agrees with the Applicant’s description of the design of the NATALEE trial above. 49 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 8 Statistical and Clinical Evaluation 8.1 Review of Relevant Individual Trials Used to Support Efficacy 8.1.1 Study CLEE011O12301C Trial Design The Applicant’s Description: Study CLEE011O12301C is a Phase III, multicenter, randomized, open-label study to evaluate the efficacy and safety of ribociclib with ET versus ET alone as an adjuvant treatment in pre- and postmenopausal women plus men with HR-positive, HER2-negative eBC. Approximately 5,000 patients were planned to be randomized (using an IRT system) in a 1:1 ratio to either the investigational arm (ribociclib + ET) or the control arm (ET only). Randomization to the two treatment arms was stratified by menopausal status (premenopausal women, and men vs. postmenopausal women), AJCC 8th edition Stage II vs. Stage III, prior neoadjuvant/adjuvant chemotherapy (yes vs. no), and Geographical region (North America/Western Europe/Oceania vs. rest of the world). The planned study treatment phase duration was 60 months. In total, 5101 female and male patients were randomized in a 1:1 ratio; 2549 patients to the ribociclib + ET arm and 2552 patients to the ET only arm (Figure 1: Study design). 50 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Figure 1: Study design The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the design of the NATALEE trial. Letrozole and anastrozole were used as endocrine therapy in NATALEE, due to the following reasons provided by the Applicant in an IR response from Sept 9, 2024: • Exemestane was not excluded explicitly in the protocol as safety and efficacy data have been generated in combination of ribociclib and exemestane in the metastatic disease setting. 51 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. • The AROMASIN (exemestane) indication for adjuvant treatment is as follows: adjuvant treatment of postmenopausal women with estrogen-receptor positive eBC who have received two or three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy. • Therefore, given the protocol eligibility criteria for prior ET duration of up to 1 year, patients eligible to receive exemestane would have had to receive at least 2 years of prior tamoxifen, thus becoming ineligible for NATALEE • From a purely practical and operational perspective, and in light of the above, only anastrozole or letrozole were made available. The rationale for primarily using letrozole and anastrozole in the NATALEE trial is reasonable for the reasons outlined by the Applicant, and does not impact the overall benefit-risk assessment. Eligibility Criteria The Applicant’s Description: The pivotal study O12301C supporting this submission has participation across all demographic patient populations and included patients of diverse race and ethnicities with the majority of patients being White (73.4%) and not of Hispanic or Latino origin (81.0%). Details are presented in Table 10: Demographic Characteristics. The study population consisted of female and male patients ≥18 years of age (and if female, with a known menopausal status at the time of randomization) with histologically confirmed diagnosis of ER and/or PgR-positive, HER2- negative eBC with Anatomic Stage Group III, IIB, or a subset of IIA cases, after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who were deemed eligible for adjuvant ET for at least a 60-month duration. Stage IIA patients with no nodal involvement had either tumor grade 3 or tumor grade 2 with high-risk genomic profile or Ki67 ≥20%. In general, the patients enrolled in this study were representative of the intended target patient population and allow the resultant data to be extrapolated to all patients with the proposed indication. Detailed demographic and baseline characteristics are discussed in Section 8.1.2. Trial location 393 sites across 20 countries in Europe, North America/Australia, Asia, and Latin America enrolled a total of 5101 patients [Study O12301C Primary Analysis CSR-Section 2]. Choice of control group The choice of control treatment (ET) was based on its recommended use as a standard of care in patients with ER-positive eBC. Another consideration behind the choice of ET for this study was the fact that, as per the Kisqali® prescribing information, ribociclib is not indicated for use in combination with tamoxifen due to the increased risk of QT prolongation. Hence, for this study, patients in the control arm were treated with standard AI, either letrozole or anastrozole, administered for a duration of at least 60 months from randomization, according to the local 52 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. clinical guidelines and current prescribing information. Gonadal suppression was achieved by using the GnRH agonist goserelin [CO Study O12301C-Section 1.3.2]. Diagnostic criteria The study population had histologically confirmed diagnosis of ER and/or PgR-positive, HER2- negative breast cancer within 18 months prior to randomization. Patients with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis within 18 months prior to randomization were included. Patients with a multicentric and/or multifocal tumor were eligible if all the histopathologically examined lesions met the pathologic inclusion criteria [Study O12301C Primary analysis CSR- Section 9.3.1] In the United States, breast cancer is projected to be the most common cancer diagnosed in 2023 with an estimated incidence of 297,790 new cases and 43,170 deaths (SEER 2023). Almost all newly diagnosed BC cases are early BC (eBC), localized to the breast tissue and regional lymphatics, which are potentially curable with surgical resection and a variety of treatment modalities. Based on SEER Program data collected between the years 2010 and 2019, among all HR-positive, HER2-negative breast cancer cases in females, 94.8% of cases diagnosed were eBC, with 68.9% localized to the breast tissue and 25.9% within both the breast tissue and regional lymph nodes (SEER 2022) [CO Study O12301-Section 1.1]. Key inclusion/exclusion criteria The study population consisted of female and male patients ≥ 18 years of age (and if female with a known menopausal status at the time of randomization) with HR-positive, HER2-negative eBC. Patients were included if they had a histologically confirmed diagnosis of ER and/or PgR positive (HR-positive), HER2-negative eBC (Anatomic Stage Group III, IIB, IIA), irrespective of nodal status, after adequate surgical resection and radiotherapy (if indicated), within 18 months prior to randomization and who were deemed eligible for adjuvant ET for at least a 60- month duration. Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of informed consent, but randomization was to occur within 12 months of the initial start date of ET. Note, Stage IIA patients who were node negative were required to have either tumor grade 3 or tumor grade 2 with high risk genomic profile or Ki67 ≥ 20%. Eligible patients were also required to have adequate bone marrow and organ function as defined in the Study Protocol, and standard 12-lead ECG values assessed by a central laboratory. Key exclusion criteria included prior treatment with any CDK4/6 inhibitor; tamoxifen, raloxifene or AIs for chemoprevention of breast cancer and/or treatment for osteoporosis (within 2 years of randomization); anthracyclines (specified doses of doxorubicin and epirubicin); and systemic corticosteroids (within 2 weeks of starting trial treatment). Patients receiving treatment with any other antineoplastic therapy (except for adjuvant ET) were not eligible. Patients with breast cancer metastases beyond regional lymph nodes (Stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery; patients who had major surgery, chemotherapy, or radiotherapy (within 14 days of randomization); patients with a known hypersensitivity to any of the excipients of ribociclib and/or ET; and patients with clinically significant, uncontrolled heart 53 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. disease and/or cardiac repolarization abnormality were excluded [Study O12301C-Section 2 synopsis]. Dose selection As extended duration of treatment is critical to prolong cell cycle arrest and drive more tumor cells into senescence/death, a 3-year duration of treatment was chosen at a dose of 400 mg to improve tolerability while maintaining efficacy. Of note, there are sufficient safety data on long- term use of ribociclib (> 60 months) in the aBC setting to support the longer treatment duration in Study O12301C. The 400 mg dose was selected based on consistent efficacy in post hoc exploratory analyses from the MONALEESA program, and a potentially improved safety profile in terms of dose-dependent toxicities such as QTc prolongation and neutropenia as compared to the 600 mg starting dose. Therefore, this dose and treatment duration were chosen to optimize efficacy while improving tolerability in this patient population with no detectable disease [SCE Study O12301C-Section 4.1]. Study treatments, assignment, and blinding Ribociclib, the investigational drug for this study, was considered an IMP. The other drugs used in this study were NSAIs (letrozole or anastrozole) and goserelin. Ribociclib was administered orally on a 28-day cycle; on Days 1 to 21 at a dose of 400 mg (two 200 mg film-coated tablets once daily), followed by 7 days off ribociclib (days 22 to 28). ET was administered (in both the investigational and control arms) as follows: for postmenopausal women, letrozole 2.5 mg (orally) once daily and continuously or anastrozole 1 mg (orally) once daily and continuously; for premenopausal women and men, letrozole 2.5 mg (orally) once daily and continuously or anastrozole 1 mg (orally) once daily and continuously, combined with goserelin 3.6 mg (subcutaneously) once every 4 weeks [Study O12301C Primary analysis CSR-Section 2]. Patients were randomized via IRT to the investigational or control arm, in a ratio of 1:1, as per the stratification factors. Although this is an open-label study, to minimize bias during data review, the study team was blinded to aggregate reports by treatment arm until the time of the final iDFS analysis (or until after interim iDFS analysis if futility or superiority was declared). At the time of interim analyses for iDFS, unblinded results from the interim analyses were not communicated to the Novartis clinical team or to any party involved in the study conduct (apart from the independent statistician and DMC members) until the DMC had determined that either (i) iDFS analysis had crossed the pre-specified boundary for efficacy, or (ii) the study needed to be terminated due to any cause including futility or safety reasons [Study O12301C Primary analysis CSR-Sections 9.4.1 and 9.4.3]. Dose modification, dose discontinuation Investigators were permitted to interrupt and/or reduce the ribociclib dose to allow patients to continue treatment. Dose modifications were considered for patients who did not tolerate the protocol-specified dosing schedule for ribociclib or where clinical judgment of the treating physician determined that ribociclib dose interruptions and/or reductions were recommended 54 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. (based on the individual benefit/risk assessment). For patients who did not tolerate the protocol-specified dosing schedule, one dose reduction was permitted to allow patients to continue ribociclib. If a second dose reduction was required to manage ribociclib-related AEs, then ribociclib was discontinued. No dose re-escalation was permitted. ET-related AEs were managed according to local clinical guidelines and Investigators’ judgment. In cases when ET required interruption for more than 4 weeks due to ET-related AEs, discussions on the risks/benefits of study treatment continuation were held with the Medical Monitor [Study O12301C Primary analysis CSR-Sections 9.4.4 and 9.4.6]. Discontinuations are discussed in the sections below. Administrative structure The administrative structure of the study, including internal and external participants, the list of Investigators, as well as members of the Data Monitoring Committee and Study Steering Committee, is provided in [Study O12301C-Appendix 16.1.4]. Concurrent medications Medications required to treat AEs, manage cancer symptoms, concurrent diseases, and supportive care agents, such as pain medications, antiemetics and antidiarrheals were allowed. Permitted concomitant therapy included bisphosphonates and denosumab, corticosteroids (topical applications, inhaled sprays, eye drops or local injections or short duration of systemic corticosteroids less than or equal to the anti-inflammatory potency of 4 mg dexamethasone), hematopoietic growth factors, concomitant surgery during Ribociclib treatment ‘week-off’. Medications to be used with caution during ribociclib treatment included medications that carry a possible risk for QT prolongation and/or TdP, moderate inhibitors or inducers of CYP3A4/5, sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index, strong inhibitors of Bile Salt Export Pump, sensitive substrates of the renal transporters, MATE1 and OCT2, and sensitive substrates of transporter of Breast Cancer Resistance Protein. Prohibited concomitant therapy included strong inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow therapeutic index, medications with a known risk for QT prolongation and/or TdP, concomitant tamoxifen or toremifene use [Study O12301C Primary analysis CSR-Sections 9.4.5] Treatment compliance Patients were instructed on how to take the study treatment as per protocol. Site staff ensured that the patient clearly understood the treatment schedule and that the appropriate dose of study treatment was provided at each cycle. Additionally, patients completed a diary to record their daily intakes. The administration of study treatment was recorded in the appropriate sections of the eCRF. Study treatment compliance was assessed by the Investigator and/or study personnel at each visit using pill counts and information provided by the patient and/or caregiver. Patients were instructed to return all unused ribociclib (and ET if provided by Novartis), including all partially used and empty containers, at each visit during the Treatment phase. A record of study 55 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. treatment receipt and dispensing was maintained in a drug accountability log which was reviewed by a study monitor during regular site visits. [Study O12301C Primary analysis CSR- Sections 9.4.1 and 9.4.3.4] Subject completion, discontinuation, or withdrawal Study completion: If the primary endpoint, iDFS, was statistically significant at the second, third interim or at final analysis, data collection was to continue, and end of study was to be declared when 60 months + 30 days (Safety follow up) have elapsed from the date the last patient has been randomized. [Study O12301C Primary analysis CSR-Sections 9.4.7] Study discontinuation or withdrawal: The Investigator was obliged to discontinue study treatment for a given patient if he/she believed that continuation would be detrimental to the patient’s well-being. In the investigational arm, patients were discontinued from ribociclib treatment for any of the following reasons: completion of 36 months of treatment from the randomization date (approximately 39 cycles), regardless of any treatment interruption, first recurrence (any of the following or combination of local, regional, or distant recurrences, or contralateral invasive BC, or second primary non-breast invasive cancer), adjustments to study treatment due to toxicity that result in treatment discontinuation, ribociclib dosing was interrupted for > 28 days due to ribociclib-related toxicity, withdrawal of consent by the patient, patient is lost to follow-up, death, discontinuation from the study treatment due to any other reason, or Novartis termination of the study. [Study O12301C Primary analysis CSR-Sections 9.4.6] Censoring pattern of iDFS: Number of patients with an iDFS event and number of patients censored for the iDFS analysis were summarized. In addition, a summary of reasons for iDFS censoring was provided by treatment arm. For patients without an iDFS event, the iDFS censoring date was determined as the last assessment before the earliest of the following dates, with the earliest of these also determining the censoring reason (as indicated in parentheses): • Analysis cut-off date (censoring reason: ‘Ongoing without event’) • Date of consent withdrawal (censoring reason: ‘Withdrew consent’) • Date of Last Contact for patients lost to follow-up at EOT or Date of Visit/contact for patients lost to follow-up during follow-up phase (censoring reason: ‘Lost to follow up’) [Study O12301C Primary Analysis CSR Appendix 16.1.9-Section 2.5.6] The FDA’s Assessment: 56 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. FDA generally agrees with the Applicant’s description of the design of the NATALEE trial as stated above. Analysis sets The Applicant’s Description: The Full analysis set (FAS) comprised all patients to whom study treatment has been assigned by randomization. According to the intent to treat principle, patients were analyzed according to the treatment and strata they had been assigned to during the randomization procedure. The Per protocol set (PPS) consisted of a subset of patients in the FAS who were compliant with requirements of the protocol. Sensitivity analyses of the primary endpoint of iDFS could be performed using data from the PPS if the FAS and PPS differ and if the primary analysis was significant. The Safety set included all randomized patients who received any study treatment (i.e., at least one dose of ribociclib or ET). Patients were analyzed according to the study treatment received. The actual treatment received corresponded to: • Ribociclib + ET if patients took at least one dose of ribociclib • ET if patients took at least one dose of ET but ribociclib was never received The Pharmacokinetic analysis set (PAS) consisted of all patients who provided at least one evaluable PK concentration [Study O12301C Primary Analysis CSR-Section 9.7.2] Study Endpoints The Applicant’s Description: Objective Endpoint Primary To compare iDFS for ribociclib + ET versus ET in patients with HR-positive, HER2-negative, eBC iDFS using STEEP criteria, as assessed by Investigator Secondary To evaluate the two treatment arms with respect RFS RFS using STEEP criteria To evaluate the two treatment arms with respect to DDFS DDFS using STEEP criteria To evaluate the two treatment arms with respect to OS OS defined as time from date of randomization to date of death due to any cause To evaluate PRO for health-related QoL in the two treatment arms Change from baseline in the physical functioning sub- scale score and global health status / QoL scale score as assessed by EORTC QLQ-C30 To evaluate safety and tolerability of the treatment regimen Frequency and severity of AEs, laboratory and Electrocardiogram (ECG) abnormalities To characterize the PK of ribociclib when given in combination with NSAI (and goserelin if applicable) PK parameters such as Ctrough and other applicable parameters for ribociclib Exploratory 57 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Objective Endpoint To explore the two treatment arms with respect to LRRFS LRRFS defined as time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, or death due to any cause To explore use of subsequent antineoplastic therapy Incidence of subsequent antineoplastic therapy and time to first subsequent antineoplastic therapy To explore healthcare resource utilization Number of patients hospitalized, total number of hospitalizations, and length of stay in hospitals, number of patients with Emergency Room and additional visits Source: [Study O12301C Primary Analysis CSR-Section 8]. The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the design and protocol aspects of the NATALEE trial as stated above. Note that the NATALEE trial opened in December 2018, at which time iDFS using STEEP v1.0 criteria was the standard endpoint for most adjuvant breast cancer trials in the US. That endpoint includes second non-breast primary malignancy as one of the components of the definition. STEEP v2.0 recommended use of invasive breast cancer-free survival (IBCFS), which excludes second non-breast primary malignancy from the endpoint, over iDFS in most adjuvant trials, but these criteria were not published until May 2021. Given the concern for potentially increased risk of second primary malignancies related to nitrosamine impurities with ribociclib, the FDA review team considers the iDFS endpoint to be particularly relevant in NATALEE. As the number of second primary malignancies was ultimately very similar in the two treatment arms, inclusion of these events would be expected to increase the chance of a false negative outcome to the study. Statistical Analysis Plan and Amendments The Applicant’s Description: Efficacy analysis: All efficacy analyses were performed using the FAS which consisted of all patients to whom study treatment has been assigned by randomization. According to the intent to treat principle, patients were analyzed according to the treatment and strata they had been assigned to during the randomization procedure. The primary efficacy variable of the study, iDFS, was defined as the time from the date of randomization to the date of the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). The primary efficacy analysis was the comparison of the distribution of iDFS between the two treatment arms. The null hypothesis stating that iDFS survival distributions of the two treatment arms are equivalent was tested against a one-sided alternative. iDFS was analyzed using a Lan-DeMets (O’Brien-Fleming) alpha spending function and a non-binding Lan-DeMets (O’Brien-Fleming) beta spending function based on the data observed in the FAS up to the cut-off date, according to the treatment arm and strata assigned at 58 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. randomization. The survival distribution of iDFS was estimated using the Kaplan-Meier method. A stratified Cox regression was used to estimate the hazard ratio (HR) of iDFS along with 95% confidence interval (CI) using the same strata information as the primary efficacy comparison. As a sensitivity analysis to assess the impact of stratification, the two treatment arms were compared using the unstratified log-rank test. The HR together with the associated 95% confidence interval obtained using the unstratified Cox regression model was also presented. A multivariate stratified Cox regression model was fitted to evaluate the effect of other baseline demographic and disease characteristics on the estimated HR. The distributions of the secondary efficacy endpoints RFS, DDFS and OS were estimated using the Kaplan-Meier method and compared between treatment groups using a stratified log-rank test at one-sided 2.5% level of significance. The HR for RFS, DDFS and OS were calculated, along with their 95% CI, using a stratified Cox model based on strata assigned at randomization. Analysis of patient reported outcomes: As the main analysis and to best utilize the repeated PRO assessments, a repeated measures model for longitudinal data was used to estimate differences in PRO scores in all sub-scales obtained from EORTC QLQ-C30, the breast symptoms score of QLQ-BR23, the VAS of EQ-5D-5L and the anxiety domain and depression domain scores of HADS between treatment arms. The repeated measures model included terms for treatment, stratification factors assigned at randomization, time, baseline value as main effects, and an interaction term for treatment by time. All data collected until confirmation of first recurrence (including the assessment at confirmation of first recurrence) was included in the analysis. Pharmacokinetic analysis: All PK analyses were based on the PAS, unless otherwise specified. Only evaluable PK concentrations which were not flagged for exclusion were used for summaries. Safety analysis: All safety analyses were performed using the Safety set, which consisted of all randomized patients who received any study treatment (i.e., at least one dose of ribociclib or ET). Patients were analyzed according to the study treatment received. Separate AE summaries were presented by number and percentage of patients who had at least one AE, having at least one AE in each primary system organ class SOC and for each preferred term PT using MedDRA (version 25.1) coding. The safety summary tables within included treatment-emergent events/assessments with on-treatment AEs (new or worsened). Separate summaries for on-treatment deaths and all deaths (including post-treatment deaths), were produced by treatment arm, system organ class and preferred term. The primary cause of death was also displayed [Study O12301C Primary Analysis CSR-Section 2]. The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the design and protocol aspects of the NATALEE trial as stated above. The statistical test for iDFS was based on ~5,000 patients randomized in a 1:1 ratio, where 500 iDFS events would provide a power of approximately 93% to detect a hazard ratio (HR) of 0.73, or approximately 85% to detect a HR of 0.76, with a 1-sided type 1 error of 0.025. There were three planned interim analyses 59 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. for iDFS (at 200, 350, and 425 iDFS events) in addition to the final analysis (at 500 iDFS events), using a Lan-DeMets (O’Brien-Fleming) alpha spending function. There was no type-1 error control for any secondary endpoint, including OS. Protocol Amendments The Applicant’s Description: The study protocol and the SAP were amended 3 times during the study. The key features of each protocol amendment are provided in the below table: Amendment 1 (20-Jun-2019): Clinical safety was updated to include a statement that ribociclib is not recommended for use in combination with tamoxifen (due to increased risk of QT prolongation). Following consultation with EMA Scientific Advice Working Party and with the Steering Committee, the enrollment criteria were updated to include a subset of higher risk Stage II patients to reduce the heterogeneity of the study population. Also, identification of higher risk Stage II patients via gene expression tests was included. Study design rationale was updated to justify the open label study-design. Capping rule was amended to allow for a better representation of stage II and III patients. OS analysis at approximately two years after primary iDFS was added to OS analysis timelines. Statistical calculations were updated to reflect the increase in power for the iDFS endpoint (iDFS event rate was expected to increase as result of the change in population). Amendment 2 (23-Jan-2020): Inclusion criteria was updated to reflect the postmenopausal definition as outlined in the breast cancer clinical guideline from the National Comprehensive Cancer Network (version 3.2019). Wording was added to provide clear guidance on ribociclib discontinuation when TEN is diagnosed, based on updates made to IB Ed.14. Urinalysis was removed from the Clinical Laboratory Collection Plan. Amendment 3 (27-Aug-2020): Role of the CDK4/6 pathway in breast cancer was updated to describe emerging data from other CDK4/6 inhibitor studies. The study design rationale was updated to include an additional 1000 patients with Stage III eBC, with Stage II capped at 40% of total study population of approximately 5,000, based on emerging information external to the study. "Interim and final iDFS" and "Sample size calculation" sections updated because of the sample size increase. The required number of events for the final analysis of iDFS was updated to approximately 500 events to ensure the study power is retained at 85% for a hazard ratio of up to 0.76. An additional interim efficacy analysis at 85% information fraction) was added. Number of randomized patients required to observe the new targeted number of iDFS events was updated from 4,000 to 5,000 [Study O12301C Primary Analysis CSR-Section 9.8.1]. SAP amendments The SAP was amended 3 times with key features outlined below: • Amendment 1 (26-Jul-2021) was mainly to implement changes due to Protocol amendment 3 (protocol v4.0) and to align with Novartis guidelines and program standards. The main 60 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. changes were the increase in sample size to 5000 patients, addition of an interim analysis at 85% IF, and updated futility boundary for IA 1. • Amendment 2 (15-Aug-2022): The key changes were clarifications of some analysis conventions such as central ECG assessments being a primary source of QT analysis , sensitivity analyses to assess the impact of COVID-19 deaths on iDFS and OS, gap analysis for iDFS and OS, subgroup definitions, updated time to event and duration of event endpoints, updated RDI/DI presentations, addition of a stratified multivariate Cox model, clarification of date derivations, and handling of censoring dates. • Amendment 3 (30-Aug-2023): The key changes were update for on-treatment window to align with the 3-year duration of ribociclib treatment, OS subgroup analysis added for stratification factors, and OS subgroup analysis added for stratification factors censoring COVID-19 deaths. Additional OS sensitivity analysis was performed to further evaluate the robustness of OS survival benefit. The OS analysis was repeated using the PPS, using the unstratified log-rank test and a multivariate stratified Cox regression model (fitted to evaluate the effect of other baseline demographic and disease characteristics on the estimated hazard ratio). The fitted model adjusted the treatment difference for key baseline and prognostic factors and included the following covariates: age (< 45 vs. 45-54 vs. 55-64 vs. ≥ 65), ER/PR status (ER+PR+ vs. other) and type of ET (letrozole vs. anastrozole). Based on its clinical relevance, the on-treatment death period was redefined taking the 36- month treatment period for ribociclib into account, i.e., deaths reported during and up to 30 days after the last dose of the treatment, up to a maximum of 36 months plus 30-days in either study arm. The FDA’s Assessment: FDA generally agrees with the Applicant’s description of the key elements of amendments to the protocol and SAP for the NATALEE trial. 8.1.2 Study Results Compliance with Good Clinical Practices The Applicant’s Position: The study was conducted in full conformance with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in conformance with the principles of the Declaration of Helsinki. Written informed consent was obtained from each participant in the study. The study protocol and 3 amendments were approved by local Independent Ethics Committees (IEC) or Institutional Review Boards (IRB). The FDA’s Assessment: 61 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. FDA generally agrees with the Applicant’s statement of compliance with GCP in the NATALEE trial. Financial Disclosure The Applicant’s Position: Details are presented in Appendix 19.2. The FDA’s Assessment: The financial disclosure information in Appendix 19.2 was reviewed. There were no financial conflicts identified that would be expected to compromise the integrity of NATALEE trial results. Patient Disposition Data: Table 8: Patient disposition (final iDFS analysis, 21-Jul-2023 data cut-off) by treatment arm (FAS) Disposition/Reason ET + ribociclib N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Number of patients randomized 2549 (100) 2552 (100) 5101 (100) Number of patients randomized but not treated 23 (0.9) 111 (4.3) 134 (2.6) Number of patients treated with any treatment 2526 (99.1) 2441 (95.7) 4967 (97.4) Number of patients who discontinued all treatment components 612 (24.0) 693 (27.2) 1305 (25.6) Number of patients who discontinued ribociclib 1996 (78.3) 1 (< 0.1) 1997 (39.1) Number of patients who discontinued NSAI 612 (24.0) 693 (27.2) 1305 (25.6) Number of patients still on treatment 1914 (75.1) 1748 (68.5) 3662 (71.8) Primary reason for ribociclib discontinuation Completed 1091 (42.8) 0 1091 (21.4) Adverse event 498 (19.5) 0 498 (9.8) Patient decision to discontinue treatment 135 (5.3) 0 135 (2.6) Disease recurrence 122 (4.8) 0 122 (2.4) Withdrawal by patient 82 (3.2) 0 82 (1.6) Physician decision 24 (0.9) 0 24 (0.5) Other 23 (0.9) 0 23 (0.5) Lost to follow-up 8 (0.3) 0 8 (0.2) Protocol deviation 6 (0.2) 1 (< 0.1) 7 (0.1) Death 4 (0.2) 0 4 (0.1) Endocrine therapy discontinuation 3 (0.1) 0 3 (0.1) Primary reason for NSAI discontinuation Disease recurrence 168 (6.6) 224 (8.8) 392 (7.7) Patient decision to discontinue treatment 138 (5.4) 126 (4.9) 264 (5.2) Adverse event 131 (5.1) 113 (4.4) 244 (4.8) Withdrawal by patient 117 (4.6) 162 (6.3) 279 (5.5) Physician decision 28 (1.1) 32 (1.3) 60 (1.2) Lost to follow-up 10 (0.4) 18 (0.7) 28 (0.5) 63 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. part due to the design of the trial, which provides for 3 years of ribociclib and at least 5 years of ET, discontinuations due to AE were also much more common on the ribociclib + ET arm compared to the arm receiving ET alone (19.5% vs 5.1%). In addition, see FDA analyses of the primary endpoint in Section 8.1.2 below. Protocol Violations/Deviations Data: Table 9: Protocol deviations (FAS) PD Term Deviation Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Number of patients with at least one protocol deviation 1868 (73.3) 1713 (67.1) 3581 (70.2) IMP/NIMP 659 (25.9) 370 (14.5) 1029 (20.2) Dosing & Administration 606 (23.8) 284 (11.1) 890 (17.4) Supply 93 (3.6) 97 (3.8) 190 (3.7) Wrong Treatment Administration 3 (0.1) 4 (0.2) 7 (0.1) Informed Consent 477 (18.7) 480 (18.8) 957 (18.8) Consenting Process 278 (10.9) 305 (12.0) 583 (11.4) Timing of Consent 176 (6.9) 161 (6.3) 337 (6.6) Failure to Obtain 54 (2.1) 38 (1.5) 92 (1.8) Version 10 (0.4) 10 (0.4) 20 (0.4) Other 9 (0.4) 14 (0.5) 23 (0.5) Protocol Compliance 1591 (62.4) 1522 (59.6) 3113 (61.0) Study Assessments & Procedures 1201 (47.1) 1259 (49.3) 2460 (48.2) Inclusion / Exclusion 586 (23.0) 571 (22.4) 1157 (22.7) Prohibitive Medication or Treatment 304 (11.9) 51 (2.0) 355 (7.0) Other 26 (1.0) 11 (0.4) 37 (0.7) Safety 39 (1.5) 33 (1.3) 72 (1.4) Late / Unreported SAE / AESI / Pregnancy 39 (1.5) 33 (1.3) 72 (1.4) Major/Critical Deviation Leading to Exclusion from Analysis Sets 29 (1.1) 18 (0.7) 47 (0.9) Inclusion / Exclusion 29 (1.1) 17 (0.7) 46 (0.9) Wrong Treatment Administration 0 1 (0.0) 1 (0.0) A patient with multiple protocol deviations within the same PD term is counted only once for this PD term. Patients may have protocol deviations in more than one PD term. Source: [Study O12301C Primary analysis CSR-Table 10-2] The Applicant’s Position: Overall, 70.2% of patients reported at least one protocol deviation. The percentage of patients with deviations was slightly higher in the ribociclib + ET arm compared to that in the ET only arm (73.3% vs. 67.1%). A total of 47 patients (0.9%) were excluded from the PPS due to major deviations. Forty-six patients (0.9%) were excluded from the PPS due to inclusion/exclusion criteria not being met. In total, 2460 patients (48.2%) reported at least one study assessment and procedure PD and 1157 patients (22.7%) reported at least one inclusion/exclusion PD. The most commonly reported study assessment and procedure PD was mammography not regularly 64 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. assessed as per protocol (1062 patients, 20.8%). The most commonly reported inclusion/exclusion PD was baseline laboratory results criteria (blood salts i.e., potassium, calcium and magnesium) not met (218 patients, 4.3%) [Study O12301C Primary analysis CSR- Section 10.2]. The FDA’s Assessment: FDA reviewed the Applicant’s position above. While the majority of protocol deviations was balanced between the two arms, the ribociclib + ET arm had higher protocol deviations due to “Dosing & Administration” and “Prohibitive Medication or Treatment.” In response to an Information Request (IR), the Applicant provided additional information on the cause of the higher incidence of protocol deviations due to these two reasons, particularly on the ribociclib + ET arm. Protocol deviations due to “Dosing & Administration”: The primary cause was due to ribociclib “dose greater than the prescribed dose for >3 days or duration exceeded by 3 days or single dose >900 mg/day”, in 245 patients. These patients received a mean of 2.7 extra days of ribociclib (median 2.0 days). The TEAEs experienced by these patients was compared with the TEAEs experienced overall by the patients who received ribociclib + ET, and generally comparable. No patient received a single dose >900 mg/day, and only one patient received ribociclib 600 mg for 147 days before this dose error was identified; the patient subsequently received ribociclib 400 mg. Section 2 Dosage & Administration of the ribociclib product labeling will clearly state that in the adjuvant treatment setting, the approved ribociclib dosage is 400 mg days orally for 21 days out of a 28 day cycle. For the prohibited concomitant medications, the primary cause was due to short-term co- administration. One safety concern of prohibited concomitant medications for patients who received ribociclib + ET is QT prolongation. FDA’s analysis of QT prolongation is provided in Section 8.2.4 below, and QT prolongation is already included in the ribociclib USPI as a Section 5 Warning and Precaution. The ribociclib USPI already clearly states prohibited concomitant medications. Overall, the protocol deviations do not significantly impact the finding of a favorable benefit-risk assessment of ribociclib. Table of Demographic Characteristics Data: Table 10: Demographic Characteristics Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Age group <45 611 (24.0) 591 (23.2) 1202 (23.6) 45 to 54 849 (33.3) 895 (35.1) 1744 (34.2) 55 to 64 682 (26.8) 700 (27.4) 1382 (27.1) 65 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) ≥ 65 407 (16.0) 366 (14.3) 773 (15.2) Age (years) n 2549 2552 5101 Mean 52.9 52.7 52.8 SD 10.75 10.77 10.76 Min 24 24 24 Median 52.0 52.0 52.0 Max 90 89 90 Gender Male 11 (0.4) 9 (0.4) 20 (0.4) Female 2538 (99.6) 2543 (99.6) 5081 (99.6) Race White 1876 (73.6) 1868 (73.2) 3744 (73.4) Black or African American 42 (1.6) 47 (1.8) 89 (1.7) Asian 341 (13.4) 334 (13.1) 675 (13.2) Native Hawaiian or Other Pacific Islander 3 (0.1) 1 (0.0) 4 (0.1) American Indian or Alaska Native 4 (0.2) 3 (0.1) 7 (0.1) Other 145 (5.7) 172 (6.7) 317 (6.2) Missing 138 (5.4) 127 (5.0) 265 (5.2) Ethnicity Hispanic or Latino 212 (8.3) 223 (8.7) 435 (8.5) Not Hispanic or Latino 2076 (81.4) 2054 (80.5) 4130 (81.0) Unknown 172 (6.7) 201 (7.9) 373 (7.3) Missing 89 (3.5) 74 (2.9) 163 (3.2) Region* Asia 281 (11.0) 290 (11.4) 571 (11.2) Europe 1505 (59.0) 1506 (59.0) 3011 (59.0) North America/Australia 624 (24.5) 612 (24.0) 1236 (24.2) Latin America 139 (5.5) 144 (5.6) 283 (5.5) ECOG performance status 0 2106 (82.6) 2132 (83.5) 4238 (83.1) 1 440 (17.3) 418 (16.4) 858 (16.8) Missing 3 (0.1) 2 (0.1) 5 (0.1) Weight (kg) n 2534 2542 5076 Mean 72.4 72.2 72.3 SD 16.20 15.53 15.86 Min 38 41 38 Median 70.0 70.0 70.0 Max 166 169 169 Height (cm) n 2523 2522 5045 Mean 162.9 162.7 162.8 SD 6.78 6.85 6.81 Min 140 140 140 Median 163.0 163.0 163.0 Max 198 191 198 BMI (kg/m²) 66 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) n 2518 2521 5039 Mean 27.3 27.3 27.3 SD 5.81 5.70 5.76 Min 16 15 15 Median 26.3 26.5 26.4 Max 56 59 59 Weight and height are the last non-missing assessments on or before the date of randomization. BMI: body mass index is calculated based on raw data measurements. Asia includes China, Republic of Korea, and Taiwan. Europe includes Austria, Belgium, France, Germany, Hungary, Ireland, Italy, Poland, Romania, Russian Federation, Spain, and United Kingdom. North America/Australia includes Australia, Canada, and United States. Latin America includes Argentina and Brazil. Source: [Study O12301C Primary analysis CSR-Table 10-7] The Applicant’s Position: Demographic characteristics were well-balanced between the two treatment arms. Patients were representative of the population of pre- and postmenopausal women plus men with HR-positive, HER2-negative eBC. The median age of patients in the study was 52 years (range: 24 to 90), with 34.2% of patients within the 45 to 54 years age group. Overall, 99.6% of patients were women and 0.4% of patients were men. The patients included were White (73.4%), Asian, (13.2%), Black or African American (1.7%), American Indian or Alaska Native (0.1%) and Pacific Islander (0.1%) The most frequent ethnicity was non-Hispanic or Latino (81.0%), followed by Hispanic or Latino (8.5%). Over half the patients (59.0%) in each treatment arm were based in Europe followed by North America/Australia (24.2%), Asia (11.2%) and Latin America (5.5%). The vast majority of patients (83.1%) had an ECOG performance status of zero at baseline [Study O12301C Primary analysis CSR-Section 10.4.1] The FDA’s Assessment: FDA disagrees with the Applicant’s characterization of the NATALEE trial as representative of the racial demographics of the U.S. population. More than half of the trial was enrolled in the European Union, and nearly three-quarters of the overall trial population was White. In 2022, according to the Pew Research Center, there were approximately 48 million people in the United States who identified as Black, which is about 14% of the U.S. population. Black patients are markedly underrepresented (total n=89; 1.7%) in the NATALEE trial. According to American Cancer Society, among U.S. patients who develop breast cancer, Black patients were less likely to have HR+, HER2-negative subtype than white patients overall (57% vs 71%), but more likely to have regional disease (31% vs 24%) at diagnosis, with much higher mortality rates. The stage-matched five-year relative survival rates for patients with regional disease at diagnosis are 10% lower for Black 67 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. patients than for white patients. Black men are also more likely than men of other races to develop breast cancer both overall and considering the HR+, HER2-negative breast cancer subtype specifically. Black patients therefore have a very high degree of unmet medical need. Given that the NATALEE trial enrolled patients with high-risk Stage II or III HR+, HER2-negative disease, it should have been enriched for Black patients. While this underrepresentation does not preclude approval of ribociclib in the adjuvant setting, it provides limited information with which to counsel Black patients on the risks and benefits of adding ribociclib to ET. More efforts to increase the diversity of the patients enrolled on cancer clinical trials to reflect the diversity of the U.S. patient population are urgently needed. A postmarketing commitment (PMC) will ask the Applicant to provide data from ongoing/planned clinical trials (e.g., adjuvant WIDER trial) or other sources to better characterize the efficacy and safety of ribociclib in racial minority subgroups, including the Black or African-American population. The rationale for and details of the PMC are discussed further in Section 13. Other Baseline Characteristics Data: Table 11: Disease characteristics (FAS) Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Tumor Location Right 1277 (50.1) 1258 (49.3) 2535 (49.7) Left 1271 (49.9) 1287 (50.4) 2558 (50.1) Bilateral 1 (0.0) 7 (0.3) 8 (0.2) Missing 0 0 0 Histopathological grade at diagnosis - n (%) GX 30 (1.2) 32 (1.3) 62 (1.2) G1 218 (8.6) 240 (9.4) 458 (9.0) G2 1458 (57.2) 1451 (56.9) 2909 (57.0) G3 521 (20.4) 549 (21.5) 1070 (21.0) Not Done 292 (11.5) 258 (10.1) 550 (10.8) Missing 30 (1.2) 22 (0.9) 52 (1.0) T stage at diagnosis - n (%) TX 175 (6.9) 173 (6.8) 348 (6.8) T0 4 (0.2) 7 (0.3) 11 (0.2) Tis 2 (0.1) 3 (0.1) 5 (0.1) T1 471 (18.5) 442 (17.3) 913 (17.9) T2 1181 (46.3) 1235 (48.4) 2416 (47.4) T3 471 (18.5) 472 (18.5) 943 (18.5) T4 200 (7.8) 184 (7.2) 384 (7.5) Missing 45 (1.8) 36 (1.4) 81 (1.6) N stage at diagnosis - n (%) NX 272 (10.7) 264 (10.3) 536 (10.5) N0 694 (27.2) 737 (28.9) 1431 (28.1) N1 1050 (41.2) 1049 (41.1) 2099 (41.1) 68 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) N2 332 (13.0) 292 (11.4) 624 (12.2) N3 151 (5.9) 175 (6.9) 326 (6.4) Missing 50 (2.0) 35 (1.4) 85 (1.7) Ki67 score at initial diagnosis n 1861 1908 3769 Mean 27.1 27.1 27.1 SD 19.88 19.50 19.69 Min 0 0 0 Median 20.0 20.5 20.0 Max 99 100 100 Ki67 category at initial diagnosis ≤ 14% 508 (19.9) 508 (19.9) 1016 (19.9) > 14% 1353 (53.1) 1400 (54.9) 2753 (54.0) ≤ 20% 938 (36.8) 954 (37.4) 1892 (37.1) >20% 923 (36.2) 954 (37.4) 1877 (36.8) Missing 688 (27.0) 644 (25.2) 1332 (26.1) Histopathological grade on surgical specimen - n (%) GX 32 (1.3) 30 (1.2) 62 (1.2) G1 213 (8.4) 217 (8.5) 430 (8.4) G2 1460 (57.3) 1432 (56.1) 2892 (56.7) G3 684 (26.8) 702 (27.5) 1386 (27.2) Not Done 159 (6.2) 168 (6.6) 327 (6.4) Missing 1 (0.0) 3 (0.1) 4 (0.1) T stage on surgical specimen - n (%) TX 20 (0.8) 9 (0.4) 29 (0.6) T0 56 (2.2) 52 (2.0) 108 (2.1) Tis 16 (0.6) 19 (0.7) 35 (0.7) T1 774 (30.4) 761 (29.8) 1535 (30.1) T2 1162 (45.6) 1198 (46.9) 2360 (46.3) T3 427 (16.8) 422 (16.5) 849 (16.6) T4 92 (3.6) 91 (3.6) 183 (3.6) Missing 2 (0.1) 0 2 (0.0) N stage on surgical specimen - n (%) NX 2 (0.1) 5 (0.2) 7 (0.1) N0 378 (14.8) 418 (16.4) 796 (15.6) N1 1062 (41.7) 1039 (40.7) 2101 (41.2) N2 733 (28.8) 690 (27.0) 1423 (27.9) N3 372 (14.6) 399 (15.6) 771 (15.1) Missing 2 (0.1) 1 (0.0) 3 (0.1) Ki67 score on surgical specimen 1 n 1269 1332 2601 Mean 20.6 20.9 20.7 SD 17.82 18.15 17.99 Min 0 0 0 Median 15.0 15.0 15.0 Max 99 98 99 Ki67 category on surgical specimen 69 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) ≤ 14% 541 (21.2) 577 (22.6) 1118 (21.9) > 14% 728 (28.6) 755 (29.6) 1483 (29.1) ≤ 20% 817 (32.1) 864 (33.9) 1681 (33.0) > 20% 452 (17.7) 468 (18.3) 920 (18.0) Missing 1280 (50.2) 1220 (47.8) 2500 (49.0) Time since initial diagnosis (months) n 2517 2528 5045 Mean 11.8 11.8 11.8 SD 3.53 3.58 3.55 Min 1 1 1 Median 11.7 11.7 11.7 Max 23 27 27 Predominant histology - n (%) Invasive ductal carcinoma NOS 1857 (72.9) 1881 (73.7) 3738 (73.3) Invasive lobular 455 (17.9) 450 (17.6) 905 (17.7) Carcinoma medullary 1 (0.0) 1 (0.0) 2 (0.0) Mucinous 17 (0.7) 16 (0.6) 33 (0.6) Papillary 18 (0.7) 12 (0.5) 30 (0.6) Tubular 5 (0.2) 3 (0.1) 8 (0.2) Ductal Carcinoma In Situ 1 (0.0) 0 1 (0.0) Lobular Carcinoma In Situ 0 0 0 Other 194 (7.6) 189 (7.4) 383 (7.5) Missing 1 (0.0) 0 1 (0.0) Prior surgery - n (%) Mastectomy 1664 (65.3) 1691 (66.3) 3355 (65.8) Breast conserving surgery 978 (38.4) 963 (37.7) 1941 (38.1) Axillary lymph node dissection 2165 (84.9) 2149 (84.2) 4314 (84.6) Sentinel lymph node biopsy 926 (36.3) 920 (36.1) 1846 (36.2) Other 143 (5.6) 162 (6.3) 305 (6.0) Missing 0 0 0 HER2 ISH result prior to surgery (reported only if performed) - n (%) Amplification 4 (0.2) 7 (0.3) 11 (0.2) Non-Amplification 612 (24.0) 653 (25.6) 1265 (24.8) Equivocal 19 (0.7) 13 (0.5) 32 (0.6) Unknown 6 (0.2) 11 (0.4) 17 (0.3) HER2 ISH result from the surgical specimen (reported only if performed) - n (%) Amplification 2 (0.1) 1 (0.0) 3 (0.1) Non-Amplification 417 (16.4) 423 (16.6) 840 (16.5) Equivocal 1 (0.0) 1 (0.0) 2 (0.0) Unknown 2 (0.1) 2 (0.1) 4 (0.1) HER2 IHC score prior to surgery (reported only if performed) - n (%) 0 856 (33.6) 881 (34.5) 1737 (34.1) 1+ 862 (33.8) 813 (31.9) 1675 (32.8) 2+ 464 (18.2) 480 (18.8) 944 (18.5) 3+ 5 (0.2) 5 (0.2) 10 (0.2) 70 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Unknown 21 (0.8) 21 (0.8) 42 (0.8) HER2 IHC score from the surgical specimen (reported only if performed) - n (%) 0 625 (24.5) 610 (23.9) 1235 (24.2) 1+ 513 (20.1) 516 (20.2) 1029 (20.2) 2+ 235 (9.2) 262 (10.3) 497 (9.7) 3+ 1 (0.0) 3 (0.1) 4 (0.1) Unknown 6 (0.2) 10 (0.4) 16 (0.3) ER/PR combination statuses - n (%) ER+/PR+ 2172 (85.2) 2132 (83.5) 4304 (84.4) ER+/PR- 359 (14.1) 392 (15.4) 751 (14.7) ER-/PR+ 3 (0.1) 12 (0.5) 15 (0.3) ER+/UNK 10 (0.4) 13 (0.5) 23 (0.5) UNK/PR+ 2 (0.1) 2 (0.1) 4 (0.1) UNK/PR- 1 (0.0) 1 (0.0) 2 (0.0) UNK/UNK 2 (0.1) 0 2 (0.0) AJCC 8th ed. anatomic stage - n (%) Stage 0 0 0 0 Stage I 9 (0.4) 5 (0.2) 14 (0.3) Stage II 1011 (39.7) 1034 (40.5) 2045 (40.1) Stage III 1528 (59.9) 1512 (59.2) 3040 (59.6) Stage IV 0 0 0 Missing 1 (0.0) 1 (0.0) 2 (0.0) Genomic test Endopredict 23 (0.9) 28 (1.1) 51 (1.0) Mammaprint 46 (1.8) 51 (2.0) 97 (1.9) Oncotype DX 120 (4.7) 129 (5.1) 249 (4.9) Pam50 38 (1.5) 29 (1.1) 67 (1.3) Other 109 (4.3) 103 (4.0) 212 (4.2) N status for subgroup analysis used in AJCC Stage derivation 2 N0 285 (11.2) 328 (12.9) 613 (12.0) N1-N3 2261 (88.7) 2219 (87.0) 4480 (87.8) >N3 0 0 0 Missing 3 (0.1) 5 (0.2) 8 (0.2) 71 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Characteristic Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) Total N=5101 n (%) Subjects may have had more than one prior surgery but are only counted once per category. T stage category T1 collects T1mi, T1a, T1b, and T1c. Category T4 collects T4a, T4b, T4c, and T4d. N stage category N0 collects N0 and N0(i+). Category N1 collects N1, N1a, N1c, and N1mi. Category N2 collects N2a, N2b, and N2c. Category N3 collects N3a, N3b, and N3c. AJCC 8th ed. category Stage 1 collects Stage IA and Stage IB. Category Stage II collects Stage IIIA and Stage IIB. Category Stage III collects Stage IIIA, Stage IIIB, and Stage IIIC. Stage is derived using TNM from surgery for patients having not received neo-/adjuvant treatment, or as worst stage derived using TNM at diagnosis and TNM from surgery for patients having received neo-/adjuvant treatment. Patients may have had more than one Genomic test type but are only counted once per type. 1 Ki67 per surgical specimen (if available, otherwise at diagnosis) was used for subgroup iDFS analysis. 2 Included in missing category are patients having Nx. These patients are either unable to be staged or have been staged with Nx and T4(x) as Stage IIIB. Source: [Study O12301C Primary analysis CSR-Table 10-8] The Applicant’s Position: Treatment arms were generally well balanced and represented the intended eBC patient population with respect to baseline characteristics (including Anatomic Stage Group and nodal status). The proportion of patients with Anatomic Stage Group II disease was well balanced between both treatment arms (39.7% of patients in the ribociclib + ET arm vs. 40.5% of patients in the ET only arm). Similarly for Anatomic Stage Group III disease, a balance between both treatment arms was observed (59.9% of patients in the ribociclib + ET arm vs. 59.2% of patients in the ET only arm). A total of 285 patients (11.2%) in the ribociclib + ET arm and 328 patients (12.9%) in the ET only arm were N0 based on nodal status used in AJCC Stage derivation. The predominant histology was invasive ductal carcinoma (reported in 72.9% of patients in the ribociclib + ET arm and 73.7% of patients in the ET only arm. Although not required for all patients (and performed locally), the total number of patients enrolled with Ki67 scores ≤ 20% and > 20% were comparable (37.1% vs. 36.8%). All patients were HER2-negative (by protocol definition) with the exception of 8 patients (0.3%) in the ribociclib + ET arm and 10 patients (0.4%) in the ET only arm who were excluded from the Per Protocol Set [Study O12301C Primary analysis CSR-Section 10.4.2]. The FDA’s Assessment: FDA agrees that the disease characteristics at baseline are generally well-balanced between the two treatment arms and are reflective of the population for which the Applicant is seeking an indication in early breast cancer. As discussed elsewhere in the review, the patients in the NATALEE trial were much higher risk than the overall population with HR+, HER2-negative breast cancer in the US, based upon the grade, stage, and extent of nodal involvement, and therefore these results should not be extrapolated to a lower-risk population of patients. The proposed indication in patients with stage II and III HR+, HER2-negative breast cancer accurately reflects the study population; however, there is more limited information 72 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. on the benefit of ribociclib in patients with node-negative breast cancer as only 613 (12%) patients on NATALEE had N0 disease based upon nodal status used in AJCC staging, including 285 (11.2%) of patients on the ribociclib + ET arm. In subgroup analyses by nodal status, the iDFS favored ribociclib + ET over ET alone regardless of nodal status; the hazard ratio point estimates were similar for patients with N0 disease [HR 0.72 (95% CI: 0.41, 1.27)] and with N1-N3 disease [HR 0.76 (95% CI: 0.63, 0.91)], albeit with wider confidence intervals that cross 1, given the smaller sample size in the N0 subgroup. See FDA’s analysis of iDFS by Stage and nodal status in Section 8.1.2 and Table 20. Stratification Data: Table 12: Randomization by stratification factor (Full analysis set) Ribociclib + ET N=2549 n (%) ET only N=2552 n (%) All patients N=5101 n (%) Stratification factor at randomization Menopausal Status Premenopausal women and men 1125 (44.1%) 1128 (44.2%) 2253 (44.2%) Postmenopausal women 1424 (55.9%) 1424 (55.8%) 2848 (55.8%) AJCC Stage Anatomic Stage Group II 1076 (42.2%) 1078 (42.2%) 2154 (42.2%) Anatomic Stage Group III 1473 (57.8%) 1474 (57.8%) 2947 (57.8%) Prior Chemotherapy Yes 2214 (86.9%) 2218 (86.9%) 4432 (86.9%) No 335 (13.1%) 334 (13.1%) 669 (13.1%) Geographic Region NA/WE/O 1563 (61.3%) 1565 (61.3%) 3128 (61.3%) ROW 986 (38.7%) 987 (38.7%) 1973 (38.7%) Strata as entered in the IRT during randomization NA/WE/O: North America/Western Europe/Oceania; ROW: Rest of World Source: Study O12301C Primary analysis CSR-Table 10-5 The Applicant’s Position: Stratification according to menopausal status (premenopausal women, and men vs. postmenopausal women), AJCC 8th edition Stage (Stage II vs. Stage III), prior neoadjuvant/adjuvant chemotherapy (yes vs. no), and geographical region (North America/Western Europe/Oceania vs. rest of the world) was incorporated in the randomization design. The number of patients randomized according to each stratification factor (by IRT) was comparable between the ribociclib + ET arm and ET only arms [Study O12301C Primary analysis CSR-Section 10.3.1]. 73 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: FDA agrees that stratification factors are generally well-balanced between the two treatment arms. In addition, the concordance rates were high between IRT and CRF, with 98% concordance in menopausal status, 95% concordance in AJCC 8th edition staging, 98% concordance in prior neoadjuvant/adjuvant chemotherapy, and 100% concordance in geographical region. Of note, consistent with the baseline characteristics noted above, including a high rate of node positivity and grade 2 or 3 tumors, 87% of participants received (neo)adjuvant chemotherapy, which reflects the high-risk nature of the NATALEE population. The benefit-risk assessment should not be extrapolated to a lower-risk U.S. population of patients with HR+, HER-2 negative early breast cancer. Treatment Compliance, Concomitant Medications, and Rescue Medication Use The Applicant’s Position: Treatment compliance: No formal treatment compliance measurements for ribociclib, letrozole, anastrozole and goserelin were performed. Compliance was assessed by the Investigator examining the records of drug administration and the numbers of boxes as well as the tablets/capsules dispensed, received, and returned. The records of administration for ribociclib, NSAI (letrozole or anastrozole), and goserelin are provided [Study O12301C Primary analysis CSR-Section 10.6.3]. Concomitant therapy: Overall, a similar proportion of patients received concomitant medications during the study in the ribociclib + ET arm and in the ET only arm (92.3% vs. 85.9%). No imbalance was evident in the frequency or type of medication used. Concomitant use of bisphosphonates was similar between treatment arms (15.1% of patients in the ribociclib + ET arm and 15.2% of patients in the ET only arm). Concomitant use of denosumab, primarily for the treatment of osteoporosis and to increase bone mass due to high risk of fracture in the adjuvant setting, was also reasonably well balanced between treatment arms (2.35% of patients in the ribociclib + ET arm and 2.94% of patients in the ET only arm). The use of concomitant systemic corticosteroids was low and comparable in both treatment arms (0.4% of patients in ribociclib + ET arm and 0.5% of patients in the ET only arm). Systemic corticosteroid combinations were concomitantly used by 0.3% of patients in the ribociclib + ET arm and 0.1% of patients in the ET only arm. Overall, 17.8% of patients in the ribociclib + ET arm and 18.4% of patients in the ET only arm received at least one concomitant medication that was prohibited by this study. The most commonly (≥ 2.5%) used prohibited medications in the ribociclib + ET arm compared to the ET only arm were ondansetron (3.7% vs. 2.5%), azithromycin (3.1% vs. 2.5%) and ciprofloxacin (2.5% vs. 2.4%) [Study O12301C Primary analysis CSR-Section 10.5.2]. Rescue medication Not applicable as no rescue medications were allowed in the study. 74 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The FDA’s Assessment: FDA generally agrees with the Applicant’s summary of the data. The number of patients who received a concomitant medication prohibited by the study (approximately 18% in each arm) is high and of concern given that many of these drug-drug interactions, including the three most common prohibited concomitant medications used in the study, can increase the risk of QT prolongation and Torsades de Pointes. The use of prohibited concomitant medications was distributed equally across study arms. This likely reflects what will inadvertently occur in more typical use in the postmarket setting with three years of ribociclib in a curative intent population. It is therefore reassuring that even with 1 in 5 patients on study having received a prohibited medication, both QT prolongation of >60 ms from baseline or to >480 ms in patients on ribociclib + ET, as well as AESIs that may reflect undetected QT prolongation, were uncommon, likely due to the lower dose of 400 mg used in the adjuvant setting. See additional safety information regarding this issue in Section 8.2. Efficacy Results Efficacy claims for use of ribociclib 400 mg in combination with ET (AI: anastrozole or letrozole) and goserelin, if applicable, as adjuvant therapy for HR-positive, HER2-negative eBC are based on results from the final iDFS analysis (data cut-off date: 21-Jul-2023) and primary iDFS analysis at IA3 (data cut-off date: 11-Jan-2023) from the Phase III Study O12301C [CO Study O12301C-Section 4]. • The prespecified primary iDFS analysis IA3 was performed at 426 iDFS events, after which the DMC concluded that the iDFS results met the criteria to demonstrate statistically significant efficacy. As of the DCO date for IA3, the median duration of study follow-up from randomization to DCO was 34.0 months. The median follow-up for iDFS was 27.7 months. • The results of the final iDFS analysis (509 iDFS events) are reported in this document. The median duration of study follow-up for this DCO was 40.3 months (from randomization to DCO), with a minimum duration of follow-up of 27 months. The median follow-up for iDFS is 33.3 months for both arms. The totality of the data for the primary iDFS analysis (IA3) is provided in [Study O12301C Primary analysis CSR]. The updated data from the final iDFS analysis is provided in [Study O12301C EA&SU]. Primary Endpoint - Magnitude of treatment effect and robustness of iDFS analysis Data: Table 13: Log-rank test results for iDFS (FAS) Treatment n/N (%) Comparison Z-statistic p-value Primary iDFS Analysis (DCO 11-Jan-2023) Ribociclib + ET 189/2549 (7.4) vs. ET Only -2.9847 0.0014 75 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Treatment n/N (%) Comparison Z-statistic p-value* ET Only 237/2552 (9.3) Final iDFS Analysis (DCO 21-Jul-2023) Ribociclib + ET 226/2549 (8.9) vs. ET Only -3.2528 0.0006 ET Only 283/2552 (11.1) n is the number of iDFS events. N = total number of patients included in the analysis. * 1-sided p-value for log-rank test stratified by premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world. Source: [CO Study O12301C-Table 4-2] Figure 2: Kaplan-Meier plot for iDFS (FAS) - final iDFS analysis (21-Jul-2023 data cut-off) Source: [SCE Study O12301C-Figure 3-1] The Applicant’s Position: The ribociclib + ET arm demonstrated statistically significant and clinically superior efficacy over the ET only arm for the primary endpoint of iDFS per Investigator assessment [Study O12301C Primary analysis CSR], which was maintained over time. At the final iDFS analysis, 76 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. there was an estimated 25.1% relative reduction in the risk of an iDFS event (HR 0.749; 95% CI: 0.628, 0.892; one-sided stratified log-rank test nominal p-value = 0.0006) [SCE Study O12301C- Tables 3-10 and 3-11], [SCE Add. Study O12301C-Tables 3-2 and 3-3]. At the final iDFS analysis, the Kaplan-Meier iDFS curves diverged from approximately 3 months after start of treatment, corresponding to time of first STEEP clinical evaluation. In general, the iDFS event-free probability remained higher in the ribociclib + ET arm, indicating an early, sustained benefit with the ribociclib combination, which was maintained over time (Figure 2). As of the data cut-off date for the final iDFS analysis, there were approximately 5.6 months of additional follow-up for iDFS, with median duration of iDFS follow-up (from randomization to last recurrence assessment) of 33.3 months for both arms. The 3-year iDFS rates for the final iDFS analysis were 90.7% (95% CI: 89.3, 91.8) in the ribociclib + ET arm and 87.6% (95% CI: 86.1, 88.9) in the ET only arm, reflecting a 3.1% absolute benefit favoring ribociclib + ET. There were fewer iDFS events (8.9% vs. 11.1%) reported in the ribociclib + ET arm compared to the ET only arm. This trend is consistent with the primary iDFS analysis results (4.7% vs. 6.7%, distant recurrence events). Robustness and consistency of iDFS analysis Results of the iDFS analysis based on the PPS were consistent with the final iDFS analysis based on the FAS (one-sided stratified log-rank test p-value=0.0005; stratified Cox regression model HR=0.746; 95% CI: 0.626, 0.890). In addition, multiple sensitivity analyses based on excluding missing iDFS assessment, backdating iDFS, new anticancer therapy, clinical recurrence, and death due to COVID-19, were supportive of the final iDFS analysis results. Consistent treatment effect-iDFS subgroup analyses Consistency of iDFS benefit was evident across stratification factors of anatomic stage, prior (neo)adjuvant chemotherapy, menopausal status, and geographic region, and other subgroups. The ITT results of IDFS did not appear to be driven by any particular subgroup [CO Study O12301-Section 4.3.1.1]. The FDA’s Assessment: FDA agrees that the ribociclib + ET arm demonstrated a statistically significant improvement compared to the ET only arm for the primary endpoint of iDFS per investigator assessment at IA3. However, at IA3, there was a large amount of censoring for iDFS as only 20% of patients had completed 3-years of adjuvant ribociclib. Due to the FDA’s concern for a possible diminishing iDFS effect with longer follow-up, FDA requested that the Applicant continue NATALEE until the final iDFS analysis. At the final iDFS analysis (DCO: July 21, 2023), 43% of patients had completed 3 years of adjuvant ribociclib. There were 226 iDFS events in 2549 patients in the ribociclib + ET arm compared to 283 iDFS events in 2552 patient in the ET only arm at the final iDFS analysis. The final iDFS HR was 0.75 (95% CI: 0.63, 0.89), which was consistent with iDFS results at 77 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. IA3. The reasons for iDFS censoring at the time of final iDFS analysis are summarized in Table 14 below. Table 14: FDA – iDFS Censoring Reasons (final iDFS analysis) Ribociclib + ET N=2549 (%) ET only N=2552 (%) Number of patients with iDFS event 226 (8.9) 283 (11.1) Number of patients censored 2323 (91.1) 2269 (88.9) Reason for censoring Ongoing without event 2073 (81.3) 1901 (74.5) Withdrew consent 233 (9.1) 343 (13.4) Lost to follow-up 17 (0.7) 25 (1.0) Source: FDA Analysis Of note, FDA was concerned that there appeared to be an imbalance in the number of patients censored due to withdrawal of consent. FDA further examined the timing of censoring for patients who were censored for withdrawal of consent, as shown in Table 15. Table 15: FDA – Timing of Censoring for Patients Censored for Withdrawal of Consent Time Censored Ribociclib + ET N=2549 (%) ET Only N=2552 (%) Randomization 84 (3.3) 201 (7.9) >0-6 Months 66 (2.6) 43 (1.7) 6-12 Months 30 (1.2) 21 (0.8) 12-24 Months 31 (1.2) 47 (1.8) 24-48 Months 22 (0.9) 31 (1.2) Total 233 (9.1) 343 (13.4) Source: FDA Analysis From this, it appeared that the imbalance was largely due to patients who were censored at randomization for withdrawal of consent. Therefore, FDA conducted several sensitivity analyses to assess the impact of the imbalance in patients who were censored at randomization due to withdrawal of consent. The sensitivity analyses considered various approaches to impute iDFS data for these patients, and results are summarized in Table 16. 78 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 16: FDA – iDFS Sensitivity Analyses to Account for Imbalance in Patients Censored at Randomization for Withdrawal of Consent Sensitivity Analysis Description HR (95% CI) For patients censored at randomization for withdrawal of consent: 1. Impute iDFS for patients in both arms from the best 20% for iDFS in both arms 0.80 (0.67, 0.95) 2. Impute iDFS for patients in both arms from the best 20% for iDFS in ET Only arm only 0.82 (0.69, 0.98) 3. Impute iDFS for patients in the ET Only arm from the best 20% for iDFS in both arms 0.81 (0.68, 0.97) 4. Impute iDFS for patients in the ET Only arm from the best 20% for iDFS in the ET Only arm only 0.82 (0.69, 0.97) Source: FDA Analysis Results of the sensitivity analyses were generally consistent with results of the final iDFS analysis (iDFS HR of 0.75 [95% CI: 0.63, 0.89]), even when considering the most conservative scenario in which only patients on the ET only arm had iDFS times imputed from the best 20% for iDFS in both arms. FDA also examined the baseline characteristics for the patients who were censored at baseline for withdrawal of consent and did not identify any major difference in prognosis for this group of patients. Thus, it does not appear that this imbalance impacted results in a way that would change the overall benefit- risk assessment. In addition, FDA agrees that the iDFS results at the final analysis were consistent across multiple sensitivity analyses, including those excluding missing assessments and those considering different censoring rules. Results of iDFS in exploratory subgroups of interest are shown in the next section and were generally consistent with the primary analysis. Efficacy Results – Secondary and other relevant endpoints Data: Table 17: Secondary efficacy results (Study O12301C) - final iDFS analysis (21-Jul-2023 data cut-off) Overall study population N FAS = 5101: 2549 patients in ribociclib + ET arm, and 2552 patients in ET only arm RFS 7.5% vs. 9.7% in favor of ribociclib + ET (one sided stratified log-rank test p-value=0.0004) Cox regression model: estimated 27.3% reduction in the risk of RFS in the ribociclib + ET arm; hazard ratio=0.727 (95% CI: 0.602, 0.877) Kaplan-Meier method: 3-year RFS rates of 92.1% (95% CI: 90.9, 93.2) in the ribociclib + ET arm and 89.1% (95% CI: 87.6, 90.4) in the ET only arm, translating to a 3.0% improvement in the 3-year rate of RFS in favor of ribociclib + ET 79 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Overall study population DDFS 8.0% vs. 10% in favor of ribociclib + ET (one sided stratified log-rank test p-value=0.0010) Cox regression model: estimated 25.1% reduction in the risk of DDFS in the ribociclib + ET arm; hazard ratio=0.749 (95% CI: 0.623-0.900) Kaplan-Meier method: 3-year DDFS rates of 91.5% (95% CI: 90.2, 92.7) in the ribociclib + ET arm and 88.9% (95% CI: 87.4, 90.2) in the ET only arm, translating to a 2.6% improvement in the 3-year rate of DDFS in favor of ribociclib + ET OS No detriment observed for patients in the ribociclib + ET arm Log-rank analysis: 84 (3.3%) deaths in the ribociclib + ET arm, and 88 (3.4%) in the ET only arm: (one-sided stratified log-rank test nominal p-value = 0.2263) Cox regression model: estimated 10.8% reduction in the risk of death in the ribociclib + ET arm; hazard ratio=0.892 (95% CI: 0.661, 1.203) Kaplan-Meier method: 3-year OS rates were 97.0% (95% CI: 96.2, 97.6) in the ribociclib + ET arm and 96.1% (95% CI: 95.1, 96.9) in the ET only arm Sensitivity analyses for OS (including based on PPS, per CRF, unstratified log-rank test and Cox model, stratified Cox model adjusting for baseline covariates, and censoring for patients with death due to COVID) provide further support that there is a positive trend in favor of the ribociclib + ET arm, with HRs ranging from 0.837 to 0.910 Exploratory Source: [CO Study O12301C-Section 4.3.2] The Applicant’s Position: Secondary efficacy endpoints Results for the secondary efficacy endpoints support the clinical benefit of ribociclib in combination with ET as adjuvant therapy, with no detriment in OS. Ribociclib + ET was associated with significant improvements in RFS and DDFS, with HRs of 0.72 (95% CI: 0.584, 0.884) and 0.74 (95% CI: 0.603-0.905) for the primary analysis/IA3, and HRs of 0.73 (95% CI: 0.602, 0.877) and 0.75 (95% CI: 0.623-0.900) for the final iDFS analysis, respectively. While OS results were immature, OS data at this final iDFS analysis showed no detriment in OS with the addition of ribociclib to ET. A numerically lower mortality rate in the ribociclib + ET arm has been reported, with a total of 84 (3.3%) events in the ribociclib + ET arm, and 88 (3.4%) in the ET only arm. Of note, in this analysis, the OS event rate is lower than anticipated (172 deaths observed vs. 271 deaths anticipated in the protocol at the final iDFS analysis) [CO Study O12301C- Section 4.3.2]. DRFS (exploratory efficacy analysis) For the final iDFS analysis, there was an estimated 26.2% relative reduction in the risk of DRFS for patients in the ribociclib + ET arm (hazard ratio = 0.738; 95% CI: 0.606, 0.898). The DRFS distribution was estimated using the Kaplan-Meier method. There were 178 events in the ribociclib + ET arm vs. 227 events in the ET only arm; one-sided nominal p-value = 0.0012 [CO Study O12301C-Section 4.3.2.1]. 80 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Efficacy in subpopulations Data: Figure 3: Forest plot of iDFS by stratum (final iDFS analysis, 21-Jul-2023 data cut-off (FAS) * Hazard rate in group ET + ribociclib versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors. The group ET only is the reference in the hazard ratio calculation. Source: [SCE Add. Study O12301C-Figure 3-7] Figure 4: Forest plot of iDFS – subgroup analysis (final iDFS analysis, 21-Jul-2023 data cut-off (FAS) 81 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 82 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 83 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 84 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. NE=not evaluable. -Hazard rate in group ribociclib + ET versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors. Th group ET only is the reference in the hazard ratio calculation. Source: [SCE Add. Study O12301C-Figure 3-8] 85 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The Applicant’s Position: Subgroup analyses of iDFS (21-Jul-2023 cut-off) demonstrated a treatment benefit of ribociclib + ET across stratification factors of anatomic stage, prior (neo)adjuvant chemotherapy, menopausal status, and geographic region (Figure 3), as well as other predefined clinically relevant subgroups, including nodal status (Figure 4) [CO Study O12301C-Section 4.4.1]. The FDA’s Assessment: FDA agrees with the Applicant’s assessment that a variety of exploratory subgroup analyses by sex, menopausal status, stage, prior therapy, and pathology results generally were supportive of the addition of ribociclib to ET with point estimates for the iDFS HR <1. FDA emphasizes that NATALEE was not designed to formally test any secondary endpoints, including OS, and cannot support a labeling claim for the other efficacy endpoints but generally agrees with the Applicant’s summary of the efficacy data for the secondary endpoints of RFS, DDFS, and OS. These secondary endpoint results are considered supportive of the iDFS benefit for the addition of ribociclib to ET. The endpoints of RFS and DDFS, which include events earlier than death, are clinically informative in view of the unexpectedly low number of deaths observed in NATALEE at the time of the final iDFS analysis. Given that the number of deaths was lower than anticipated at the final iDFS analysis, prior to the sNDA submission, FDA requested that the applicant provide simulations to estimate the probability of OS detriment with addition of ribociclib to ET based on a total of 340 events projected to occur at end of study. Results of the simulation provided by the Applicant are shown in Table 18 below: Table 18: Applicant's OS Simulation True HR for future OS events Mean est.HR at 340 events (95% CI) P(est.HR>1) (%) P(est.HR>1.1) (%) P(est.HR>1.2) (%) 0.8920.7=0.624 0.752 (0.580, 0.976) 0 0 0 0.8920.8=0.714 0.802 (0.618, 1.041) 0.3 0 0 0.8920.9=0.802 0.849 (0.653, 1.103) 1.3 0.2 0 0.892 0.894 (0.688, 1.162) 7.3 0.3 0 0.8921.1=0.981 0.937 (0.722, 1.217) 20.3 1.7 0.1 0.8921.2=1.070 0.978 (0.753, 1.270) 37.3 5.9 0.4 0.8921.3=1.160 1.017 (0.783, 1.321) 58.6 15.8 1.5 Source: Provided by Applicant In addition, FDA requested an additional OS analysis with the 90-day safety update. At the 90-day safety update, with a data cutoff of October 26, 2023, there were a total of 91 (3.6%) deaths in the ribociclib + ET arm, and 98 (3.8%) deaths in the ET only arm. The OS HR was 0.88 (95% CI: 0.66, 1.17) for the ribociclib + ET arm vs the ET only arm. 86 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Overall, results of OS at the time of final iDFS and at the 90-day safety update support that there appears to be no detriment in OS at this time with addition of ribociclib to ET. A postmarketing requirement (PMR) will be issued for the applicant to provide all additional OS analyses as prespecified in the protocol and SAP, including OS at the time of end of trial. This is discussed further in Section 13. Data Quality and Integrity The Applicant’s Position: No data integrity concerns were reported following Investigator site audits [Study O12301C Primary analysis CSR-Section 9.6.5.1]. The FDA’s Assessment: FDA inspected 5 clinical sites for NATALEE. Table 19: FDA – Clinical Site Inspections Site Contact Site # Pt # Primary Endpoint Verification Dr. Bozena Kukielka-Budny Doktora Kazimierza Jaczewskiego 7 LUBLIN, NA 20-090 Poland Phone: 48509518811 Email: bozena-budny@wp.pl 1810 84 Please ask inspector to verify all subjects in the investigational arm (patients who received ribociclib and endocrine therapy) who were reported as not having an iDFS event by July 21, 2023. Please audit 10% of the subjects in the investigational arm at each site reported to have an iDFS event by July 21st, 2023. If 50% of these positive events are misclassified, please verify all subjects in the investigational arm reported to have an iDFS event by July 21, 2023. Specifically, verify the iDFS Event Type (i.e. NPM, death, recurrence) and Date of Event. If time permits, please also audit 10% of the subjects on the control arm (patients who received endocrine therapy only) at each site reported to have an iDFS event and those without an iDFS event by July 21, 2023. Dr. Zbigniew Nowecki I The Maria Sklodowska Curie Memorial Cancer Centre And Institute Of Oncology (Mcmcc) WARSAW, NA 02-78 Poland Phone: 48225462522 Email: zbigniew.nowecki@pib-nio.pl 1811 131 Dr. Shaker Dakhil R 818 North Emporia Wichita, KS 67214 Phone: 3162624467 Email: shaker.dakhil@cancercenterofkansas.com 5007 21 Dr. Priyanka Sharma 2330 Shawnee Mission Pkwy Westwood, KS 66205 Phone: 9135886029 Email: psharma2@kumc.edu 5057 25 87 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Site Contact Site # Pt # Primary Endpoint Verification Dr. Lowell Hart 3840 Broadway Fort Myers, FL 33901 Phone: 2392749930 Email: llhart@flcancer.com 5075 40 Refer to Section 4.1 for further details on the findings of inspections. Complete information can be found in the FDA OSI review memo. Overall, no action was indicated for the sites. Dose/Dose Response The Applicant’s Position: Results of Study O12301C demonstrated that the 400 mg ribociclib dose is safe and efficacious for use for eBC in the adjuvant setting, where patients have a lower tumor burden than in the advanced or metastatic setting. Thus, the recommended dose of ribociclib for the adjuvant setting for eBC is 400 mg (two 200-mg film-coated tablets) of ribociclib once daily, Days 1 to 21 of each 28-day cycle for 3 years combined with 5 years of ET. Dose reductions: Recommended dose modification guidelines in the adjuvant setting are as follows: • Starting dose 400 mg/day (two 200-mg tablets) • Dose reduction 200 mg/day (one 200-mg tablet) If further dose reduction below 200 mg/day is required, the treatment should be permanently discontinued [SCE Study O12301C-Section 4.2]. Dose justification: Both neutropenia and QTcF prolongation, the adverse events related to ribociclib PK exposure, are lower in eBC patients in Study O12301C at the dose of 400 mg than in aBC patients at the dose of 600 mg, supporting improved tolerability of the 400 mg dose in eBC patients. The PK-QT modeling confirmed the exposure-QTcF relationship in eBC patients, and patient population is a significant covariate where eBC patients showed less QTcF response than aBC patients. Efficacy in patients with eBC was demonstrated by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Due to limited sample size of patients with iDFS events, exposure-efficacy relationship cannot be characterized. In conclusion, based on the observed efficacy and safety data of Study O12301C, exposure- response analysis, and the historical data in patients with aBC, 400 mg ribociclib (once daily for 88 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 3 weeks on/1 week off in a 28-day cycle) is demonstrated to be a safe and effective dose in patients with eBC. The relationship between Ctrough concentration quartiles and iDFS events was examined for patients included in the PK-iDFS set; however, no conclusions could be drawn due to limited data [CO Study O12301-Sections 3.3 and 3.2.1.1]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. Refer to FDA’s clinical pharmacology review in Section 6.3.2. Durability of Response The Applicant’s Position: At the final iDFS analysis a substantial majority of patients, 1996 (78.3%) in the ribociclib + ET group, had discontinued ribociclib, with 1091 patients (42.8%) having completed 3 years of ribociclib treatment per protocol [SCE Add. Study O12301C-Section 3.1]. As of the data cut-off date of 21-Jul-2023 for the final iDFS analysis, there were approximately 5.6 months of additional follow-up for iDFS, with median duration of iDFS follow-up (from randomization to last recurrence assessment) of 33.3 months for both arms [SCE Add. Study O12301C-Section 3.2.1]. The statistically significant improvement in iDFS in the ribociclib + ET arm compared with the ET only arm seen at IA3 was further confirmed with more mature data at final iDFS analysis. With longer follow-up, additional iDFS events, and a larger proportion of patients completing the 3-year treatment regimen of ribociclib, the hazard ratios were very similar when comparing results from the second and third interim analyses, as well as the final iDFS analysis. These results reflect the stability of the data over time. In addition, the confidence intervals are narrowing, indicating that the data are becoming more mature. These results indicate that although the study is ongoing, it is not expected that the overall assessment of the benefit:risk of ribociclib in eBC would change [CO Study O12301C-Section 4.5.1]. The FDA’s Assessment: As noted in Section 8.1, the majority of iDFS events in HR+, HER2-negative early breast cancer occur in years 5-20+ after diagnosis. It would be very unlikely for the overall assessment of the benefit-risk of ribociclib to become unfavorable over time given the trend in iDFS HRs observed to this point; however, the impact of ribociclib on late recurrences cannot be determined from the available data with the current duration of follow-up. A PMC to provide further OS data is discussed in Section 13. 89 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Persistence of Effect The Applicant’s Position: The persistent, beneficial effect of ribociclib on the primary iDFS endpoint was further supported by a series of subgroup analyses. Consistency of the iDFS improvement was generally evident across all subgroups assessed for both the primary and final iDFS analyses, including stratification factors (anatomic stage, prior (neo)adjuvant chemotherapy, menopausal status, geographic region), and other predefined clinically relevant subgroups, demonstrating the validity of the results across the broad study population, with no particular subgroup driving these results. Results for secondary endpoints, including RFS and DDFS were also consistent with and supportive of the iDFS primary endpoint results. At the final iDFS analysis, ribociclib demonstrates persistent efficacy in patients with HR- positive, HER2-negative, Stage II and III eBC with continued separation of the KM curves, consistent HRs between the primary and final iDFS analyses, and narrower confidence intervals across the primary and secondary endpoints [CO Study O12301C-Section 4.5.2] The FDA’s Assessment: While there was no alpha spending on efficacy endpoints other than iDFS or on analysis of iDFS in these subgroups, and therefore these results cannot support any labeling claims, FDA agrees that the results of subgroup analyses and analysis of secondary endpoints were supportive of the results of the primary iDFS analysis in the ITT population. FDA requested that the Applicant conduct an additional OS analysis with the 90-day safety update. As of the data cutoff of October 26, 2023, there had been 91 deaths in 2549 patients in the ribociclib + ET arm compared to 98 deaths in 2552 patients in the ET only arm. Median OS was not reached in either arm. The OS HR was 0.88 (95% CI: 0.66, 1.17). A PMC will require the Applicant to submit pre-specified OS analyses, including the results of OS at the planned end of the study, as discussed in Section 13. Efficacy Results – Secondary or exploratory COA (PRO) endpoints The Applicant’s Position: Patient-reported outcomes (11-Jan-2023 cut-off) Overall, treatment with ribociclib + ET maintained HR QoL scores over time, further supporting the clinical benefit of the proposed treatment regimen in the target population. In general, the primary QoL measure of interest, EORTC QLQ-C30 physical functioning, of patients treated with ribociclib + ET was similar to that of patients treated with ET only. Physical functioning scores were generally similar between the two treatment arms throughout the study, with no meaningful differences at any post-baseline timepoint through to EOT. 90 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Furthermore, PRO scores in the ribociclib + ET arm, upon treatment, remained within 0.5 SD of their baseline scores. A longitudinal analysis of differences in physical functioning score between treatment arms using a repeated measures model (RMM) revealed no substantial or meaningful effect of treatment or treatment by time interaction on the physical functioning scores of EORTC QLQ- C30. In addition, results for the RMM were generally consistent with the change from baseline analyses and related time profile for physical functioning. Analysis of mean change from Baseline scores of global health status/QoL, emotional functioning and social functioning sub-scale scores of the EORTC QLQ-C30, the breast cancer symptoms scores of the EORTC QLQ-BR23, the VAS scores of the EQ-5D-5L, and the anxiety domain and depression domain scores of HADS indicated no meaningful differences between treatment arms over time. Results of the RMM for health status/QoL, emotional functioning and social functioning sub- scale scores of the EORTC QLQ-C30, the breast cancer symptoms scores of the EORTC QLQ- BR23, the VAS scores of the EQ-5D-5L, and the anxiety domain and depression domain scores of HADS confirmed that there was no evidence of a difference between treatment arms during the treatment period [CO Study O12301C-Section 4.3.2]. The FDA’s Assessment: FDA reviewed the PRO results submitted by the Applicant but did not independently verify all of the results. PRO data were collected at screening, every 12 weeks (±2 weeks) after randomization during the first 24 months and every 24 weeks (±2 weeks) thereafter, at EOT, at confirmation of first recurrence, at confirmation of distant recurrence (if the first recurrence was not a distant recurrence), and during the first 12 months after confirmation of distant recurrence (every 12 weeks [±2 weeks] if confirmation of distant recurrence happened during the first 24 months after date of randomization or every 24 weeks [±2 weeks] if confirmation of distant recurrence happened after the first 24 months after the date of randomization). In terms of data quality, from baseline through EOT, the compliance rate was >80% in both arms. The PRO results from this study cannot support any efficacy claims as PRO assessment was sparse, and there was no plan for formal testing of any PRO endpoints. FDA does not agree with the statement that the PRO results support the clinical benefit of the proposed treatment regimen in the target population as this study was not designed to support such conclusions. Furthermore, there was no observed difference in patient reported disease symptoms (e.g., breast cancer symptom scores of the EORTC WLW-BR23), which does not support the Applicant claim of clinical benefit based upon PROs. Lastly, the PRO strategy lacked a comprehensive tolerability assessment including side effects of treatment and overall side effect impact. No post-baseline PRO assessment occurred until week 12, obscuring important tolerability information. 91 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Additional Analyses Conducted on the Individual Trial The Applicant’s Position: Not applicable The FDA’s Assessment: FDA conducted exploratory subgroup analyses of iDFS by anatomic stage and nodal status (Anatomic Stage IIA [Node+ and Node-], Anatomic Stage IIB, and Anatomic Stage III. Results are presented below. Table 20: FDA – Final iDFS by Anatomic Stage and Nodal Status Ribociclib + ET Number of Events/N ET Only Number of Events/N HR (95% CI) Anatomic Stage IIA 15/480 32/521 0.48 (0.26, 0.89) Node positive 4/268 12/280 0.31 (0.10, 0.96) Node negative 11/212 20/241 0.65 (0.31, 1.36) Anatomic Stage IIB 40/531 48/513 0.82 (0.54, 1.26) Anatomic Stage III 170/1528 203/1512 0.76 (0.62, 0.93) Source: FDA Analysis 8.1.3 Integrated Review of Effectiveness The FDA’s Assessment: Not applicable. The Applicant submitted a single trial NATALEE conducted in the adjuvant setting. Ribociclib is already FDA-approved for adults with advanced or metastatic HR+, HER2-negative breast cancer in combination with fulvestrant or an aromatase inhibitor. 8.1.4 Assessment of Efficacy Across Trials The Applicant’s Position: Not applicable The FDA’s Assessment: Not applicable. The Applicant submitted a single trial NATALEE conducted in the adjuvant setting. 92 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Additional Efficacy Considerations The FDA’s Assessment: Not applicable. The Applicant submitted a single trial NATALEE conducted in the adjuvant setting. 8.1.5 Integrated Assessment of Effectiveness The Applicant’s Position: At the final iDFS analysis (509 events, DCO 21-Jul-2023), the addition of ribociclib to ET continued to show a statistically significant and clinically superior efficacy for iDFS, using STEEP criteria as per Investigator assessment, compared with ET only. The median duration of iDFS follow-up between randomization and the data cut-off date was 33.3 months, representing an additional 5.6 months of iDFS follow up since the primary analysis. • Based on a stratified Cox regression analysis, there was an estimated 25.1% relative reduction in the risk of an iDFS event (hazard ratio = 0.749; 95%CI: 0.628, 0.892 (one-sided stratified log-rank test nominal p-value = 0.0006). • The iDFS rate at 3 years is 90.7% (89.3%, 91.8%) for ribociclib + ET vs. 87.6% (86.1%, 88.9%) for ET only, representing a 3.1% absolute benefit in favor of ribociclib + ET. • Consistency of the iDFS improvement was generally evident across all subgroups assessed, including key subgroups (anatomic staging, menopausal status, nodal involvement), demonstrating the validity of the results across the broad study population. • Stage III – hazard ratio = 0.755 (95% CI: 0.616, 0.926); Stage II – hazard ratio = 0.700 (95% CI: 0.496, 0.986) • Premenopausal women & Men – hazard ratio = 0.688 (95% CI: 0.519, 0.913); Postmenopausal – hazard ratio = 0.806 (95% CI: 0.645, 1.007) • N0 subgroup – hazard ratio = 0.723 (95% CI: 0.412, 1.268); N1-N3 subgroup – hazard ratio = 0.759 (95% CI: 0.631, 0.912) • A statistically significant improvement in RFS was demonstrated for the ribociclib + ET arm compared with the ET only arm; RFS HR is 0.727, 95% CI (0.602,0.877) (nominal p-value = 0.0004), with an estimated 27.3% relative reduction in the risk of RFS per Cox regression model. • A statistically significant improvement in DDFS was demonstrated for the ribociclib + ET arm compared with the ET only arm: DDFS HR is 0.749, 95% CI (0.623,0.900) (nominal p- value = 0.0010), with an estimated 25.1% relative reduction in the risk of DDFS per Cox regression model. • There was an estimated 26.2% relative reduction in the risk of DRFS for patients in the ribociclib + ET arm (hazard ratio = 0.738; 95% CI: 0.606, 0.898) (nominal p-value = 93 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 0.0012). The 3-year DRFS rates at the final iDFS analysis (DCO 21-Jul-2023) were 92.6% (95% CI: 91.4, 93.7) in the ribociclib + ET arm and 90.1% (95% CI: 88.7, 91.3) in the ET only arm, reflecting a 2.5% absolute benefit favoring ribociclib + ET. • Although the OS data were still immature, there was no detrimental effect on OS for the final iDFS analysis. With this final iDFS analysis, a substantial majority of patients have completed 3 years of treatment, and efficacy has been sustained as demonstrated by continued separation of the KM curves, consistent HRs and narrower confidence intervals across the primary and secondary endpoints. This further confirms the benefit for a broad population of eBC patients receiving ribociclib for a 3-year duration [SCE Add. Study O12301C-Section 6]. The FDA’s Assessment: NATALEE was a randomized (1:1) multicenter trial for the adjuvant treatment of patients with HR+, HER2-negative stage II and III early breast cancer. Patient were randomized to receive ribociclib (400 mg daily 3 weeks on/1 week off for 3 years) + endocrine therapy (ET, non-steroidal aromatase inhibitor [NSAI], as well as goserelin in men and premenopausal women, dosage per SOC for 5 years) vs. ET only. The primary endpoint of NATALEE was invasive disease-free survival (iDFS) by investigator assessment in the intent to treat (ITT) population. A total of 2549 patients were randomized to the ribociclib + ET arm and 2552 patients to the ET only arm. NATALEE met its primary endpoint of iDFS at IA3 demonstrating a statistically significant improvement in iDFS (hazard ratio [HR] 0.748, 95% confidence interval [CI] 0.619-0.906). The 3-year iDFS was 90.4% (88.6-91.9) on the ribociclib + ET arm compared to 87.1% (85.3-88.8) on the ET only arm, for an absolute difference of 3.3%. However, at IA3, due to a large amount of censoring for iDFS with only 20% of patients having completed 3 years of adjuvant ribociclib and immature OS with 134 total deaths (OS HR 0.759, 95% CI 0.539-1.068), FDA advised the Applicant to continue to follow participants until the final iDFS analysis. The sNDA submission for 209092/S-018 was received on December 22, 2023, and the Applicant used a priority review voucher (PRV). The sNDA submission for 209935/S-027 (co-pack) was received on March 11, 2024, and cross-references sNDA 209092/S-018. The sNDA submission is based on final iDFS, with a data-cutoff date of July 21, 2023. At final iDFS analysis, the HR was 0.75 (95% CI 0.63-0.89). While the median iDFS was not estimable on either treatment arm, the 3-year iDFS rates were 90.7% (95% CI: 89.3, 91.8) in the ribociclib + ET arm and 87.6% (95% CI: 86.1, 88.9) in the ET only arm. The interim OS analysis at the time of final iDFS analysis was immature with 84 deaths (3%) on the ribociclib + ET arm and 88 deaths (3%) on the ET only arm. The OS HR was 0.89 (95% CI 0.66-1.20) with median OS not estimable. As of the July 21, 2023 data cut-off, 43% of patients had completed 3 years of ribociclib + ET, and 69% had completed ≥2 years of ribociclib + ET. There were 172 total deaths on 94 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. study as of the final iDFS analysis. On-treatment deaths were uncommon overall, but higher on the ribociclib + ET arm, 20 deaths (0.8%) compared to 9 deaths (0.4%) on the ET only arm, and more often due to adverse events. The 90-day safety update submitted on March 21, 2024 had a data-cut off of October 26, 2023 and provided approximately 3 additional months of information. At the safety update, there continued to be fewer overall deaths on study in the ribociclib + ET arm: 83 (3.3%) in the ribociclib + ET group and 89 (3.6%) in the ET only group, most of which were attributed to disease progression. Overall safety findings were consistent with the original submission and the known safety profile of ribociclib + ET as reflected in the current USPI. 95 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 8.2 Review of Safety The Applicant’s Position: The key safety data in support of this application are from the primary and final iDFS analyses of Study O12301C. In this large study (N=5101, FAS; N=4968; Safety set), ribociclib 400 mg in combination with standard adjuvant ET (AI; anastrozole or letrozole) is compared with standard of care adjuvant ET alone. The population enrolled in this study reflects the target population of adult patients (including pre- and postmenopausal women plus men) with HR-positive, HER2- negative, Stage II or Stage III eBC who are at risk of recurrence [SCS Study O12301C-Section 1.1.2]. Based on the Safety set, this study population consists of patients with anatomic Stage II (40.3%) or Stage III (59.4%) disease as per AJCC staging (eighth ed.) who had completed surgery, followed by chemotherapy, and/or radiotherapy with curative intent. In view of the stratification (by menopausal status, anatomic stage group, use of prior neoadjuvant/adjuvant chemotherapy, and geographic region), 1:1 randomization, and balanced demographic and disease characteristics between the two arms, comparisons between the ribociclib + ET and ET only groups allow for valid assessment of safety in this population. This population is also considered appropriate for the detection and characterization of AEs and to provide guidance on toxicity management [CO Study O12301C-Section 5.1.1]. The FDA’s Assessment: FDA agrees with the Applicant’s characterization of the safety population. The stratification criteria are appropriate for the population studied. The population enrolled includes sufficient numbers of patients with Stage II (approximately 40%) and III (approximately 60%) breast cancer to support the proposed indication. Baseline characteristics were well-balanced. Overall, the NATALEE participants, of whom 88% had N1-N3 disease, <10% had grade 1 disease, and 87% received (neo)adjuvant chemotherapy, represent a markedly higher risk subset of the broader US population of patients with HR+, HER2-negative early breast cancer; therefore, the efficacy and safety results of this study should not be extrapolated to a lower-risk population of patients. Black or African-American patients, who are more likely to be diagnosed with high-risk early breast cancer than patients of other races, and more likely to experience recurrence or death after a diagnosis of early breast cancer, are extremely under-represented in the NATALEE trial. A postmarketing commitment (PMC) to provide data from ongoing/planned clinical trials or other data sources to better characterize the efficacy and safety of ribociclib in racial minority subgroups, including Black or African-American patients, is planned as discussed in Section 13. 8.2.1 Safety Review Approach The Applicant’s Position: The key safety data include results for the 4967 patients with eBC in the Safety set of Study O12301C who received study treatment based on the final iDFS analysis (DCO of 21-Jul-2023). The final iDFS analysis was conducted after 40.3 months of median study follow-up, when 96 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. patients were treated for a median duration of 36 months in both arms, with an additional 6.3 months of study follow-up from the primary analysis. Additionally, long-term safety has already been established for the ribociclib 600 mg starting dose in the aBC setting for a pool of 1065 patients from Studies LEE011A2301, LEE011E2301 (excluding patients treated with tamoxifen), and LEE011F2301 based on a total exposure of 2262 patient-years. These pooled safety data provide further context for the safety of ribociclib at 400 mg in patients with eBC. Novartis considers the body of evidence based on Study O12301C as substantial to assess the ribociclib safety profile in patients with HR-positive, HER2-negative, eBC in the context of the known and established safety profile at 600 mg in the aBC setting (pooled aBC dataset = 1,065 patients exposed to ribociclib with an estimated exposure of 2081 patient-years [Study A2301 SCS Add.-Table 1-8]). The known important identified risks with ribociclib remain as: Myelosuppression, Hepatobiliary toxicity, QT interval prolongation, and Reproductive toxicity. One important potential risk with ribociclib is Renal toxicity. These are discussed in detail in [CO Study O12301C-Section 5.3] [SCS Add. Study O12301C-Section 2.6] and [SCS Study O12301C-Section 2.6]. The FDA’s Assessment: The size of the safety population from the NATALEE trial (N=4967) is appropriate for a trial conducted in the adjuvant setting. The safety data from the NATALEE trial, especially within the context of a well-characterized AE profile from multiple prior studies of ribociclib + ET in the metastatic setting and 7.5 years of postmarketing experience, is adequate for benefit-risk assessment of ribociclib in a curative intent population. FDA generally agrees with the Applicant’s assessment of the most important adverse events of special interest (AESI) as discussed later in the review with one addition. The risk of both SARS-CoV-2 infection and deaths attributed to COVID-19/COVID-19 pneumonia was increased in patients who received ribociclib + ET. This is discussed in further detail in Section 8.2.4. 8.2.2 Review of the Safety Database Overall Exposure Data: Table 21: Duration of exposure to study treatment by group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Adherence Ribociclib + ET N=2525 n (%) ET only N=2442 n (%) Duration of exposure 0 to < 3 months 122 (4.8) 167 (6.8) 3 to < 6 months 84 (3.3) 79 (3.2) 6 to < 9 months 58 (2.3) 50 (2.0) 9 to < 12 months 48 (1.9) 54 (2.2) 12 to < 15 months 40 (1.6) 45 (1.8) 97 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Adherence Ribociclib + ET N=2525 n (%) ET only N=2442 n (%) 15 to < 18 months 33 (1.3) 44 (1.8) 18 to < 21 months 45 (1.8) 56 (2.3) 21 to < 24 months 33 (1.3) 35 (1.4) 24 to < 27 months 25 (1.0) 28 (1.1) 27 to < 30 months 285 (11.3) 259 (10.6) 30 to < 33 months 124 (4.9) 126 (5.2) 33 to < 36 months 341 (13.5) 290 (11.9) ≥ 36 months 1287 (51.0) 1209 (49.5) Duration of exposure (mo) Mean 32.8 31.9 SD 12.83 13.66 Minimum 0 0 Median 36.2 35.9 Maximum 54 54 Patient years 6904.3 6487.3 Source: [SCS Add. Study O12301C Table 1-2] The Applicant’s Position: The duration and extent of study treatment exposure was considered adequate to assess the ribociclib safety profile in this patient population with HR-positive, HER2-negative, eBC. At the final iDFS analysis, the median duration of exposure was 36.2 months (range: 0 to 54) for ribociclib + ET treatment vs. 35.9 months (0 to 54) for ET only treatment. A total of 1228 patients (48.6%) had 33 months or longer of ribociclib exposure. A total of 1628 patients (64.5%) had 33 months or longer of study treatment exposure in the ribociclib + ET group, which includes the last dosing visit of the 3-year ribociclib regimen. The total exposure to study treatment was 6904.3 patient-years for the ribociclib + ET treatment group (N=2525) and 6487.3 patient-years for the ET only treatment group (N=2442). Importantly, the difference since IA3 was +1018.4 patient-years in the ribociclib + ET group. By each drug component, ribociclib exposure was 5352.1 patient-years (N=2525); NSAI exposure was 6879.1 patient-years in the ribociclib + ET group vs. 6467.5 patient-years in the ET only group (N=4967). The median relative dose intensity (RDI) for ribociclib was 94.0% (range: 14 to 132), and the median RDI for NSAI in both the ribociclib + ET and ET only groups was 100%, indicating the addition of ribociclib continued to not affect the tolerability of NSAI/ET. Generally, ribociclib dose reduction/interruption occurred early during study treatment administration. Dose adjustments (interruptions and reductions) of ribociclib were allowed for safety concerns per guidelines presented in the study protocol. Dose reductions of ribociclib occurred in 26.7% of patients and were primary attributable to AEs (22.8%). Dose interruptions of ribociclib occurred in 86.1% of patients and were also primarily attributable to AEs (66.2%). Dose interruptions for NSAI/AI occurred in 44.5% of patients in the ribociclib + ET arm, and in 98 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 35.7% of patients in the ET only arm. Overall, the primary reasons for dose adjustments were AEs. Discontinuation of ribociclib (reported for 78.3% of patients) was primarily due to completion of ribociclib treatment (42.8%), followed by AE (19.5%). Generally, ribociclib discontinuation due to AEs also occurred early during study treatment administration [SCS Add. Study O12301C- Section 1.2.1]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. As of the July 21, 2023 data cut-off, 82% of participants had completed >24 months of ribociclib + ET and approximately half had completed a full 36 months of treatment. The dose of ribociclib used in the NATALEE trial (400 mg daily) is lower than the dose in the metastatic setting (600 mg daily), and ribociclib was better tolerated in the adjuvant setting than in prior metastatic trials. In spite of a lower starting dose, dose modification of ribociclib, however, remained common. In total, 86% had treatment interruption, mostly for adverse reactions, more than one-quarter of participants required ribociclib dose reduction, and one in five patients discontinued due to an AE. On trial, discontinuations due to AE occurred in the first few months of treatment, and many of these were based upon laboratory abnormalities. Outside of a clinical trial, these early adverse reactions and need for one or more treatment interruptions may result in decreased patient adherence to ribociclib given that the treatment is self-administered to patients with no evidence of disease. The adverse reactions of ribociclib and ET are largely non-overlapping, and thus despite the increased toxicity resulting from addition of CDK 4/6 inhibitor to endocrine therapy, interruptions of endocrine therapy were only 9% more common in the ribociclib + ET arm, indicating that addition of ribociclib did not significantly compromise ability to deliver the known effective adjuvant endocrine therapy. AI-induced musculoskeletal symptoms (AIIMS) are among the most common tolerability issues that result in interruption or discontinuation of AIs in clinical practice. Based on FDA’s analysis of musculoskeletal pain as a grouped term, these AEs occurred in 56% (1.5% grade 3) of those on ribociclib + ET versus 58% (1.8% grade 3) on ET only, and therefore were not increased with the addition of ribociclib to AI. Relevant characteristics of the safety population: Data: Table 22: Overview of clinical studies with safety data Key feature Study O12301C Controlled study Yes Phase III Study design // endpoints Open-label, multicenter, randomized, active-controlled vs. standard-of-care // Efficacy, PK, safety, tolerability, exploratory. Population Salient demographic data 99 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Key feature Study O12301C North America/Western Europe/Oceania1 region=3032 patients Premenopausal women and men=2193 patients (based on eCRF stratum) Yes, had prior chemotherapy=4309 patients (based on eCRF stratum) Age: median=52.0 y (range: 24 to 90); ECOG PS score 0=83.1% Salient diagnostic data AJCC Stage II (40.3%) or Stage III (59.5%) Predominant histology: invasive ductal carcinoma NOS=73.0%. Prior mastectomy=65.7%. At diagnosis: G1=9.0%, G2=57.3%, G3=20.7%; N0=28.1%, N1=41.0%, N2=12.3%, N3=6.2%; Ki67 at diagnosis: median score=20.0; categories: ≤ 14%=20.0%, > 20%=36.8%. Surgical specimen: G1=8.4%, G2=56.8%, G3=27.0%; N0=15.7%, N1=41.3%, N2=27.8%, N3=15.0%; Ki67 of surgical specimen: median score=15.0; categories: ≤ 14%=22.0%, > 20%=18.1%. Treatment duration (fixed-term as adjuvant treatment) Ribociclib (36 mo) plus ET (at least 60 mo) ET only: at least 60 mo No. of patients (N) treated No. (n) by treatment combination 4968 Ribociclib (400 mg) plus ET: 2524 (female=2514; male=10, 0.4%) ET only: 2444 (female=2435; male=9, 0.4%) Relevant entry criteria (key only) Age, sex Disease/stage ≥ 18 years: females with known menopausal status; males HR-positive, HER2-negative, Stage II or Stage III eBC, irrespective of nodal status Inclusion criteria May have received any standard neoadjuvant and/or adjuvant ET upon ICF signing: randomization should have occurred within 12 mo of initial start date of ET. Of note: ovarian suppression or short-term ET (fertility preservation) was not considered neoadjuvant/adjuvant ET. If tamoxifen or toremifene received: washout as 5 half-lives (35 d) prior to randomization. By centralized 12-lead ECG: Screening QTcF < 450 ms; resting heart rate ≥ 50 to ≤ 90 bpm. Exclusion criteria Clinically significant, uncontrolled HD, and/or cardiac repolarization abnormality, included: history of documented MI, angina pectoris, symptomatic pericarditis, coronary artery bypass graft within 6 mo of study entry; documented cardiomyopathy; LVEF < 50% (by optional MUGA or ECHO); long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome; clinically significant cardiac arrhythmia, complete left bundle branch block, high-grade AV block; or uncontrolled arterial HTN with systolic BP > 160 mm Hg. Status // milestone Ongoing // First-patient-first-visit (FPFV): 07-Dec-2018; DCO: 11-Jan-2023 At enrollment, population was controlled to ~40% Stage II. 1Only patients from Australia were enrolled within the Oceania geographical region. Source: [SCS Study O12301C Table 1-2] The FDA’s Assessment: Only 16% of the NATALEE study population was enrolled from the United States. Therefore, it is important to assess whether the results of the trial can be generalized to a U.S. population. The median age of 52 with a range of 24 to 90 is representative of the demographics of HR+, HER2-negative breast cancer in the U.S. The patient population includes robust representation of patients with stage II (~40%) and stage III (~60%) disease, as well as a range of menopausal status; however, as noted earlier in the review, the NATALEE population was much higher risk than the broader US population with HR+, HER2-negative early breast cancer as 87% of participants had received (neo)adjuvant chemotherapy and only 12% had N0 disease. There were only 19 male patients enrolled in NATALEE, which is a limitation for the assessment of efficacy and safety/tolerability by sex, but their inclusion is important given 100 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. the rarity of the condition and the presently inadequate access to investigational agents and limited evidence base for male breast cancer. Despite typically having a higher stage at presentation and a greater risk of recurrence or death after early breast cancer in the U.S. population, Black or African-American patients are significantly under-represented in NATALEE. Only 1.7% of participants (n=86, of whom 41 were randomized to receive ribociclib + ET) were Black or African-American. As a result, the NATALEE trial contains only 118 patient-years of experience with ribociclib + ET in Black patients with early breast cancer compared to 5116 patient-years of experience with the combination in white patients. Sixty percent of participants had tumors that were stage III, 88% were N1-N3, 87% had received (neo)adjuvant chemotherapy, and very few were grade 1, which reflects a substantially higher risk population than most patients in the U.S. with HR+, HER2- negative early breast cancers. The benefit-risk assessment of adjuvant ribociclib based on the NATALEE trial should therefore not be extrapolated to a more typical lower-risk US population of patients with early-stage HR+, HER2-negative breast cancer. As noted in Table 22 above, patients with a variety of cardiac conditions were excluded from NATALEE. These conditions are not rare in the U.S., especially in the older adults who represent the majority of patients with HR+, HER2-negative breast cancer. Clinicians should counsel patients with pre-existing cardiac conditions regarding the limitations of the NATALEE safety data and consider whether treatment with ribociclib is appropriate and whether more routine monitoring of ECGs beyond 4 weeks is warranted. In addition, the majority of patients in NATALEE (83%) were ECOG performance status 0, and 17% were ECOG 1. Patients with ECOG ≥2 were excluded from the trial. The safety of ribociclib in the adjuvant setting for patients with poorer performance status or other comorbid conditions may differ. Adequacy of the safety database: The Applicant’s Position: Novartis considers the body of evidence based on Study O12301C as substantial to assess the ribociclib safety profile in patients with HR-positive, HER2-negative, eBC in the context of the known and established safety profile at 600 mg in the aBC setting (pooled aBC dataset = 1065 patients exposed to ribociclib with an estimated exposure of 2081 patient-years) [Study A2301 SCS Add.-Table 1-8]. The key safety data in support of this application are from the primary and final analysis of Study O12301C. In this large study (N=5101, FAS; N=4968; Safety set), ribociclib 400 mg in combination with standard adjuvant ET (AI; anastrozole or letrozole) is compared with standard of care adjuvant ET alone. The population enrolled in this study reflects the target population of adult patients (including pre- and postmenopausal women plus men) with HR-positive, HER2- negative, Stage II or Stage III eBC who are at risk of recurrence. Based on the Safety set, this study population consists of patients with anatomic Stage II (40.3%) or Stage III (59.4%) disease as per AJCC staging (eighth ed.) who had completed surgery, followed by chemotherapy, and/or radiotherapy with curative intent [CO Study O12301-Sections 5.1.1 and 5.1.2]. 101 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. As of the 21-Jul-2023 cut-off date, 1091 patients (42.8%) in the ribociclib + ET group have completed the 3-year ribociclib treatment duration per protocol, with 69.4% having completed at least 2 years of ribociclib treatment, based on all patients randomized to the ribociclib + ET group (FAS). The safety follow-up in Study O12301C in terms of patient-years of exposure was 6904.3 patient-years for the ribociclib + ET group vs. 6487.3 patient-years for the ET only group, or an additional 1018.4 patient-years since IA3 [SCS Add. Study O12301C-Section 1.2.1]. These data show that the level of safety follow-up completed in the study thus far is adequate to detect any signals that are related to the safety profile of ribociclib, including those that are not dose-dependent and/or rare events, and is unlikely to change substantially with longer follow-up [CO Study O12301-Section 6.3.1.1]. The FDA’s Assessment: FDA agrees that the NATALEE trial is adequate to characterize the benefits and risks of ribociclib to endocrine therapy in adults with high-risk stage II and III HR+, HER2- negative breast cancer, but notes that the majority of stage II disease was based upon tumor size as only 12% of participants had N0 disease. The size of the safety population is typical for an adjuvant breast cancer trial; however, the sample size may not be adequate to detect rare adverse events in the adjuvant setting. The majority of known adverse reactions related to ribociclib occurred on active treatment and resolved with treatment discontinuation, and therefore the duration of follow-up, which includes the full treatment period in the majority of patients as of the 90-day safety update, is acceptable to characterize adverse reactions with the following caveat. Given that patients with HR+, HER2-negative early breast cancer are being treated with curative intent, with a life expectancy measured in years to decades, the limited period of follow-up is not informative about the risk of late post-treatment adverse events, including secondary malignancy. 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments Issues Regarding Data Integrity and Submission Quality The Applicant’s Position: No meaningful concerns are anticipated in the quality and integrity of the submitted datasets and individual case narratives; these were sufficiently complete to allow for a thorough review of safety. Furthermore, no data integrity concerns were reported following completion of site inspections; data in the CRFs and adverse event databases were consistent. The FDA’s Assessment: FDA agrees with the Applicant’s assessment. An audit of randomly selected case report forms by the clinical safety reviewer did not identify any data integrity concerns. FDA inspected three U.S. and two foreign clinical trial sites for NATALEE. Per the inspectors, the NATALEE trial appears to have been conducted adequately, and the data generated by the clinical investigator sites appear acceptable in support of this sNDA. The overall assessment was that no action was indicated. Results of the inspections are discussed in further detail above in Section 4.1. Full details are available in the FDA OSI review. 102 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Categorization of Adverse Event The Applicant’s Position: The safety evaluations were conducted on the overall Safety set (N=4968) for Study O12301C. The safety of ribociclib in combination with ET (plus goserelin in premenopausal women plus men), was evaluated on the basis of the following: • Frequency, type, severity, and causal relationship of AEs to study treatment: AEs were graded according to the CTCAE v4.03 for all studies used in this safety assessment. • Frequency of deaths, serious adverse events (SAEs), and other clinically significant AEs (including AEs leading to discontinuation and AEs requiring dose interruption and/or reduction) • Frequency and type of AEs in key demographic subgroups (including sex, race, menopausal status at baseline, age group (< 65 years vs. ≥ 65 years) at baseline) and by Baseline disease characteristics • Changes in laboratory variables, with particular attention to grade 3/4 laboratory abnormalities • Electrocardiogram (ECG) changes Based on its clinical relevance, the on-treatment period was redefined taking the 36-month treatment period for ribociclib into account, to include a maximum of 36 months plus 30 days in either study group. Adverse events were coded using MedDRA version 25.1 [Study O12301C Primary Analysis CSR], [SCS Study O12301C] and MedDRA version 26.0 [Study O12301C EA&SU], [SCS Add. Study O12301C]. The FDA’s Assessment: FDA agrees with Applicant’s description of AE categorization and the clinical relevance of the approach to analysis of ribociclib safety in the adjuvant setting. The definition of the on-treatment death period of 36 months of investigational product (IP) administration plus 30 days after last dose of treatment is appropriate given the study drug half-life of <2 days. Routine Clinical Tests The Applicant’s Position: Safety assessments included the regular monitoring of hematology, blood biochemistry, and coagulation (at Screening) performed at local laboratories. Laboratory data summaries included all assessments available from samples collected no later than 30 days after the last study treatment administration date. Laboratory values converted to the International System of Units (SI) were analyzed using the CTCAE grading, and notable abnormal values were summarized for both hematology and blood biochemistry. The calculation of CTCAE grades was based on observed laboratory values only: clinical assessments were not considered. The severity grade of 0 was assigned for all non- missing values if a value was within normal laboratory limits for that parameter; grade 5 was not used. For laboratory tests where grades were not defined by CTCAE, results were categorized as 103 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. a low/normal/high classification(s) based on the normal laboratory range. The grading and criteria to define all laboratory toxicity grades were assigned programmatically by the coding dictionary. Safety assessments included the monitoring of vital signs, including height (Screening only) and weight, body temperature, heart rate, and BP at the site during the in-person visit(s); and 12-lead ECG performed at the local and/or central laboratories. ECG data were read both locally and centrally. The analyses were based on central ECG assessments as all local data were read centrally. Heart rate, QT interval, and QTcF were assessed [SCS Study O12301-Section 1.1.3.6 and 1.1.3.7]. The FDA’s Assessment: FDA agrees with Applicant’s description and approach to analysis of routine clinical tests. 8.2.4 Results Deaths Data: Table 23: On-treatment deaths in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Category Preferred term Ribociclib + ET N=2525 n (%) ET Only N=2442 n (%) No. pts who died on treatment 20 (0.8) 9 (0.4) Primary reason: disease recurrence/progression 9 (0.4) 4 (0.2) Primary reason: adverse event 11 (0.4) 4 (0.2) Primary reason: other 0 1 (< 0.1) Death 0 1 (< 0.1) SAEs with fatal outcome 11 (0.4) 4 (0.2) Brain oedema 1 (< 0.1) 0 COVID-19 3 (0.1) 1 (< 0.1) COVID-19 pneumonia 3 (0.1) 0 Cardiac arrest 1 (< 0.1) 0 Cardiac failure congestive 0 1 (< 0.1) Cardiopulmonary failure 1 (< 0.1) 0 Epilepsy 1 (< 0.1) 0 Ischaemic cardiomyopathy 0 1 (< 0.1) Myocardial infarction 0 1 (< 0.1) Pulmonary embolism 2 (0.1) 0 Respiratory failure 0 1 (< 0.1) Road traffic accident 1 (< 0.1) 0 Sepsis 0 1 (< 0.1) Treatment-related SAEs with fatal outcome 1 (< 0.1) 0 On-treatment deaths are defined as occurring on or after treatment start date and up to 30 days after 36 months of treatment or earlier treatment discontinuation. MedDRA Version 26.0 has been used for reporting. 111 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 357 (14.1) 252 (10.0) 44 (1.7) 11 (0.4) 256 (10.5) 192 (7.9) 26 (1.1) 4 (0.2) COVID-19 20 (0.8) 13 (0.5) 0 3 (0.1) 13 (0.5) 9 (0.4) 0 1 (< 0.1) Pneumonia 14 (0.6) 12 (0.5) 0 0 9 (0.4) 7 (0.3) 0 0 Pulmonary embolism 15 (0.6) 11 (0.4) 1 (< 0.1) 2 (0.1) 5 (0.2) 5 (0.2) 0 0 Dyspnoea 12 (0.5) 9 (0.4) 0 0 5 (0.2) 3 (0.1) 0 0 Alanine aminotransferase increased 9 (0.4) 1 (< 0.1) 7 (0.3) 0 0 0 0 0 Breast cellulitis 9 (0.4) 9 (0.4) 0 0 3 (0.1) 3 (0.1) 0 0 COVID-19 pneumonia 9 (0.4) 5 (0.2) 0 3 (0.1) 5 (0.2) 4 (0.2) 1 (< 0.1) 0 Humerus fracture 8 (0.3) 7 (0.3) 0 0 4 (0.2) 3 (0.1) 0 0 Cellulitis 7 (0.3) 7 (0.3) 0 0 6 (0.2) 6 (0.2) 0 0 Cholelithiasis 7 (0.3) 6 (0.2) 1 (< 0.1) 0 5 (0.2) 5 (0.2) 0 0 Pyrexia 7 (0.3) 2 (0.1) 0 0 1 (< 0.1) 1 (< 0.1) 0 0 Atrial fibrillation 7 (0.3) 5 (0.2) 1 (< 0.1) 0 8 (0.3) 7 (0.3) 0 0 Drug-induced liver injury 6 (0.2) 2 (0.1) 3 (0.1) 0 0 0 0 0 Urinary tract infection 6 (0.2) 6 (0.2) 0 0 3 (0.1) 3 (0.1) 0 0 Aspartate aminotransferase increased 5 (0.2) 2 (0.1) 3 (0.1) 0 0 0 0 0 Diarrhoea 5 (0.2) 3 (0.1) 0 0 0 0 0 0 Hepatotoxicity 5 (0.2) 3 (0.1) 2 (0.1) 0 0 0 0 0 Papillary thyroid cancer 5 (0.2) 5 (0.2) 0 0 2 (0.1) 2 (0.1) 0 0 Postoperative wound infection 5 (0.2) 5 (0.2) 0 0 2 (0.1) 2 (0.1) 0 0 Appendicitis 4 (0.2) 3 (0.1) 1 (< 0.1) 0 2 (0.1) 2 (0. 1) 0 0 Cerebrovascular accident 5 (0.2) 2 (0.1) 0 0 1 (< 0.1) 0 1 (< 0.1) 0 Acute myocardial infarction 4 (0.2) 1 (< 0.1) 3 (0.1) 0 0 0 0 0 Mastitis 4 (0.2) 2 (0.1) 0 0 2 (0.1) 2 (0.1) 0 0 Osteoarthritis 4 (0.2) 4 (0.2) 0 0 4 (0.2) 4 (0.2) 0 0 Pneumonia viral 4 (0.2) 0 0 0 3 (0.1) 1 (< 0.1) 0 0 Suspected COVID-19 4 (0.2) 0 0 0 1 (< 0.1) 0 0 0 Syncope 4 (0.2) 4 (0.2) 0 0 2 (0.1) 2 (0.1) 0 0 112 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Erysipelas 4 (0.2) 2 (0.1) 0 0 3 (0.1) 2 (0.1) 0 0 Source: [SCS Add. Study O12301C-Table 2-8] The Applicant’s Position: Incidence of SAEs was 14.1% in the ribociclib + ET group vs. 10.5% in the ET only group. The most frequently reported SAEs by PT (in at least 10 patients) in the ribociclib + ET group were COVID-19 (0.8%), pneumonia (0.6%), pulmonary embolism (0.6%), and dyspnea (0.5%). COVID-19 (0.5%) was the only SAEs reported in 10 or more patients in the ET only group. Considering the low rates of individual PTs, no pattern in the reported SAEs was identified in either treatment group [CO Study O12301-Section 5.2.2]. The FDA’s Assessment: Detailed narratives and case report forms for NATALEE participants with grade ≥3 SAEs on the ribociclib plus endocrine therapy arm have been reviewed, and the incidence of SAEs has been verified by FDA. FDA generally agrees with the Applicant’s assessment of SAEs. SAEs occurred in 14% of patients on ribociclib + ET compared to 10% on ET only. Most SAEs were grade 3. Grade ≥4 SAEs occurred in 2.1% of participants randomized to receive ribociclib versus 1.3% of the control group. As reflected in the USPI and discussed in further detail in Section 8.2.5.3 under hepatobiliary AESIs, hepatic SAEs (increased AST or ALT, hepatotoxicity, or drug- induced liver injury) were among the most common SAEs and occurred exclusively in patients who received ribociclib. These were also the most common grade 4 SAEs. Given the very high incidence of neutropenia with ribociclib and the prolonged exposure to ribociclib in the adjuvant setting, infections were expected to be among the most common SAEs in NATALEE. As discussed in Section 8.2.5.1 on the neutropenia AESI, the risk of serious infections was low in both arms, but there was a consistent slight increase in infectious SAEs with the addition of ribociclib to endocrine therapy compared to endocrine therapy alone. The majority of these were respiratory or cutaneous. COVID-19 and COVID-19 pneumonia, including fatal cases, were more common in patients on the ribociclib + ET arm. COVID-19 has been discussed in further detail above in Section 8.2.4 on on-treatment deaths. In addition to these confirmed cases of COVID-19 and COVID-19 pneumonia, there were additional SAEs that suggested a small increase in risk of SAEs due to potentially undiagnosed COVID-19 or other respiratory infections, including pneumonia (0.6% vs 0.4%), viral pneumonia (0.2% vs 0.1%), and suspected COVID-19 (0.2% vs <0.1%). The incidence of oral herpes was also noted to be increased (1.5% vs 0.5%). As described above, grade 3/4 lymphopenia was more common in patients receiving ribociclib in combination with ET (19.1% vs 6.3%) and may have contributed to an increased risk of viral infection. 113 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Most of the remaining infectious SAEs were local/cutaneous infections. While rare overall, these local/cutaneous infections including breast cellulitis (0.4% vs 0.1%), mastitis (0.2% vs 0.1%), postoperative wound infection (0.2% versus 0.1%), and erysipelas (0.2% vs 0.1%) were similarly slightly more common in patients who received ribociclib. An FDA analysis of thrombosis overall as a grouped term found an approximate doubling of the incidence of all-grade AEs with ribociclib + ET (1.7%) compared to ET alone (0.9%). Most of these AEs were grade 1-2 in severity, but the incidence of the rare, more severe, AEs related to thrombosis was similarly doubled: 15 patients (0.6%) had a grade ≥ 3 thrombosis AE on the ribociclib + ET arm compared with 8 (0.3%) on ET alone. This includes one patient with grade 4 AE and 2 patients with fatal thrombosis-related AEs on the ribociclib + ET arm compared with none on the ET only arm. Thromboembolic SAEs including pulmonary emboli (0.6% vs 0.2%), myocardial infarction (0.2% vs 0.1%), and cerebrovascular accidents (0.2% vs 0%) were also reported slightly more commonly in the ribociclib + ET only group. Narratives for the two patients with grade 5 AEs, both pulmonary emboli, on the ribociclib + ET arm are discussed in further detail above in Section 8.2.4. These hepatic and thromboembolic SAEs may be observed more commonly in the postmarketing setting as patients who would have been excluded from NATALEE due to comorbid conditions are treated with ribociclib for early breast cancer. Adverse events in these system organ classes will continue to be monitored in the postmarket setting and the ribociclib USPI updated for safety as appropriate. Dropouts and/or Discontinuations Due to Adverse Effects Data: Table 26: Adverse events leading to discontinuation by preferred term and worst toxicity grade, irrespective of causality, with at least 0.2% / either group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 524 (20.8) 201 (8.0) 36 (1.4) 2 (0.1) 134 (5.5) 38 (1.6) 5 (0.2) 3 (0.1) Alanine aminotransferase increased 180 (7.1) 84 (3.3) 19 (0.8) 0 2 (0.1) 1 (< 0.1) 0 0 Aspartate aminotransferase increased 71 (2.8) 28 (1.1) 7 (0.3) 0 0 0 0 0 Arthralgia 37 (1.5) 4 (0.2) 0 0 49 (2.0) 9 (0.4) 0 0 Fatigue 18 (0.7) 3 (0.1) 0 0 1 (< 0.1) 0 0 0 Neutropenia 19 (0.8) 15 (0.6) 2 (0.1) 0 0 0 0 0 114 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Neutrophil count decreased 7 (0.3) 7 (0.3) 0 0 0 0 0 0 Nausea 13 (0.5) 1 (< 0.1) 0 0 1 (< 0.1) 0 0 0 Hepatotoxicity 7 (0.3) 4 (0.2) 2 (0.1) 0 0 0 0 0 Rash 7 (0.3) 2 (0.1) 0 0 2 (0.1) 0 0 0 Asthenia 11 (0.4) 5 (0.2) 0 0 0 0 0 0 Blood magnesium decreased 7 (0.3) 0 0 0 0 0 0 0 Headache 7 (0.3) 1 (< 0.1) 0 0 3 (0.1) 0 0 0 Blood creatinine increased 8 (0.3) 1 (< 0.1) 0 0 0 0 0 0 COVID-19 8 (0.3) 2 (0.1) 2 (0.1) 1 (< 0.1) 1 (< 0.1) 0 1 (< 0.1) 0 Diarrhoea 7 (0.3) 2 (0.1) 0 0 2 (0.1) 0 0 0 Electrocardiogram QT prolonged 7 (0.3) 2 (0.1) 0 0 0 0 0 0 Hypomagnesaemia 6 (0.2) 0 0 0 0 0 0 0 Alopecia 5 (0.2) 0 0 0 0 0 0 0 Pneumonitis 5 (0.2) 0 0 0 0 0 0 0 Pulmonary embolism 4 (0.2) 3 (0.1) 1 (< 0.1) 0 1 (< 0.1) 1 (< 0.1) 0 0 Anxiety 4 (0.2) 1 (< 0.1) 0 0 1 (< 0.1) 0 0 0 Hyperkalaemia 4 (0.2) 1 (< 0.1) 0 0 0 0 0 0 Hypertransaminasaemia 4 (0.2) 1 (< 0.1) 0 0 0 0 0 0 Papillary thyroid cancer 4 (0.2) 4 (0.2) 0 0 0 0 0 0 Gamma-glutamyltransferase increased 3 (0.1) 2 (0.1) 0 0 0 0 0 0 Hypercalcaemia 5 (0.2) 0 0 0 0 0 0 0 Myalgia 2 (0.1) 1 (< 0.1) 0 0 5 (0.2) 2 (0.1) 0 0 Source: [SCS Add. Study O12301C-Table 2-9] The Applicant’s Position: Overall, AEs leading to discontinuation of study treatment were observed at a higher frequency (relative difference between treatment groups) in the ribociclib + ET group (20.8%) vs. the ET only group (5.5%) [SCS Add. Study O12301C-Table 2-9]. The discontinuation rate was relatively low for each individual event, indicating these events were manageable. The median 115 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. relative dose intensity (RDI) for ribociclib was 94.0% (range: 14 to 132), and the median RDI for NSAI in both the ribociclib + ET and ET only groups was 100%, indicating the addition of ribociclib continued to not affect the tolerability of NSAI/ET. The most frequently reported AEs (in ≥ 10 patients) leading to study treatment drug discontinuation in the ribociclib group plus ET group were increased ALT (7.1%), increased AST (2.8%), arthralgia (1.5%), neutropenia (0.8%), fatigue (0.7%), and nausea (0.5%,). The most frequent AE leading to study treatment discontinuation in the ET only group was arthralgia (2.0%). Overall, the proportion of grade-3 and grade-4 AEs leading to discontinuation continued to be higher with ribociclib + ET (8.0% and 1.4%, respectively) vs. ET only (1.6% and 0.2%, respectively). When required, most ribociclib discontinuations occurred early during study treatment, with a median of approximately 4 months [CO Study O12301-Section 5.2.2]. The FDA’s Assessment: FDA has analyzed AEs leading to discontinuation of study drug and generally agrees with the Applicant’s assessment. As discussed earlier, the toxicities of ribociclib and ET are largely non-overlapping, and co-administration of ribociclib with ET had a limited effect on the delivery of standard adjuvant ET. Adverse events leading to treatment discontinuation were increased almost fourfold with the addition of ribociclib to ET (20.8% vs 5.5%). The most common AEs that led to discontinuation in the ribociclib group were increased transaminases, which most commonly occur in the first two to three months of treatment and are a known AESI with ribociclib for which there is an existing warning in the USPI. Hepatotoxicity as an AESI associated with ribociclib is discussed in further detail in Section 8.2.5.3. While neutropenia is also common and tended to occur early in treatment, it was well- managed with treatment interruption or dose reduction, as discussed below, and required ribociclib discontinuation in <1% of patients. As noted in the section above on SAEs, serious infections were uncommon and predominantly respiratory or cutaneous. Neutropenia as an AESI is discussed in further detail in Section 8.2.5.1. The only on-study deaths due to infections in the ribociclib + ET arm were COVID-19 or COVID-19 pneumonia and not associated with treatment-emergent neutropenia. These deaths are reviewed in further detail above in Section 8.2.4. Dose Interruption/Reduction Due to Adverse Effects Data: Table 27: Adverse events leading to study drug interruption by preferred term and worst toxicity grade, irrespective of causality, with incidence at least 2% / either group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred Term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 1858 (73.6) 1226 (48.6) 87 (3.4) 0 199 (8.1) 67 (2.7) 8 (0.3) 0 116 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred Term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Neutropenia 683 (27.0) 637 (25.2) 30 (1.2) 0 1 (< 0.1) 0 1 (< 0.1) 0 Neutrophil count decreased 441 (17.5) 411 (16.3) 17 (0.7) 0 2 (0.1) 1 (< 0.1) 1 (< 0.1) 0 Alanine aminotransferase increased 255 (10.1) 116 (4.6) 16 (0.6) 0 7 (0.3) 2 (0.1) 1 (< 0.1) 0 COVID-19 228 (9.0) 8 (0.3) 2 (0.1) 0 20 (0.8) 3 (0.1) 0 0 Aspartate aminotransferase increased 171 (6.8) 56 (2.2) 8 (0.3) 0 7 (0.3) 4 (0.2) 0 0 Hypomagnesaemia 127 (5.0) 0 1 (< 0.1) 0 0 0 0 0 SARS-CoV-2 test positive 115 (4.6) 0 0 0 8 (0.3) 0 0 0 Leukopenia 81 (3.2) 45 (1.8) 0 0 0 0 0 0 Hyperkalaemia 81 (3.2) 3 (0.1) 0 0 0 0 0 0 Hypocalcaemia 81 (3.2) 1 (< 0.1) 0 0 0 0 0 0 Hypokalaemia 70 (2.8) 4 (0.2) 0 0 0 0 0 0 White blood cell count decreased 70 (2.8) 43 (1.7) 1 (< 0.1) 0 0 0 0 0 Blood magnesium decreased 63 (2.5) 1 (< 0.1) 0 0 0 0 0 0 Pyrexia 73 (2.9) 3 (0.1) 0 0 8 (0.3) 0 0 0 Arthralgia 42 (1.7) 6 (0.2) 0 0 54 (2.2) 15 (0.6) 0 0 Source: [SCS Add. Study O12301C-Table 2-10] Table 28: Adverse events leading to study drug dose reduction by preferred term and worst toxicity grade, irrespective of causality with incidence at least 0.2% / either group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) No. pts with at least 1 AE 586 (23.2) 338 (13.4) 36 (1.4) 0 0 0 0 0 Neutropenia 215 (8.5) 157 (6.2) 23 (0.9) 0 0 0 0 0 117 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET N=2525 ET Only N=2442 Preferred term All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Neutrophil count decreased 141 (5.6) 114 (4.5) 13 (0.5) 0 0 0 0 0 Alanine aminotransferase increased 49 (1.9) 21 (0.8) 0 0 0 0 0 0 Fatigue 26 (1.0) 4 (0.2) 0 0 0 0 0 0 White blood cell count decreased 26 (1.0) 6 (0.2) 0 0 0 0 0 0 Leukopenia 17 (0.7) 7 (0.3) 0 0 0 0 0 0 Aspartate aminotransferase increased 16 (0.6) 3 (0.1) 0 0 0 0 0 0 Nausea 11 (0.4) 2 (0.1) 0 0 0 0 0 0 Asthenia 10 (0.4) 2 (0.1) 0 0 0 0 0 0 Alopecia 6 (0.2) 0 0 0 0 0 0 0 Rash 6 (0.2) 1 (< 0.1) 0 0 0 0 0 0 Gamma-glutamyltransferase increased 5 (0.2) 2 (0.1) 0 0 0 0 0 0 Stomatitis 4 (0.2) 0 0 0 0 0 0 0 Diarrhoea 4 (0.2) 2 (0.1) 0 0 0 0 0 0 Headache 4 (0.2) 3 (0.1) 0 0 0 0 0 0 Arthralgia 4 (0.2) 0 0 0 0 0 0 0 Source: [SCS Add. Study O12301C Table 2-11] The Applicant’s Position: AEs leading to study treatment interruption were observed more frequently in the ribociclib + ET group compared to the ET only group (73.6% vs 8.1%, respectively). Despite the higher frequency of AEs leading to dose interruptions in the ribociclib + ET group, the discontinuation rate was relatively low for each individual event, indicating these events were manageable. In addition, the median RDI of ribociclib was 94.0%, and importantly there was no impact on the ET dose maintenance, which is supported by RDI of 100% for ET in both treatment arms. The most frequent AEs (overall: ≥ 10%) leading to interruption with ribociclib + ET were neutropenia (all grades: 27.0% vs. < 0.1%), followed by neutrophil count decreased (17.5% vs. 0.1%) and increased ALT (10.1% vs. 0.3%) [SCS Add. Study O12301C-Table 2-10]. All remaining AEs leading to study drug interruption were < 10%. The most frequent grade 3/4 AEs leading to study drug interruption in the ribociclib + ET group were also neutropenia and neutrophil count decreased [SCS Add. Study O12301C-Table 2-1 0]. The most frequently reported AEs (with incidences ≥ 2%) that required dose reduction in the ribociclib + ET group were neutropenia (8.5%) and neutrophil count decreased (5.6%). The most frequently reported grade 3 and grade 4 AEs that required ribociclib dose reduction were 118 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. neutropenia (grade 3: 6.2%; grade 4: 0.9%) and neutrophil count decreased (grade 3: 4.5%; grade 4: 0.5%) [SCS Add. Study O12301C-Table 2-11]. Neutropenia AEs (PT) leading to dose interruption were frequent in the ribociclib + ET group (27.0%), but the corresponding frequency of neutropenia AEs (PT) leading to discontinuation was only 0.8%. Importantly, the majority of AEs were effectively resolved with ribociclib dose interruptions and/or reductions [CO Study O12301C-Section 5.2.2]. The FDA’s Assessment: FDA has analyzed AEs leading to study drug interruption and dose reductions and generally agrees with the Applicant’s assessment. Approximately three-quarters of patients on the ribociclib + ET arm required temporary treatment interruption due to an adverse event, most of which were abnormal laboratory values. This is markedly increased over the ET only arm where only 8% of patients required treatment interruption. Combining laboratory abnormalities of neutrophil counts decreased and reported AEs of neutropenia, neutropenia accounted for the majority of ribociclib interruptions/dose reductions. Neutropenia tended to occur in the first few cycles of treatment and was effectively managed for most patients via interruption. About one in seven participants on ribociclib required a dose reduction to 200 mg/day due to grade 3/4 neutropenia. Both permanent discontinuation due to neutropenia (<1%) and clinical complications of neutropenia were rare and are discussed in further detail below. As noted above, while both infections of all grades, as well as SAEs related to infections, were more common in participants receiving ribociclib + ET, infections other than SARS-CoV-2 occurred rarely overall in NATALEE. In addition to myelosuppression, the other common causes of study drug interruption were also mostly laboratory-related: elevated ALT or AST, SARS-CoV2 test positive or COVID- 19, and electrolyte abnormalities (increased or decreased potassium, calcium, or magnesium). A small number of patients also had treatment interruption due to fatigue, arthralgia, and pyrexia. Ribociclib dose reductions were required in almost 1 in 4 participants on the ribociclib + ET arm and occurred for similar reasons to treatment interruption. More than half of the dose reductions were due to neutropenia/neutrophil count decreased. Other than myelosuppression, the next most common reason for dose reductions was abnormal liver function tests (ALT, AST, or GGT), which resulted in ribociclib discontinuation in approximately 3% of patients. The remaining causes of dose reduction occurred in ≤1% of patients on the ribociclib + ET arm with constitutional symptoms (fatigue, asthenia) and GI symptoms (stomatitis, nausea, and diarrhea) being most common. Significant Adverse Events The Applicant’s Position: The significant AEs reported are described in other sections of this document, “Serious Adverse Events” and “Treatment Emergent Adverse events and Adverse Reactions”. The FDA’s Assessment: 119 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. FDA generally agrees with the Applicant’s assessment with the addition of the concern regarding an increased incidence of severe/fatal COVID-19 and COVID-19 pneumonia. This appears to have been mitigated later in the trial with availability of COVID-19 vaccination and therapeutics, as well as likely immunity related to prior infections. This risk is discussed in further detail earlier in Section 8.2.4 in the section about on-treatment deaths. Treatment Emergent Adverse Events and Adverse Reactions Data: Table 29: Common adverse events with grade ≥ 3 events at incidence ≥ 1.0% in either group, by preferred term in Study O12301C (Safety set) Final iDFS Analysis (21-Jul-2023 data cut-off) AE Ribociclib + ET only N=2525 N=2442 Ribociclib + ET only N=2525 N=2442 All grades n (%) All grades n (%) Grade ≥ 3 n (%) Grade ≥ 3 n (%) Total no. patients with at least 1 TEAE 2474 (98.0) 2145 (87.8) 1607 (63.6) 469 (19.2) Neutropenia 1047 (41.5) 73 (3.0) 707 (28.0) 14 (0.6) Neutrophil count decreased 609 (24.1) 41 (1.7) 448 (17.7) 8 (0.3) Alanine aminotransferase increased 492 (19.5) 136 (5.6) 192 (7.6) 17 (0.7) Aspartate aminotransferase increased 426 (16.9) 139 (5.7) 118 (4.7) 13 (0.5) White blood cell count decreased 246 (9.7) 38 (1.6) 94 (3.7) 6 (0.2) Leukopenia 337 (13.3) 50 (2.0) 94 (3.7) 2 (0.1) Hypertension 212 (8.4) 185 (7.6) 54 (2.1) 59 (2.4) Gamma-glutamyltransferase increased 119 (4.7) 67 (2.7) 26 (1.0) 22 (0.9) Lipase increased 58 (2.3) 33 (1.4) 25 (1.0) 12 (0.5) Arthralgia 942 (37.3) 1058 (43.3) 25 (1.0) 31 (1.3) Grade ≥ 3 AEs are sorted by decreasing order of frequency in the ribociclib + ET column. Source: [CO Study O12301C-Table 5-1] The Applicant’s Position: Most frequent AEs by Preferred term Overall, AEs were observed at a higher frequency (relative difference between treatment groups) in the ribociclib + ET group vs. ET only group of +10.2%. AEs observed at a higher frequency (with a ≥ 10% relative difference between treatment groups in overall decreasing order of frequency with ribociclib + ET) included: neutropenia (+38.5%), decreased neutrophil count (+22.4%), nausea (+15.5%), increased ALT (+13.9%), leukopenia (+11.3%), alopecia (+10.5%), and increased AST (+11.2%). In the ET only group, no PT met this criterion. Arthralgia was reported in a greater proportion (6% relative difference) of ET only-treated patients, compared with ribociclib + ET-treated patients [SCS Add. Study O12301C-Section 2.2.2]. Severity of AEs The majority of the most frequent (≥ 1.0%/either group) grade ≥ 3 AEs were consistent with the known safety profile of ribociclib, predominantly pertaining to the known risk of myelosuppression, occurring usually within the first few cycles of therapy, and the incidence did 120 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. not increase over time. The clinical impact of grade ≥ 3 TEAEs on patients in the ribociclib + ET group was limited, as the majority of events were asymptomatic laboratory abnormalities and completely resolved with appropriate management as per protocol [CO Study O12301C CO- Section 5.2.1.2] Adverse drug reactions The screening, methodology, and selection process used to identify ADRs for the target population are described in [SCS Study O12301C-Section 1.1.3.5] and [SCS Study O12301C- Appendix 2]. No new ADRs were identified based on the Novartis comprehensive medical evaluation of data from Study O12301C. In addition, the ribociclib ADR profile in patients with HR-positive, HER2-negative eBC is compared favorably with the established safety profile of Kisqali in patients with aBC [SCS Study O12301C-Section 2.9], (Kisqali USPI 2022, Kisqali SmPC 2023). This is due to a considerable number of pre-existing ADRs that did not qualify as ADRs in the eBC setting and several pre-existing ADRs that were downgraded in their frequency category for this patient population. For further details, see [SCS Study O12301C-Section 2.9]. These data are considered robust based on the adequate overall sample size of Study O12301C (N=4968; Safety set) and study design, including the control arm [CO Study O12301-Section 5.5]. No new ADRs or changes in the frequency categories of ADRs identified based on the primary analysis were identified in the target population based on the Novartis comprehensive medical evaluation of data from Study O12301C for the final iDFS analysis. The FDA’s Assessment: FDA’s analysis of common and grade 3/4 AEs generally agrees with the Applicant’s analysis/assessment except regarding COVID-19. As SARS-CoV-2 did not yet exist at the time the ribociclib trials were conducted in the metastatic setting, COVID-19 represents a new ADR. The incidence of SARS-CoV-2 infection and COVID-19 illness, including severe or fatal cases, was increased in patients who received ribociclib, as discussed above in Section 8.2.4. Addition of a Warning and Precaution related to COVID-19 was discussed by the review team, but given that the risk of severe illness appears to have diminished over the course of the trial, likely due to the availability of vaccines and COVID-19 therapeutics, as well as immunity related to prior infection, it was not added. If an increase in severe or fatal COVID-19 is observed in the postmarket setting, the USPI will be updated accordingly. As discussed above and in Section 8.2.5, the most common overall and grade ≥3 treatment- emergent AEs were laboratory findings, in particular myelosuppression and liver function abnormalities, most of which were asymptomatic. Laboratory Findings Data: Table 30: New or worsening postbaseline hematology and clinical chemistry abnormalities, with incidence at least 10% / either group in Study O12301C (Safety set) 121 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Safety endpoint (hyper / hypo grade) Ribociclib + ET N=2525 ET only N=2442 Grade 1/2 Grade 3 Grade 4 Grade 1/2 Grade 3 Grade 4 n (%) n (%) n (%) n (%) n (%) n (%) Hematology abnormalities Hemoglobin (hypo) 1178 (46.7) 14 (0.6) 0 619 (25.3) 8 (0.3) 0 Leukocytes (hypo) 1714 (67.9) 688 (27.2) 5 (0.2) 1089 (44.6) 12 (0.5) 2 (0.1) Lymphocytes (hypo) 1980 (78.4) 413 (16.4) 67 (2.7) 1998 (81.8) 98 (4.0) 55 (2.3) Neutrophils (hypo) 1225 (48.5) 1083 (42.9) 55 (2.2) 818 (33.5) 35 (1.4) 6 (0.2) Platelets (hypo) 705 (27.9) 9 (0.4) 1 (< 0.1) 312 (12.8) 7 (0.3) 1 (< 0.1) Clinical chemistry abnormalities ALT (hyper) 926 (36.7) 167 (6.6) 38 (1.5) 837 (34.3) 24 (1.0) 1 (< 0.1) ALP (hyper) 884 (35.0) 5 (0.2) 0 884 (36.2) 5 (0.2) 0 Amylase (hyper) 363 (14.4) 24 (1.0) 8 (0.3) 328 (13.4) 29 (1.2) 4 (0.2) AST (hyper) 978 (38.7) 113 (4.5) 20 (0.8) 780 (31.9) 26 (1.1) 0 Calcium corrected (hyper) 247 (9.8) 5 (0.2) 3 (0.1) 356 (14.6) 9 (0.4) 6 (0.2) Calcium corrected (hypo) 517 (20.5) 6 (0.2) 16 (0.6) 386 (15.8) 9 (0.4) 29 (1.2) Creatinine (hyper) 815 (32.3) 7 (0.3) 0 278 (11.4) 0 0 Direct bilirubin (hyper) 456 (18.1) 26 (1.0) 8 (0.3) 426 (17.4) 14 (0.6) 1 (< 0.1) GGT (hyper) 865 (34.3) 90 (3.6) 8 (0.3) 760 (31.1) 83 (3.4) 6 (0.2) Glucose (hyper) 1478 (58.5) 48 (1.9) 12 (0.5) 1396 (57.2) 36 (1.5) 12 (0.5) Lipase (hyper) 407 (16.1) 67 (2.7) 12 (0.5) 400 (16.4) 69 (2.8) 9 (0.4) Magnesium (hypo) 379 (15.0) 4 (0.2) 3 (0.1) 371 (15.2) 0 1 (< 0.1) Potassium (hyper) 355 (14.1) 16 (0.6) 1 (< 0.1) 378 (15.5) 15 (0.6) 4 (0.2) Potassium (hypo) 261 (10.3) 16 (0.6) 7 (0.3) 208 (8.5) 22 (0.9) 14 (0.6) Sodium (hyper) 276 (10.9) 3 (0.1) 1 (< 0.1) 291 (11.9) 2 (0.1) 0 Sodium (hypo) 270 (10.7) 26 (1.0) 6 (0.2) 230 (9.4) 17 (0.7) 7 (0.3) Urate (hyper) 771 (30.5) 0 38 (1.5) 701 (28.7) 0 43 (1.8) Source: [SCS Add. Study O12301C-Table 3-1 and 3-2] The Applicant’s Position: Most hematology abnormalities were of low-grade, with the exception of neutrophil counts. The most common worst-post-baseline grade 1 / 2 hematological abnormalities in the ribociclib + ET group (≥ 10.0% difference relative to ET only group) were: decreased leukocytes (+23.3%), decreased hemoglobin (+21.3%), decreased platelets (+15.1%), and decreased neutrophils (+15.0%). Grade 3 hematological abnormalities in the ribociclib + ET group (≥ 10.0% difference relative to ET only group) were: decreased neutrophils (+41.5%), decreased leukocytes (+26.8%), and decreased lymphocytes (+12.4%). The highest number of patients (in both treatment groups) with grade-4 hematological abnormalities were decreased lymphocytes (2.7% of ribociclib + ET patients and 2.3% of ET only patients) [Study O12301C EA&SU-Section 4.4.1]. Most clinical chemistry abnormalities were of low-grade. Grade 1 / 2 increased creatinine (+20.9%) were the only clinical chemistry parameter reported in a higher proportion of patients (difference ≥ 10%) who received ribociclib + ET, compared with patients who received ET only. The frequency of remaining post-baseline biochemical abnormalities was similar by group. 122 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. There were no grade 3 clinical chemistry abnormalities in ribociclib + ET group with a ≥ 10% difference relative to ET only group. The most common grade 4 clinical chemistry abnormalities (with incidences ≥ 1.0%) reported in ribociclib + ET group were increased ALT (1.5% vs. < 0.1%) and increased urate (1.5% vs. 1.8%) [Study O12301C EA&SU-Section 3.1 and 3.2]. The FDA’s Assessment: FDA has analyzed laboratory abnormalities and generally concurs with the Applicant’s analysis and assessment of clinical chemistry and hematology abnormalities. The most common laboratory abnormalities were related to myelosuppression and abnormal liver function tests. The incidence and severity of neutropenia was markedly increased in patients who received ribociclib. While grade 1-2 neutropenia was reported in half of patients receiving ribociclib + ET compared to a third of patients receiving ET only, the most striking difference was in the incidence of higher grades of neutropenia. In the ribociclib + ET arm, 45% of patients had grade ≥3 neutropenia compared to 2% of those in the ET arm. Neutropenia as an AESI is discussed in further detail in Section 8.2.5.1. Grade 1-2 anemia (47% vs 25%) and thrombocytopenia (28% vs 13%) were approximately twice as common in patients who received ribociclib + ET compared to those who received ET only. Grade ≥ 3 anemia and thrombocytopenia were more common with addition of ribociclib but occurred at <1% incidence in both treatment groups. Transaminases were elevated more often in patients on ribociclib + ET. All-grade increases in ALT (ribociclib + ET 44.8% vs ET only 35.3%) and AST (44% vs 33%), as well as grade ≥3 increases in ALT (8.1% vs 1%) and AST (5.3% vs 1.1%) were more common in patients receiving ribociclib. Liver function abnormalities and hepatotoxicity are discussed in further detail as an AESI in Section 8.2.5.3. Patients who received ribociclib in addition to ET were more likely to have all-grade increased creatinine (32.5% vs 11.4%). While almost all of these were low-grade, grade 3 increased creatinine was also more common with ribociclib (0.3% vs 0%). FDA therefore analyzed acute kidney injury (AKI) as a grouped term (consisting of PT terms: acute kidney injury, GFR decreased, renal failure, renal disorder, renal impairment, oliguria, creatinine renal clearance decreased, and azotemia). While uncommon overall, this analysis found that AKI occurred more often in patients who received ribociclib + ET (2.5% vs 0.9%). As with laboratory abnormalities, most of these AKI group term AEs were grade 1/2. Grade ≥3 AKI AEs occurred in 4 patients (0.2%) of those on ribociclib compared with none of those on ET alone. This will continue to be monitored in the postmarket setting and the USPI Warnings & Precautions updated as appropriate if more severe renal dysfunction becomes apparent with wider use. Electrolyte abnormalities (magnesium, potassium, and calcium, both increased and decreased) were more common in patients who received ribociclib, but most were grade 1/2. Grade 3/4 electrolyte abnormalities occurred in <1% of patients. To further understand this issue, FDA performed an analysis using grouped terms to assess multiple gastrointestinal (GI) AEs. This found an increased risk of all-grade stomatitis (8% vs 123 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 1.3%), nausea (23% vs 8%), vomiting (8% vs 4%), and diarrhea (15% vs 6%). It is likely that most of the observed electrolyte abnormalities are related to poor oral intake and GI losses, though it is possible that the increased incidence of renal dysfunction may also be playing a role. Given the potential for electrolyte abnormalities, whether due to GI toxicity or renal dysfunction, to increase the risk of QT prolongation, which is a known AESI for ribociclib, chemistries should be monitored regularly per the USPI and electrolytes corrected as needed. Vital Signs The Applicant’s Position: No meaningful differences between the treatments groups were observed for vital signs, i.e. systolic or diastolic BP, heart rate, and body temperature. In general, median change from baseline to the lowest postbaseline median value or the highest postbaseline median value was not appreciably different by group for any vital sign [SCS Study O12301-Section 4.1]. The FDA’s Assessment: FDA agrees with the Applicant’s assessment of vital signs. Electrocardiograms (ECGs) The Applicant’s Position: Notable ECG values are discussed in detail in Section 8.2.5.2. Based on ECG, change in heart rate by treatment group was similar by group. Heart rate data were not analyzed from local ECGs. Overall clinical interpretation of centrally assessed ECG results at baseline compared with worse on-treatment did not identify a pattern. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. See detailed discussion of QTcF findings in the following section and as an AESI in Section 8.2.5.2. 124 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Data: Table 31: Clinically notable ECG values by treatment group in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off QT parameter Ribociclib + ET N=2525 ET only N=2442 Overall N=4967 n/m (%) n/m (%) n/m (%) QTcF New value > 450 and ≤ 480 ms 240/2477 (9.7) 66/2365 (2.8) 306/4842 (6.3) New value > 480 and ≤ 500 ms 7/2493 (0.3) 4/2378 (0.2) 11/4871 (0.2) New value > 480 ms 10/2493 (0.4) 4/2378 (0.2) 14/4871 (0.3) New value > 500 ms 3/2493 (0.1) 1/2378 (< 0.1) 4/4871 (0.1) Increase from baseline > 30 and ≤ 60 ms 462/2493 (18.5) 167/2378 (7.0) 629/4871 (12.9) Increase from baseline > 60 ms 19/2493 (0.8) 2/2378 (0.1) 21/4871 (0.4) Central assessments only. Patients are counted based on any notable ECG postbaseline value. Baseline is defined as the last assessment on or before start of study treatment. For any replicate/triplicate ECGs per timepoint, the average of these measurements would be calculated for baseline. n=Number of patients who meet the designated criterion. m=Number of patients at risk for a specific category. For new abnormality postbaseline, this is the number of patients with both baseline and postbaseline evaluations, and baseline not meeting the criteria. For abnormal change from baseline, it is the number of patients with both baseline and postbaseline evaluations. N=Total number of patients in the treatment group in this analysis set. Source: [SCS Add. Study O12301C-Table 2-24] The Applicant’s Position: Based on central ECG assessment, clinically notable QTcF value of > 480 ms was infrequent in both groups: in the ribociclib + ET group (10 patients, 0.4%) vs. the ET only group (4 patients, 0.2%), which included 3 patients (0.1%) with a QTcF > 500 ms in the ribociclib + ET group vs. one patient (<0.1%) in the ET only group. An increase of QTcF > 60 ms from baseline was observed in 19 patients (0.8%) in the ribociclib + ET group, and in 2 patients (0.1%) in the ET only group. Of note, overall, increase in QTcF > 60 ms from baseline or QTcF >480 ms did not result in clinically relevant abnormalities and were not associated with cardiac signs or symptoms. These ECG changes were reversible with dose interruption, and the majority occurred within the first 4 weeks of treatment. There were no reported cases of sudden death or Torsades de Pointes [CO Study O12301-Section 5.3.2]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of QT interval prolongation except as noted in the discussion below. FDA’s QT-IRT committee independently confirmed the QT results based upon central assessment provided by the Applicant in Table 31. Adding ribociclib to ET clearly increases QT interval compared to ET only. In total, based upon centrally-assessed ECGs, 481 (19%) of patients in the ribociclib + ET group had an increase in QT interval >30 ms compared with 169 (7%) of patients in the ET only group. Increases in QT interval >60 ms, while increased with the addition of ribociclib, remained uncommon overall, however, reported in 19 (0.8%) of patients on ribociclib + ET 126 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. therefore assess a patient’s individual risk, based upon baseline QT interval, comorbidities, concomitant medications, and other risk factors for QT prolongation, and discuss the limitations of available data to inform shared decision-making on further ECG monitoring in patients at higher risk of developing QT prolongation. QT prolongation as an AESI is discussed is further detail in Section 8.2.5.2. Immunogenicity The Applicant’s Position: Not applicable as this was not assessed nor expected. The FDA’s Assessment: Not applicable. 8.2.5 Analysis of Submission-Specific Safety Issues Study O12301C was properly designed to actively monitor, capture, and adequately characterize the current safety topics of interest with ribociclib in this target population in the adjuvant eBC setting. Analyses of the Safety set from Study O12301C did not reveal any new safety signal. The current safety topics of interest with ribociclib in adults with HR-positive, HER2-negative eBC reveal a predictable and manageable safety profile with a 400 mg starting dose of ribociclib in combination with ET. Three categories of events are discussed here (neutropenia, QT interval prolongation, and hepatobiliary toxicity); these are well characterized clinical issues associated with the use of ribociclib which, in general, can be effectively managed in the clinical setting (with dose interruption and/or dose modification). Analysis results for the remaining AESIs are provided in [SCS Study O12301C-Section 2.6]. 8.2.5.1 Neutropenia The Applicant’s Position: Neutropenia is an important identified risk for ribociclib. This common adverse effect associated with CDK4/6 inhibition is concentration dependent, transient, and reversible. Neutropenia associated with ribociclib therapy can be clinically managed through dose modification and interruption. Neutropenia AESI were among the most common toxicities reported (overall: 62.5% vs. 4.6%). Events were limited to (in decreasing frequency for ribociclib + ET) neutropenia (41.5%), decreased neutrophil count (24.1%), febrile neutropenia (0.3%), and granulocytopenia (0.2%). Events of Neutropenia AESI represented the vast majority of grade ≥ 3 AEs in Study O12301C. These events had limited clinical impact, as the majority of events were asymptomatic laboratory abnormalities and completely resolved with appropriate management as per protocol. In the ribociclib + ET group, Neutropenia AESIs were often severe (grade ≥3: 44.3%) and resulted in dose interruption (43.3%). However, AEs leading to dose adjustment (14.2% vs. 0) 127 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. and specifically AEs leading to discontinuation (1.1% vs. 0) due to neutropenia events were infrequent (ribociclib + ET vs. ET only). Although there was a high incidence of grade ≥ 3 neutropenia AESIs, this did not translate into a clinically significant increase in risk of severe infections in patients treated with ribociclib; grade ≥ 3 infections occurred in 5.5% and 3.2% in the ribociclib + ET and the ET only treatment arms respectively. Febrile neutropenia was limited to 7 patients (0.3%) in the ribociclib + ET group: 4 patients (0.2%) required dose interruption; 2 patients (0.1%) required dose reduction and/or discontinuation of study treatment, and 1 patient (< 0.1%) had an SAE. There were no cases of febrile neutropenia in the ET only group, and there were no fatalities related to neutropenia. Based on neutrophil counts, neutropenia events were generally observed early over the course of treatment with ribociclib and their incidences did not increase over time. Management guidelines for neutropenia remain the same as in the approved label for patients with aBC [CO Study O12301-Section 5.3.1] The FDA’s Assessment: FDA has analyzed neutropenia as an abnormal laboratory value and a grouped term AE (including PT terms neutrophil count decreased and neutropenia) and generally agrees with the Applicant’s assessment. As discussed earlier, taking into consideration both decreased neutrophils on laboratory values as well as reported adverse events of neutropenia of any grade, the majority of patients receiving ribociclib on NATALEE experienced a low neutrophil count. Neutropenia with ribociclib is concentration-dependent, and the incidence of grade ≥3 neutropenia in early breast cancer is significantly lower than that observed in the trials in metastatic breast cancer, presumably due to the lower dose of ribociclib used in the NATALEE trial. Even with the dose of ribociclib used in the NATALEE trial, which is 200 mg lower than that used in the metastatic setting, nearly half of the patients on the ribociclib + ET arm had at least one episode of grade ≥3 neutropenia. However, despite the high incidence of neutropenia, including grade ≥3 neutropenia, it was able to be managed on study for most patients with temporary interruption of the CDK inhibitor. About 1 in seven patients required a dose reduction for neutropenia, but permanent discontinuation due to neutropenia was required in only 1% of patients. Clinically meaningful complications of neutropenia occurred more often in those receiving ribociclib but were infrequent overall; grade ≥3 infections were 2.3% more common and febrile neutropenia was 0.3% more common in patients on ribociclib + ET compared to those on ET alone. There were no deaths reported to have been associated with neutropenia on ribociclib. The incidence and severity of neutropenia generally did not increase with time for patients over the course of the 36-month treatment, suggesting that neutropenia management guidelines used in the NATALEE trial and reflected in the USPI are appropriate to mitigate the risk. The Applicant’s proposed labeling has been modified to reflect both the laboratory abnormalities and adverse events of neutropenia as this better characterizes the overall incidence and ensures that clinicians monitor absolute neutrophil count (ANC) closely and modify treatment as necessary. 128 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. While neutropenia with adjuvant ribociclib is very common and often high-grade, with the recommended monitoring and treatment interruption, dose reduction, or discontinuation as described in the USPI, the risk of serious infections attributable to neutropenia in this curative intent population who will be receiving 3 years of treatment appears to be low. There was an increased risk of SARS-CoV-2 infection and COVID-19/COVID-19 pneumonia, including fatal cases that occurred during the on-treatment period, in patients receiving ribociclib + ET. This AE did not appear to be related to treatment-emergent neutropenia and is discussed in further detail in Section 8.2.4. 8.2.5.2 QT interval prolongation QT prolongation is an important identified risk for ribociclib. As previously known, ribociclib prolongs the QT interval in a concentration-dependent manner. This risk is minimized by the specific dose modification guidance and ECG and serum electrolyte monitoring plan in the current label, which is considered adequate. A comprehensive clinical safety assessment of QT prolongation is included within this dossier in a specialty safety report [QT/QTc Safety Analysis Report Study O12301C]. Per the study inclusion criteria, patients were required to have baseline QTcF < 450 ms with no significant uncontrolled cardiac disorder. Frequency of events in the QT interval prolongation AESI were as follows in the ribociclib + ET group compared with the ET only group: all grades: 5.3% vs. 1.4%; grade ≥3: 1.0% vs 0.6%. Among the AESI grouping term, the most frequent AE by PT term was ECG QT prolonged (all grades: 4.3%, ribociclib + ET; 0.7%, ET only). Following in frequency, syncope presented infrequently and similarly by group (0.7% vs. 0.6%). There was one AE (cardiac arrest) leading to death in the ribociclib + ET group. This event occurred >30 days off ribociclib and was considered not related by the Investigator. The patient had no reported ECG/QT/QTcF abnormalities. Overall, events within the QT prolongation AESI were uncommon and with limited clinical impact rarely requiring dose adjustment, interruption, or discontinuation (0.1%; 1.1%; 0.4% respectively) in the ribociclib + ET group. Notable ECG values Based on central ECG assessment, clinically notable QTcF value of > 480 ms was infrequent in both groups: in the ribociclib + ET group (10 patients, 0.4%) vs. the ET only group (4 patients, 0.2%), which included 3 patients (0.1%) with a QTcF > 500 ms in the ribociclib + ET group vs. one patient (<0.1%) in the ET only group. An increase of QTcF > 60 ms from baseline was observed in 19 patients (0.8%) in the ribociclib + ET group, and in 2 patients (0.1%) in the ET only group. Of note, overall, increase in QTcF > 60 ms from baseline or QTcF >480 ms did not result in clinically relevant abnormalities and were not associated with cardiac signs or symptoms. These ECG changes were reversible with dose interruption, and the majority occurred within the first 4 weeks of treatment. There were no reported cases of sudden death or Torsades de Pointes. Time to event analyses: Median time-to-onset of ECG QT prolongation grade ≥2 events was 0.5 months (range: 0.5 to 1.5), which correlates to approximately Cycle 1 Day 15 per protocol- 129 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. scheduled monitoring in the ribociclib + ET group, compared with 1.4 months (range: 0.9 to 2.8), or approximately Cycle 2 Day 15 per protocol-scheduled monitoring in the ET only group. Of note, the majority of notable QTcF values were observed on Cycle 1 Day 15. Median time-to-onset of ECG QT prolongation grade ≥3 events was 1.4 months (range: 0.5 to 1.5) in the ribociclib + ET group, compared with 1.9 months (range: 1.9 to 1.9) in the ET only group. Of note, there was minimal change in notable QTcF values at Cycle 2 Day 1 compared to baseline (mean change from baseline at Cycle 2 Day 1 was 0.5 ms) in the ribociclib + ET group. This minimal QTcF prolongation is expected due to the 7 days off of dose, where the concentration of ribociclib is expected to be low, based on the 3-weeks on/1-week off ribociclib dosing schedule. This is further supported by the fact that no first occurrences of notable ECG values have been observed at this timepoint in ribociclib + ET group. Management recommendations: As described above, ECG prolongation events were of low incidence (1.0% grade ≥ 3 QT ECG prolonged AESI; 0.4% QT interval > 480 ms) without associated cardiac signs or symptoms in ribociclib + ET group. The mean QTcF change (ΔQTcF) from baseline was 9.5 ms at Cycle 1 Day 15 2 hours postdose, which corresponds to steady state ribociclib concentration. The mean change from baseline was 0.5 ms at Cycle 2 Day 1 predose ECG, which corresponds to the lowest ribociclib concentration, as expected, following the 7 days off dose based on the 3-weeks on/1-week off dosing schedule. In view of these data from Study O12301C, Novartis proposes ECG monitoring for patients with eBC at baseline before initiating treatment, and approximately Cycle 1 Day 14 (steady-state ribociclib concentration), with additional ECGs as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended. Consistent with the proposal for patients with eBC, Novartis also proposes to revise the existing risk minimization measures for management of risk of QT interval prolongation in patients with aBC (ie, to remove the requirement for ECG monitoring at the beginning of the second cycle/Cycle 2 Day 1), based on the low incidence of QT prolongation events at Cycle 2 Day 1, which corresponds to the low concentration of ribociclib and minimal change in QTc interval from baseline (ΔQTcF), median time to first occurrence of Grade 2/3/4 QT prolongation of 2.1 weeks which approximates Cycle 1 Day 15, and no clinical evidence among patients with notable ECG at Cycle 1 Day 15 and Cycle 2 Day 1 that mandating Cycle 2 Day 1 QTcF monitoring for all patients would have provided additional benefit to support managing the risk of QT prolongation in patients with aBC [SCS Add. Study O12301C-Appendix 4]. Other risk mitigation measures for QT prolongation including dose modification guidance, baseline threshold of QTcF <450 ms, monitoring of electrolytes, and assessment of relevant medical history and concomitant medications are included in the proposed label. More details are provided in [QT/QTc Safety Analysis Report Study O12301C] included in this submission. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment except as noted below. The median time to grade ≥2 QT prolongation, a QTc of 481-500 ms, was 0.5 months (range: 0.5 to 1.5), which corresponds with the cycle 1 day 15 ECG. Although there were cases of QT prolongation beyond Cycle 1, there were no patients with a first occurrence of 134 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. With appropriate patient selection, including baseline QTcF <450 ms and assessment of risk based upon personal/family history, as well as risk mitigation, including avoidance of other QT prolonging medications, monitoring/correction of electrolyte abnormalities, and dose modification as needed, FDA concurs that routine ECG monitoring for all patients on Cycle 2 Day 1 is not required. The Cycle 1 Day 15 ECG, which occurs at steady state concentration, may be used by clinicians in combination with the above elements of the history and laboratories to identify the subset of patients on ribociclib for whom additional ECG monitoring beyond Cycle 1 is necessary. Patients with QT prolongation observed on the Cycle 1 Day 15 ECG, as well as patients at increased risk of QT prolongation or arrhythmia based upon medical history or concomitant medications, should have continued ECG monitoring beyond Cycle 1. The USPI will be updated to reflect this modified recommendation. While there was no difference in the incidence or severity of tachycardia between the two groups, FDA noted that palpitations were reported more commonly in patients on the ribociclib + ET arm (3.4%) compared to those on the ET only arm (1.1%). To evaluate for arrhythmias that may have occurred without QT prolongation or with QT prolongation that was not captured on ECG, FDA also analyzed arrhythmia as a grouped term (consisting of atrial fibrillation, electrocardiogram QT prolonged, Wolff-Parkinson-White syndrome, supraventricular tachycardia, sinus bradycardia, sinus arrhythmia, electrocardiogram repolarization abnormality, extrasystoles, arrhythmia, supraventricular extrasystoles, atrioventricular block first degree, ventricular extrasystoles, arrhythmia supraventricular, sinus tachycardia, atrial flutter, atrial tachycardia, electrocardiogram P wave abnormal, bundle branch block right, atrioventricular block, tachyarrhythmia, electrocardiogram PR prolongation, ventricular tachycardia, long QT syndrome, TdP, and bundle branch block left) and found an increased incidence of all-grade AEs in the ribociclib + ET group (6% vs 3.3%). While the majority of these were grade 1/2, the incidence of grade ≥ 3 AEs in this grouped term was also doubled with ribociclib use (0.6% vs 0.3%). As discussed earlier in Section 8.2.4, electrolyte abnormalities were more common in patients on ribociclib + ET, and while most were grade 1/2, it is possible that this contributed. It is important to note that patients with significant cardiac history were excluded from NATALEE (as well as trials in the metastatic setting) but may be exposed to ribociclib in the postmarket setting. In addition, nearly one in five patients on the NATALEE trial received at least one dose of a prohibited concomitant medication, including many medications prohibited due to increased risk of QT prolongation. As discussed above in the narratives in this section, although adverse cardiac events potentially related to concomitant medication use occurred on the NATALEE trial, they appear to have been rare. Attention to reports of arrythmia AEs, especially TdP, ventricular arrhythmias, or sudden cardiac death, will be especially important for postmarketing pharmacovigilance given the broader introduction of ribociclib in a curative intent setting. No cases of TdP have been 135 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. reported to date. If clinically significant QT prolongation is identified in patients with early breast cancer in the postmarket setting, consideration of a labeling change to add back routine ECG monitoring in Cycle 2, but at Day 15 rather than Day 1, given the 3 week on, 1 week off dosing regimen, is recommended. 8.2.5.3 Hepatobiliary toxicity Hepatobiliary toxicity is an important identified risk for ribociclib. The majority of hepatobiliary AESIs were laboratory findings of elevated ALT/AST concentrations, which tended to occur early during treatment and were manageable with protocol dose management guidance specific for hepatotoxicity. Hepatobiliary AESIs were one of the most common grade ≥ 3 AEs in Study O12301C, and the most common reason for treatment discontinuation but were effectively manageable with dose adjustments, and were reversible. In Study O12301C, the proportion of patients with hepatobiliary toxicity grouped AEs was greater in the ribociclib + ET group vs. the ET only group (26.4% vs. 11.2%); likewise the proportions of patients with grade ≥3 events were 8.6% and 1.7%, respectively. The most frequently reported events in this AESI category included: ALT increased (19.5% vs. 5.6%) and AST increased (16.9% vs. 5.7%) [SCS Add. Study O12301C-Table 2-19]. Importantly, these 2 PTs were amongst the most common [SCS Add. Study O12301C-Table 2-3] and more severe events [SCS Add. Study O12301C-Table 2-4] that were assessed with causal relationship to study treatment by the Investigator [SCS Add. Study O12301C-Table 2-5] in the ribociclib + ET group. All remaining PTs in the hepatobiliary toxicity grouped AEs were reported at < 5.0% in either group. No noteworthy differences were observed since IA3. No additional patients with DILI or confirmed Hy’s Law were identified since the primary analysis/IA3 [SCS Add. Study O12301C- Section 2.6.7]. • Within the Hepatobiliary toxicity AESI, DILI was reported for 9 patients (0.4%) and of these, 5 were grade ≥ 3. Of these 9, 8 patients’ events resolved as of DCO [Study O12301C Primary Analysis CSR-Listing 16.2.7-1.1]. All 9 patients with DILI are discussed in [Study O12301C Primary Analysis CSR-Section 14.3.3], and were in the ribociclib + ET group. • There were 8 clinically confirmed Hy’s Law cases, including 4 of the 9 patients with DILI. All 8 patients were in the ribociclib + ET treatment group (n=2524). Importantly, most (6 out of 8 patients) completely recovered after discontinuation of ribociclib; 2 patients had improvement in lab values after ribociclib discontinuation, albeit mild lab abnormalities were still as of DCO (1 patient, grade 2 elevated TBL; 1 patient, grade-1 elevated AST/ALT and grade-2 elevated TBL) [Study O12301C SCS-Section 2.6.6]. When assessing Hepatobiliary toxicity AESI as grade ≥ 3 AEs, SAEs, AEs leading to discontinuation, dose adjustment, and/or dose interruption, increased ALT (7.6%, 0.4%, 7.1%, 1.9%, and 10.1%, respectively) and increased AST (4.7%, 0.2%, 2.8%, 0.6%, and 6.8%, 136 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. respectively) were often the most frequent events in the ribociclib + ET group [SCS Add. Study O12301C-Appendix 1-Table 14.3.1-6.2]. There were no on-treatment deaths in the Hepatobiliary toxicity AESI [SCS Add. Study O12301C-Table 2-19]. Time-to-event analyses: Median time-to-first occurrence of grade ≥ 3 elevated ALT/AST was 2.8 months (range: 0.36 to 33.15) in the ribociclib + ET group, compared with 12.5 months (range: 0.46 to 33.28) in the ET only group [SCS Study O12301C-Appendix 1-Table 14.4-4.1], [SCS Study O12301C- Figure 2-6]. The estimated median duration of grade 3 or higher AST or ALT elevations (recovering to ≤ grade 2) was 0.7 months (95% CI: 0.7, 0.9) in the ribociclib + ET group and 2.2 months (95% CI: 1.2, 2.8) in the ET only group [Study O12301C Primary Analysis CSR- Table 14.3-6.2] Management recommendations: Hepatobiliary toxicity has been reported during treatment with ribociclib and therefore, should be closely monitored. Management guidelines remain the same as in the approved label for patients with aBC. The FDA’s Assessment: FDA has analyzed hepatobiliary AEs and laboratory abnormalities and generally agrees with the Applicant’s assessment with the following additional comments. Hepatobiliary AEs were much more common with addition of ribociclib to ET. In FDA’s analysis of liver function test AEs (as a grouped term consisting of elevation in one or more of: AST, ALT, GGT, alkaline phosphatase, and blood bilirubin), 26.4% of participants on the ribociclib + ET arm had a liver function test abnormality, of which 8.6% were grade ≥3. This is a significant increase compared to the ET only arm where only 11.2% had a liver function abnormality, of which 1.7% each were grade ≥3. Most were increases in transaminases. An FDA analysis of hepatotoxicity AEs (a grouped term consisting of PT of hepatotoxicity, drug-induced liver injury (DILI), autoimmune hepatitis, and hepatic cytolysis) was also performed and similarly identified an increased incidence of all-grade (1.4% vs 0.5%) as well as grade ≥3 hepatotoxicity AEs (0.7% vs <0.1%) in the ribociclib + ET arm compared to the ET only arm. The median time to first occurrence of grade 3/4 elevated transaminases was 2.8 months on the ribociclib + ET arm, although cases of grade 3/4 transaminase elevation occurred as early as 0.4 months and as late as 33 months into treatment. Hepatobiliary SAEs were rare overall but clearly increased for those receiving ribociclib (1.0% vs 0.2%). Liver function test abnormalities, most commonly elevated transaminases, resulted in treatment interruption of ribociclib in 12.4% of patients, dose reduction in 2.6% patients, and permanent discontinuation in 8.9% of patients. With these treatment modifications according to the protocol, the median duration of grade 3/4 elevated transaminases in the ribociclib + ET arm was 0.7 months, and there were no on-study deaths attributed to hepatobiliary toxicity, indicating that instructions in the agreed upon USPI regarding liver function abnormalities appear adequate to monitor and mitigate this 143 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Day 84, her AST was grade 3, ALT was grade 4, alkaline phosphatase was grade 1, and total bilirubin was normal. Ribociclib was interrupted on Day 85 (last dose was taken on Day 77) and never restarted. On Study Day 90, AST and ALT were grade 4, alkaline phosphatase was grade 1, and total bilirubin was grade 1. Letrozole was interrupted from Study Day 91 to 118. By Study Day 140, AST, ALT, and alkaline phosphatase were grade 1 and total bilirubin was normal, and on Study Day 252, AST and ALT were resolved, total bilirubin was normal, and alkaline phosphatase remained grade 1. These results remained the same through Study Day 1000. No biopsies, viral serologies, or autoimmune testing was reported. The Investigator, Applicant, and FDA all agree DILI was due to ribociclib, and this case satisfied clinical criteria for Hy’s Law. 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability The Applicant’s Position: Patient-reported outcomes have been discussed in Section 8.1.2. The FDA’s Assessment: Refer to the section discussing patient-reported outcomes in Section 8.1.2. 8.2.7 Safety Analyses by Demographic Subgroups The Applicant’s Position: The comprehensive discussion of intrinsic factors by demographic characteristics (sex and menopausal status, age and age categories, race and race categories, ethnicity, American Joint Committee on Cancer (AJCC) Anatomic Stage groups) and by special populations (baseline hepatic function, baseline renal function) in Study O12301C is described based on the primary iDFS analysis data cut-off. No clinically relevant differences were observed by group for TEAEs, AESI groupings, and/or on-treatment deaths, except for the following intrinsic factors: Adverse events by sex and menopausal status No trends in TEAEs by SOC were observed by menopausal status. When considering male patients, overall trends in TEAE data were no different; albeit the number of male patients was few. In the ribociclib + ET group, events belonging to the Renal toxicity AESI were numerically lower in premenopausal women (2.8%), compared with postmenopausal women (7.9%). This pattern was also observed in the ET only group (0.8% and 2.9%, respectively). Of note, there were fewer premenopausal women (0.2%) who presented AKI, compared with postmenopausal women (0.4%). This pattern was observed in the ET only group (0 vs. 0.2%, respectively). No other trends in AESI by menopausal status were observed. For male patients only, no trends in AESI groupings by sex were observed. However, as the number of male patients was low, i.e. 19 patients, these data should be interpreted with caution. No male patient presented AKI. In the ribociclib + ET group, on-treatment deaths were 0.5% in 144 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. premenopausal women, compared with 0.7% in postmenopausal women. This pattern was also observed in the ET only group (0.2% and 0.5%, respectively). There was 1 premenopausal woman (0.1%) who died due to COVID-19 pneumonia, compared with 5 postmenopausal women with COVID-19 events. This pattern was not observed in the ET only group. There was 1 on-treatment death due to AE (road traffic accident) in male patients (ribociclib + ET: 10.0%) [SCS Study O12301C-Section 5]. Adverse events by age In general, no trends in TEAEs as SOCs by age, i.e., younger than 45 years, ≥ 45 years to 54 years, ≥ 55 years to 64 years vs. the older subgroup, were observed. When assessing these data as the elderly subgroup, blood and lymphatic system disorders SOC was more frequent overall and in the ribociclib + ET group (57.1% and 11.1%, respectively), compared with patients younger than 75 years (47.0% and 8.5%). No trends in TEAEs by SOC were observed when patients were younger than median age vs. median age and older. Of note, median age was 52.0 years of age. No trends in AESI by age, younger than 65 years vs. the older subgroup, were observed. When assessing these data as the elderly subgroup, Anemia AESI was more frequent overall and in the ribociclib + ET group (25.0% and 7.9%, respectively), compared with patients younger than 75 years (7.9% and 2.9%, respectively). In general, overall Renal toxicity AESI was more frequent in elderly patients irrespective of study treatment (12.5% vs. 11.1%), but more frequent in patients younger than 75 years in the ribociclib + ET group (5.6% vs. 1.8%). There was no trend in on-treatment deaths in patients 65 years of age and younger (0.5%), compared with the older subgroup (0.8%). When assessing these data by primary reason for death, there was no trend. There was no on-treatment death in the elderly. On-treatment deaths when primary reason was AE in patients younger than the median age was 0.1% vs. those who were ≥ median age at 0.4%. In the ribociclib + ET group, patients who were younger than the median age had on-treatment deaths due to AE at 0.2% vs. those who were ≥ median age at 0.5%. The most frequent of these belonged to infections and infestations SOC (younger than median age, 0.1%; older than median age, 0.4%) and were COVID-19 events [SCS Study O12301C-Section 5]. Adverse events by race Overall, events related to ET presented less frequently in patients who were Asian (51.8% vs. 57.5%), compared to not Asian (64.2% vs. 62.1%). Several categories of TEAEs presented more frequently in patients who were Asian vs. not Asian. These were grade ≥ 3 AEs, leading to dose reduction, interruption, and those requiring additional therapy (Asian: 76.5%, 29.7%, 86.2%, 85.0%, respectively; not Asian: 60.3%, 18.7%, 70.3%, 74.5%, respectively) in the ribociclib + ET group. However, this trend was not observed in the ET only group (Asian: 13.7%, NA, 5.1%, 70.3%, respectively; Not Asian: 18.5%, NA, 7.5%, 63.0%, respectively). Trends were observed of less frequent TEAEs of several SOCs (blood and lymphatic system disorders; general disorders and administration site conditions; hepatobiliary disorders; 145 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. musculoskeletal and connective tissue disorders; reproductive system and breast disorders; vascular disorders) in Asian patients (27.1%, 42.1%, 1.8%, 48.8%, 6.2%, 19.7%), compared to not Asian (49.5%, 53.0%, 5.2%, 60.0%, 13.8%, 32.5%) in the ribociclib + ET group. However, this trend was only observed when events belonging to the blood and lymphatic system disorders; and general disorders and administration site conditions in patients in the ET only group (Asian: 2.9%, 23.0%, respectively; not Asian: 9.5%, 36.1%, respectively). Conversely, there were more frequent TEAEs within 1 SOC (investigations) in Asian patients (all grades, 82.4%; grade-3, 48.8%; grade-4, 2.9%), compared to combining patients into the category of not Asian (all grades: 61.2%; grade-3, 19.3%; grade-4, 2.1%) in the ribociclib + ET group. The trend was not observed when events belonged to investigations in the ET only group (Asian: all grades, 34.8%; grade-3, 1.9%; grade-4, 0.3% and not Asian: all grades, 30.4%; grade- 3, 2.4%; grade-4, 0.3%) [SCS Study O12301C-Section 5]. Overall, events in the Neutropenia AESI were more frequent in Asian patients (79.1% vs. 6.4%) and predominantly decreased neutrophil count, compared to not Asian (59.4% vs. 4.3%). Events belonging to the Reproductive toxicity AESI were only mastitis (0.6% vs. 0.3%) in Asian patients. This pattern was not observed in patients not Asian. For some races, the number of patients was low and data should be interpreted with caution. When patients were American Indian or Alaskan native (n=7), Infections AESI was highest (100% vs. 66.7%): 5 of these 7 patients had COVID-19, grade 1 / 2. Similarly in Black or African American patients (n=84), events in the Infections AESI (48.8% vs. 23.3%) were most frequently COVID-19 (14.6% vs. 9.3%). In general, trends in on-treatment deaths by race were not observed. There was no on- treatment death due to AE in American Indian or Alaskan native or Asian patients. There was no on-treatment death due to AE in Black or African American patients. All remaining on-treatment deaths due to AE were White patients (overall: 0.4%; 0.5% vs. 0.2%). The primary reason for all on-treatment deaths in Asian patients (overall: 0.5%) was disease recurrence (0.3% vs. 0.6%). Conversely, on-treatment deaths due to disease recurrence included not Asian patients (overall: 0.2%), but also were due to AE (overall: 0.3%) irrespective of treatment group (0.5% vs. 0.2%) [SCS Study O12301C-Section 5]. Adverse events by ethnicity Events in the skin and subcutaneous tissues disorders SOC were more frequent in patients with unknown ethnicity (43.9%), compared with the other 2 ethnic categories (Hispanic/Latino: 28.0%; non-Hispanic/non-Latino: 36.4%) in the ribociclib + ET group. However, this pattern was not observed in the ET only group (15.2%, 18.9%, 25.0%, respectively). No other trends by ethnicity were observed. No trends in AESI by ethnicity were observed. There was 1 patient (0.2%) with on-treatment death (disease recurrence) whose ethnicity was Hispanic/Latino. In non-Hispanic/non-Latino patients, on-treatment deaths due to AE (0.5% vs. 0.2%) were generally comparable to on-treatment deaths due to disease recurrence (0.3% vs. 0.2%). There was 0 on-treatment deaths in patients of unknown ethnicity [SCS Study O12301C-Section 5] [SCS Study O12301C-Section 5]. The FDA’s Assessment: 149 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. after the last dose of ribociclib, letrozole, and goserelin. On , an ultrasound T2 scan was normal. There were no infections during the pregnancy. Neonate delivery date was . The known safety information is as of (MfCtrNo NVSC2022FR246991). As part of current good pharmacovigilance practices (GVP), Novartis performs due diligence as follow-up and will continue to collect additional information on the neonate case [SCS Study O12301-Section 5.3] The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment. The Applicant’s proposed indication includes pre- and perimenopausal females. Because ribociclib is to be co- administered with an AI, and AIs are not efficacious in the setting of functioning ovaries, all females who are not in confirmed menopause require concurrent ovarian suppression, which is clinician-administered in a health care setting. The USPI reflects this, and the need for concurrent ovarian suppression is well-known to US oncologists, thus the rate of pregnancy is expected to be low; however, clinicians should emphasize that adequate contraception is required with ribociclib use for those of childbearing potential. The risk of fetal harm to humans exposed to ribociclib in pregnancy is poorly characterized. Pediatrics and Assessment of Effects on Growth The Applicant’s Position: Refer to Section 10. The FDA’s Assessment: The NATALEE trial was limited to adults age ≥18 and thus provides no new information regarding pediatrics and assessment of effects on growth. The status of agreed iPSP is summarized in Section 10. Overdose, Drug Abuse Potential, Withdrawal, and Rebound The Applicant’s Position: Overdose: No new information about overdose has been generated in support of this dossier; recommendations are described in the approved prescribing information. In Study O12301C, a grade-3 SAE of overdose was reported in 1 patient (< 0.1%) who received ribociclib + ET. This elderly patient took 3 tablets of ribociclib daily from Day 1 to Day 21, which was 600 mg instead of 400 mg, as per protocol. Concomitant AE at the time was grade 1 tremor. The last dose of 600 mg was taken on Day 21 and then 1 week off drug (second cycle was delayed due to the neutropenia). Ribociclib was interrupted on Day 28 to Day 34 due to grade 3 neutropenia (onset: Day 13). The patient recovered on Day 34 and 400 mg ribociclib dosing was restarted the next day. The patient was re-educated on the proper dosing regimen. (b) (6) (b) (6) (b) (6) 150 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Drug abuse: No new information about abuse/dependence potential has been generated in support of this dossier. There is no known potential for abuse of ribociclib and no abuse studies have been performed. Withdrawal and rebound: No new information about withdrawal and rebound has been generated in support of this dossier. No studies have been conducted to assess withdrawal and rebound effects. Based on the product profile, no withdrawal effect is expected [SCS Study O12301C-Section 5.4 to 5.6]. The FDA’s Assessment: FDA concurs that the current submission provides limited information regarding “overdose” and no new information regarding withdrawal or rebound. The review team noted that 245 (10%) of patients on the ribociclib + ET arm had a protocol deviation related to dosing. In NATALEE, a protocol deviation related to dosing was defined as any of the following: a participant did not adhere or exceeded the prescribed daily dose of ribociclib for >3 days, or exceeded the planned duration of ribociclib for >3 days, or received a single dose of ribociclib ≥900 mg, or had an off- period of <7 days in a cycle. The most common dosing protocol deviation was exceeding the planned duration of ribociclib. The mean number of extra days on ribociclib was 2.7 days. In response to an information request from the Agency, the Applicant submitted an analysis demonstrating that the incidence and severity of AEs in participants with dosing-related protocol deviations were similar to that in the overall safety population. In particular, the incidence of grade ≥3 AEs (62.4% vs 62.6%, respectively) and the incidence of AESIs were not significantly increased. The Applicant was queried about the reasons for the frequency of observed dosing-related protocol deviations on the NATALEE trial, to determine whether the USPI should be modified to provide clearer instructions on dosing in the postmarket setting. Per the Applicant, on study, dosing instructions was provided to all participants, and all were issued a medication diary to be completed for each visit by both the patient and study site staff. Patients were instructed to return the diary as well as unused medication at each visit for assessment of compliance by study staff. A drug accountability log was maintained and reviewed by the trial monitor at site visits and study completion. There was no systematic capture of details regarding the reasons for dosing-related protocol deviations, and thus the reason for the dosing errors remains uncertain. It is possible that these errors will be more common in the postmarket setting where medication diaries are seldom used, and compliance is rarely formally assessed. Given that the drug is usually dispensed monthly in clinical practice, however, the harm of likely potential dosing errors by the patient is expected to be limited. The highest dose of ribociclib to which a patient is reported to have been exposed in NATALEE was 600 mg/day, which was an error on the patient’s part, and was corrected back to the prescribed dose of 400 mg/day. As 600 mg/day is the approved dose in combination with ET in the metastatic setting, this does not provide any new information regarding “overdose.” 151 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. The lower dose of ribociclib (400 mg/day) used in the NATALEE trial and being approved in the adjuvant setting provides a margin of safety to patients with early breast cancer who may inadvertently exceed the intended adjuvant daily dose or number of days of treatment per cycle. 8.2.10 Safety in the Postmarket Setting Safety Concerns Identified Through Postmarket Experience The Applicant’s Position: Routine signal detection activities included regular review by qualified medical personnel of worldwide literature searches, frequency analyses in external and internal safety databases, registries containing safety data, blinded review of safety data reported from ongoing clinical studies, as well as postmarketing reports in the Novartis Safety Database. Cumulatively, since the time of the first marketing authorization approval of Kisqali in 2017, the established comprehensive safety monitoring identified 2 new safety signals (Interstitial Lung Disease/Pneumonitis and Toxic Epidermal Necrolysis) that eventually were added as postmarketing ADRs in the Kisqali prescribing information with appropriate communication within the Warning and precaution section. Considering the implemented risk minimization measures, there was no impact on the individual and the benefit-risk assessment of ribociclib. With the estimated cumulative exposure of approximately PTY (Kisqali PSUR 13 Mar 2022 to 12 Mar 2023-Section 5.2), the evaluation and detailed analysis of the known ribociclib- associated safety concerns in Kisqali PSURs did not reveal any evidence of increased reporting rates or increased severity of the AEs supporting the adequacy of established risk minimization activities in the currently approved indication. As demonstrated in Kisqali PSUR (Kisqali PSUR 13 Mar 2022 to 12 Mar 2023), based on the cumulative review of available safety data from all sources, the benefit-risk assessment remained favorable and unchanged [SCS Study O12301C- Section 6]. The FDA’s Assessment: FDA generally agrees with the Applicant’s assessment of safety based upon the postmarket experience. The updated USPI accurately characterizes the risks of ribociclib, and the benefit-risk assessment remains favorable for the intended use population. The safety of ribociclib will continue to be monitored in the postmarket setting. Given the safety signal for ILD identified in the postmarket use of ribociclib in the metastatic setting, there was concern for an increased risk of ILD in the adjuvant setting where most patients with stage II/III breast cancer will receive adjuvant radiotherapy to the breast/chest wall and/or regional lymph nodes. FDA therefore analyzed interstitial lung disease (ILD) in the NATALEE trial as a grouped term (consisting of PT terms of interstitial lung disease, pulmonary fibrosis, pneumonitis, and radiation pneumonitis). There were 30 (1.2%) patients who received ribociclib + ET with an ILD AE compared to 18 (0.7%) of those receiving ET only. All cases were grade 1 or 2 except for one patient (b) (4) 152 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. (<0.1%) in the ET only group with grade 3 ILD. Therefore, while there was a 0.5% increase in risk of all-grade ILD with ribociclib in NATALEE, the risk is low overall, and cases do not appear to be more severe with ribociclib use. Although FDA’s analysis of rash as a grouped term identified an increased incidence with ribociclib + ET compared to ET only (13% vs 5%), most of these were grade 1/2. Grade ≥3 rash was rare and equal (0.2%) in both arms. There were no cases of toxic epidermal necrolysis reported with ribociclib in the NATALEE trial. Expectations on Safety in the Postmarket Setting The Applicant’s Position: Overall frequency and severity of AEs, especially dose dependent toxicities, is less in Study O12301C compared with data at the 600 mg dose in the aBC setting. The safety follow-up in Study O12301C in terms of patient-years of exposure was 6904.3 patient-years for the ribociclib + ET group vs. 6487.3 patient-years for the ET only group, or an additional 1018.4 patient-years since IA3. These data show that the level of safety follow-up completed in the study thus far is adequate to detect any signals that are related to the safety profile of ribociclib, including those that are not dose-dependent and/or rare events, and is unlikely to change substantially with longer follow-up. Furthermore, the long-term safety of ribociclib is well established based on treatment in the advanced/metastatic BC population (1065 patients exposed to ribociclib in the pool of the three pivotal trials in aBC, with an estimated exposure of 2081 PTY [Study A2301 SCS Add.-Table 1- 8]) and a higher starting dose of ribociclib (600 mg), with results showing no change to the safety profile of the drug over time compared with the primary analyses. As of 12-Mar-2023, 10,289 subjects/patients have received ribociclib in clinical trials, and the cumulative post- authorization patient exposure since the first launch of ribociclib is estimated to be approximately PTY. Evaluation of the cumulative safety data from clinical trials and post-marketing sources did not reveal any new safety signal related to the long-term use of ribociclib. With longer follow-up and more patients completing ribociclib treatment in the eBC setting, no new safety signals were identified and overall, the safety profile remains unchanged, indicating stability of safety findings [CO Study O12301-Section 6.3.1]. Therefore, the safety in patients with eBC is not expected to significantly change in post-marketing setting. The FDA’s Assessment: FDA disagrees with the Applicant’s statement that “the safety in patients with eBC is not expected to significantly change in post-marketing setting.” Granting an indication in early breast cancer results in both a marked increase in the number of patients eligible to receive treatment, as well as a heightened scrutiny and level of concern for AEs given that many patients, even those at high risk, may be cured by existing local and systemic adjuvant therapy. In addition, despite modernized eligibility criteria, clinical trials enroll a population with more favorable performance status and fewer comorbidities/concomitant medications compared to the general population. We therefore cannot conclude that the (b) (4) 153 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. safety in patients with eBC will not change in the postmarket setting when a much larger and more diverse group of patients will be exposed to ribociclib. The Applicant and the FDA will continue to monitor safety in the postmarket setting and update the USPI as needed. As noted, there was an increased risk for overall and severe COVID-19 in patients who received ribociclib, although this risk diminished over the course of the study. This will also continue to be monitored in the postmarket setting. 8.2.11 Integrated Assessment of Safety Data: Table 32: Summary of deaths and adverse event categories in Study O12301C (Safety set) Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET [N=2525] ET only [N=2442] Category All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All deaths1 83 (3.3) NA NA NA 89 (3.6) NA NA NA On-treatment deaths2 20 (0.8) NA NA NA 9 (0.4) NA NA NA AEs 2474 (98.0) 1463 (57.9) 133 (5.3) 11 (0.4) 2145 (87.8) 425 (17.4) 40 (1.6) 4 (0.2) Suspected to be drug- related 2368 (93.8) 1284 (50.9) 101 (4.0) 1 (< 0.1) 1566 (64.1) 97 (4.0) 6 (0.2) 0 SAEs 357 (14.1) 252 (10.0) 44 (1.7) 11 (0.4) 256 (10.5) 192 (7.9) 26 (1.1) 4 (0.2) Suspected to be drug- related 68 (2.7) 39 (1.5) 17 (0.7) 1 (< 0.1) 13 (0.5) 9 (0.4) 0 0 AEs leading to discontinuation 524 (20.8) 201 (8.0) 36 (1.4) 2 (0.1) 134 (5.5) 38 (1.6) 5 (0.2) 3 (0.1) Suspected to be drug- related 435 (17.2) 165 (6.5) 26 (1.0) 0 94 (3.8) 18 (0.7) 0 0 AEs requiring dose interruption 1858 (73.6) 1226 (48.6) 87 (3.4) 0 199 (8.1) 67 (2.7) 8 (0.3) 0 Suspected to be drug- related 1635 (64.8) 1156 (45.8) 70 (2.8) 0 99 (4.1) 27 (1.1) 3 (0.1) 0 AEs requiring dose adjustment 586 (23.2) 338 (13.4) 36 (1.4) 0 NA NA NA NA Suspected to be drug- related 561 (22.2) 330 (13.1) 36 (1.4) 0 NA NA NA NA AEs requiring additional therapy 1962 (77.7) 499 (19.8) 61 (2.4) 2 (0.1) 1627 (66.6) 297 (12.2) 28 (1.1) 1 (< 0.1) Suspected to be drug- related 1225 (48.5) 240 (9.5) 32 (1.3) 0 696 (28.5) 58 (2.4) 3 (0.1) 0 AEs of special interest 2183 (86.5) 1291 (51.1) 114 (4.5) 7 (0.3) 1179 (48.3) 168 (6.9) 15 (0.6) 2 (0.1) 154 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Final iDFS analysis: 21-Jul-2023 data cut-off Ribociclib + ET [N=2525] ET only [N=2442] Category All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) All grades n (%) Grade 3 n (%) Grade 4 n (%) Grade 5 n (%) Suspected to be drug- related 1886 (74.7) 1188 (47.0) 100 (4.0) 0 203 (8.3) 17 (0.7) 2 (0.1) 0 1 All deaths including those not considered on-treatment deaths. Includes deaths with cause other than AE. Deaths due to disease progression or other are listed in the All Grades column. 2 On treatment deaths are defined as occurring on or after treatment start date and up to 30 days after 36 months of treatment or earlier treatment discontinuation. Includes deaths with cause other than AE. Deaths due to disease progression or other are listed in the All Grades co lumn. Suspected to be drug related refers to any component of study treatment. Additional therapy includes all non- drug therapy and concomitant medications. Discontinuation refers to discontinuation of any treatment component. n=number of patients. Patients are counted once per category at worst toxicity grade in the main category rows, and once per category per toxicity in the related rows. Source: SCS Add. Study O12301-Table 2-1 The Applicant’s Position: A predictable and manageable safety profile was observed with ribociclib in the eBC setting at the 400 mg starting dose in combination with standard of care NSAI/AI. No new safety signals or safety concerns were identified based on the thorough review of the safety data from Study O12301C. Ribociclib-related AEs are well characterized and are readily identifiable with routine laboratory work or physical examination, are manageable with appropriate intervention (standard medical care and/or through the use of ribociclib dose reduction, temporary treatment interruption or permanent discontinuation), and are generally reversible upon treatment adjustment. The majority of ribociclib discontinuations due to AEs occurred early on in the course of treatment, indicating that if patients tolerate the first few months of treatment, they are likely to tolerate for the duration of the treatment. With the lower starting dose of ribociclib at 400 mg, a lower overall incidence and severity of toxicities was observed compared with that observed at 600 mg in the aBC setting; this is specifically relevant for dose-dependent toxicities including QT interval prolongation and neutropenia. On-treatment death was reported for 20 patients (0.8%) in the ribociclib + ET group vs. 9 patients (0.4%) in the ET only group within 36 months of treatment plus 30 days of safety follow-up. The main causes of on-treatment deaths in the ribociclib + ET group and ET only group, respectively, were disease recurrence/progression: 9 patients (0.4%) vs. 4 patients (0.2%); and deaths due to COVID-19: 6 patients (0.2%) vs. 1 patient (< 0.1%). Of the 20 total patients who died in the ribociclib + ET group, 8 died within the defined on-treatment period, but >30 days after ending treatment with ribociclib [CO Study O12301-Section 5.7]. Key safety topics Neutropenia, hepatobiliary toxicity, and QT interval prolongation are known safety concerns that continue to be considered as important identified risks for ribociclib. All appear to be 155 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. manageable with appropriate monitoring, and reversible upon recommended dose modification guidance for ribociclib. Although these remain important identified risks for ribociclib, the frequency and severity of neutropenia and QT prolongation events and severity of hepatobiliary toxicity events is lower with ribociclib 400 mg in the eBC setting compared with ribociclib 600 mg in the aBC setting. The data at the final iDFS analysis support previous observations that these events happen early on treatment with ribociclib and their incidence does not increase over time. Neutropenia Neutropenia was the most common AE leading to study treatment dose adjustment or dose interruption in the ribociclib + ET group (reported for 12.6% and 42.8% of patients based on the AESI pooled event category). However, neutropenia AESIs leading to discontinuation were infrequent (1.3%; 32 patients) in the ribociclib + ET group. Neutropenia events were generally observed early over the course of treatment with ribociclib, with a median time of 1.0 month to first occurrence of grade ≥3 neutropenia and estimated median duration of grade ≥ 3 neutropenia (that recovered to grade ≤ 2) of 0.3 months in the ribociclib + ET group. The incidence of grade ≥ 3 neutropenia in Study O12301C (based on the AESI pooled event category) was 43.8% in the ribociclib + ET group (vs. 0.8% in the ET only group). Although there was a high incidence of grade ≥ 3 neutropenia, it did not translate into a clinically significant increase in risk of severe infections in patients treated with ribociclib. Febrile neutropenia events were reported uncommonly, with only two patients discontinuing study treatment due to febrile neutropenia; there were no fatal neutropenia events in either group. As expected, due to the concentration-dependent effect of ribociclib on ANC level, the incidence of grade ≥3 neutropenia in Study O12301C (43.8%; AESI grouping) with ribociclib 400 mg is lower than the incidence of grade 3/4 neutropenia (62.5%; AESI grouping) for pooled data from Studies A2301, E2301 (NSAI/AI subgroup), and F2301 in advanced/metastatic breast cancer with ribociclib 600 mg. Management guidelines for neutropenia remain the same as in the approved label for patients with aBC. QTc interval prolongation Based on the totality of data, the overall low incidence and types of QT interval prolongation AESI, the change from baseline in QTcF interval, and notable ECG values had a limited impact on patients in Study O12301C. In Study O12301C, the risk difference between the ribociclib + ET and ET only groups for QT prolongation (AESI) grade ≥3 events was 0.5% (95% CI: 0.0, 0.9). Electrocardiogram QT prolongation events (PT) occurred predominantly within the initial 2 cycles of treatment with ribociclib with the majority events detected around the middle of the first cycle, when the drug is expected to reach its steady state. Of note, no first occurrences of notable QTcF values (> 480 ms) were observed at the beginning of the second cycle of treatment after the scheduled 7-day washout period. No associated cardiac signs or symptoms were 156 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. observed at the time of QT prolongation events. Overall, events within the QT prolongation AESI were uncommon and with limited clinical impact rarely requiring dose adjustment, interruption, or discontinuation (0.1%; 0.8%; 0.2% respectively) in the ribociclib + ET group. As expected with the lower starting dose of ribociclib 400 mg in combination with ET in patients with eBC in Study O12301C, less overall incidence of QT prolongation events and considerably lower incidence of notable ECG values were observed compared to that with ribociclib 600 mg in aBC (pooled dataset). As a result of the evaluation of the safety data related to the QT interval prolongation, Novartis is proposing to update the ribociclib label in regard to ECG monitoring recommendations for patients with eBC. As described above, ECG prolongation events were of low incidence (1.0% grade ≥ 3 QT ECG prolonged AESI; 0.4% QT interval > 480 ms) without associated cardiac signs or symptoms in ribociclib + ET group. The mean QTcF change (ΔQTcF) from baseline was 9.5 ms at Cycle 1 Day 15 2 hours postdose, which corresponds to steady-state ribociclib concentration. The mean change from baseline was 0.5 ms at Cycle 2 Day 1 predose ECG, which corresponds to the lowest ribociclib concentration, as expected, following the 7 days off dose based on the 3-weeks on/1-week off dosing schedule [QT/QTc Safety Analysis Report Study O12301C]. In view of these data from Study O12301C, Novartis proposes ECG monitoring for patients with eBC at baseline before initiating treatment, and approximately Cycle 1 Day 14 (steady-state ribociclib concentration), with additional ECGs as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended. Other risk mitigation measures for QT prolongation including dose modification guidance, baseline threshold of QTcF <450 ms, monitoring of electrolytes, and assessment of relevant medical history and concomitant medications are included in the proposed label. Hepatobiliary toxicity Hepatobiliary AESIs, which tended to occur early on treatment, were manageable with protocol dose management guidance specific for hepatotoxicity, and reversible upon ribociclib dose modifications. The majority of Hepatobiliary AESI were increased ALT/AST, which were one of the most common grade ≥ 3 AEs in Study O12301C, and the most common reason for treatment discontinuation due to AE. Hepatobiliary toxicity (primarily LFT increases) has been reported during treatment with ribociclib, predominantly within the initial 3 months of treatment, and should be closely monitored. There was an 8.3% incidence of grade ≥3 Hepatobiliary toxicity AESIs in the ribociclib pus ET group, and with dose interruptions reported in 12.0% of patients, and adjustments reported in 2.5%. A total of 225 patients (8.9%) discontinued treatment due to these events in the ribociclib + ET group. The risk difference between the ribociclib + ET and ET only groups for grade ≥3 AESIs was 6.8% (95% CI: 5.6, 7.9). Within Hepatobiliary toxicity AESI, DILI was reported for 9 patients (0.4%) and of these, 5 were grade ≥ 3. Of these 8 patients’ events resolved as of DCO. There were 8 clinically confirmed 157 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Hy’s Law cases, including 4 of the 9 patients with DILI. All 8 patients were in the ribociclib + ET treatment group (n=2524). Importantly, most (6 out of 8 patients) completely recovered after discontinuation of ribociclib, and two patients were recovering as of the DCO. Of note, there were fewer grade ≥ 3 hepatobiliary toxicity AESIs for Study O12301C compared with the pooled dataset in the aBC setting at 600 mg [CO Study O12301-Section 6.3.1]. Hepatobiliary toxicity has been reported during treatment with ribociclib and therefore, should be closely monitored. Management guidelines remain the same as in the approved label for patients with aBC. Subpopulations No additional safety concerns were raised; subgroup analyses typically demonstrated patterns of events consistent with those reported for the overall population. The FDA’s Assessment: FDA generally agrees with the Applicant’s Integrated Assessment of Safety. Many ribociclib AEs are known to be concentration-dependent, and the lower dose of ribociclib used in NATALEE (400 mg/day) compared with that approved in the metastatic setting (600 mg/day) generally resulted in decreased incidence and severity of AEs in the adjuvant setting, including AESIs. Addition of ribociclib to ET nonetheless resulted in increased toxicity, including high-grade toxicity, compared to ET alone. Patients receiving ribociclib were more likely to experience a grade ≥3 AE (63.6% vs 19.2%) and more likely to experience a grade ≥3 SAE (12.1% vs 9.2%). On-treatment deaths, defined as deaths while on or within 30 days of the last dose of ribociclib, were uncommon and evenly divided between disease progressions/recurrences and AEs. While deaths during the on-treatment period were increased in the ribociclib + ET group (n=20, 0.8%) compared to those who received ET only (n=9, 0.4%) with COVID- 19/COVID-19 pneumonia the most common causes of on-treatment death, deaths overall on study were numerically lower in the ribociclib + ET group. This reflects a decrease in deaths due to disease recurrence, as well as due to COVID-19, over time. As of the 90-day safety update, 4.1% of patients on the ET only arm had died compared to 3.6% on the ET + ribociclib arm. The OS HR was <1. There were no additional on-treatment deaths reported at the 90-day safety update. Despite the lower dose of 400 mg/day used in this adjuvant trial, toxicity-related treatment interruptions were much more common in patients on ribociclib + ET (73.8% vs 8.1% on ET only), most often due to laboratory abnormalities, and nearly one-quarter of patients (23.8%) required ribociclib dose reduction to 200 mg/day. While many AEs were successfully managed with a combination of treatment interruptions and dose reductions, patients on ribociclib were also more likely to discontinue due to an AE (20.8% vs 5.5%), with nearly one in five patients ultimately discontinuing the CDK 4/6 inhibitor due to a laboratory abnormality or AE. 159 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. ribociclib has been adequately controlled to be below the recommended limit for all indications. At the time of the 90-day safety update, there were no additional on-treatment deaths or new safety signals identified, the HR for OS remained < 1, and the incidence of AESIs was almost identical to that at the time of the final iDFS analysis. Based on the available safety data, the benefits of ribociclib in iDFS in this population of patients with high-risk Stage II and III HR-positive, HER2-negative early breast cancer outweigh the risks identified in the NATALEE trial. These benefits should not be extrapolated to the broader US population of patients with early-stage HR+, HER- breast cancer, most of whom are at considerably lower risk than patients enrolled to NATALEE. Clinical trials also represent idealized conditions and exclude many patients with comorbid conditions. Therefore, it will be important to continue to monitor this product in adjuvant use in the postmarket setting where safety may differ. 160 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 8.3 Statistical Issues The FDA’s Assessment: There were no major statistical issues with this application. The NATALEE trial met its primary objective of INV-assessed iDFS, showing a statistically significant improvement in iDFS with the treatment of ribociclib + ET compared to ET at IA3. However, at IA3, there was a large amount of censoring for iDFS as only 20% of patients had completed 3 years of adjuvant ribociclib. Thus, there was a concern for a potentially diminishing iDFS effect with longer follow-up, therefore FDA requested that the Applicant continue NATALEE until the final iDFS analysis. At the final iDFS analysis (DCO: July 21, 2023), 43% of patients had completed 3 years of adjuvant ribociclib. The iDFS hazard ratio was 0.75 (95% CI: 0.63, 0.89) which was consistent with the results at IA3. The final iDFS results were also consistent across various sensitivity analyses and exploratory subgroup analyses. The study was not designed to formally test any secondary endpoints including OS. At the time of final iDFS analysis, the number of deaths observed was less than what was originally projected. Overall, results of OS at the time of final iDFS and at the 90-day safety update support that there appears to be no detriment in OS at this time. A PMC will be issued for the applicant to provide all additional overall survival analyses as prespecified in the protocol and SAP, including OS at the time of end of trial. 8.4 Conclusions and Recommendations The FDA’s Assessment: Overall the benefit/risk is favorable for ribociclib for the adjuvant treatment of adults with high-risk, stage II and III HR+, HER2-negative breast cancer, based on the results of the NATALEE trial. At the final analysis of iDFS, addition of ribociclib to ET resulted in a 25% relative risk reduction, corresponding to a 3.1% absolute improvement in iDFS. This represents a number needed to treat of 32 to prevent one iDFS event. This magnitude of improvement is considered clinically meaningful as all recurrences result in morbidity, and distant metastatic disease is presently incurable. The majority of deaths, as well as recurrences, due to HR-positive, HER2-negative breast cancer occur in years 5 and beyond. The number of deaths on study was fortunately much lower than projected on both arms, and OS remains immature at this time, but the point estimate for the OS HR is <1. While patients with both high-risk stage II and III disease were adequately represented in the study to support the indication, only 12% of patients had node-negative tumors. In FDA’s analysis, patients with N0 disease had an iDFS HR that was comparable to that of the overall ITT population, and therefore these patients were included in the indication. Importantly, the patients in the NATALEE trial represented a considerably higher risk group than the average US population of adults with HR-positive, HER2-negative breast cancer; <10% had grade 1 tumors, 87% had received prior (neo-)adjuvant chemotherapy, and 88% had N1-N3 disease. The results of the NATALEE trial should therefore not be 161 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. extrapolated to the broader US population of patients with HR-positive, HER2-negative breast cancer, most of whom are at much lower risk of recurrence. The AE profile was similar to that observed in prior trials in the metastatic setting, but the incidence and severity of most AEs was lower, likely due to the lower dose of ribociclib used in the adjuvant setting, as well as a healthier adjuvant population. Neutropenia, hepatotoxicity, and QT prolongation remain the most important identified AESIs with ribociclib. With appropriate monitoring and timely treatment interruption, as well as dose reduction or drug discontinuation for those patients who require it based upon treatment modification guidelines used in the NATALEE trial and reflected in the agreed upon USPI, these risks can be sufficiently mitigated. There was an increased incidence and severity of COVID-19 infections noted in patients receiving ribociclib, including an increased incidence of on-treatment death due to COVID- 19, with deaths confined almost entirely to patients with no prior documented vaccination. The severity of COVID-19 infections appears to have fallen over time; there were no deaths due to COVID-19 reported after early 2022, which likely represents an increasing level of population immunity due to vaccines and prior infections, as well as availability of COVID- 19 therapeutics. This safety signal will continue to be monitored in the postmarket setting. The overall determination of risk-benefit is favorable and supports regular approval. 8.4.1 Approach to Substantial Evidence of Effectiveness 1. Verbatim indication: 209092: KISQALI is indicated in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 209935: KISQALI FEMARA Co-Pack is indicated for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 2. SEE was established with a. Adequate and well-controlled clinical investigation(s): i. ☐ Two or more adequate and well-controlled clinical investigations, OR ii. ☐ One adequate and well-controlled clinical investigation with highly persuasive results that is considered to be the scientific equivalent of two clinical investigations OR b. ☒ One adequate and well-controlled clinical investigation and confirmatory evidence1,2,3 OR 163 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 9 Advisory Committee Meeting and Other External Consultations The FDA’s Assessment: Not applicable. 164 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 10 Pediatrics The Applicant’s Position: Novartis submitted an iPSP waiver for pediatric studies in eBC to IND 117796 on October 12, 2023, [SN 0974] and a revised version on November 10, 2023. The Agency provided email confirmation on November 17, 2023 that the November 10, 2023 submission of the iPSP waivers for early breast cancer are considered agreed iPSPs. The FDA’s Assessment: FDA agrees with the Applicant’s position. 171 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 12 Risk Evaluation and Mitigation Strategies (REMS) The FDA’s Assessment: Not applicable. 173 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 33: FDA – PMC/PMR Checklist for Trial Diversity and U.S. Population Representativeness The following were evaluated and considered as part of FDA’s review: Is a PMC/PMR needed? x The patients enrolled in the clinical trial are representative of the racial, ethnic, and age diversity of the U.S. population for the proposed indication. _x_ Yes __ No x Does the FDA review indicate uncertainties in the safety and/or efficacy findings by demographic factors (e.g. race, ethnicity, sex, age, etc.) to warrant further investigation as part of a PMR/PMC? __ Yes _x_ No x Other considerations (e.g.: PK/PD), if applicable: __ Yes _x_ No L 179 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 19 Appendices 19.1 References The Applicant’s References: [Arimidex USPI (2018)] Arimidex (anastrozole) 1 mg tablet - US Prescribing Information (USPI). ANI Pharmaceuticals, Inc. Last updated 13-Dec-2018. [Aromasin USPI (2021)] Aromasin (exemestane) 25 mg tablet - US Prescribing Information (USPI). Pharmacia & Upjohn Company LLC, New York, NY, USA. Last updated November 2021. [Bria E, Carlini P, Cuppone F, et al (2010)] Early recurrence risk: aromatase inhibitors versus tamoxifen. Expert Rev Anticancer Ther; 10(8):1239-53. [Clarke M, Collins R, Darby S, et al (2005)] Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet; 365(9472):1687-717. [Eggemann H, Ignatov A, Smith BJ, et al (2013)] Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Res Treat; 137(2):465- 70. [Femara USPI 2020] Femara (letrozole) 2.5 mg tablets - US Prescribing Information (USPI). Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. Last updated May 2020. [GLOBOCAN (2020)] World Health Organization. International Agency for Research on Cancer. Breast cancer fact sheet. (Online) Accessed 15-Nov-2022. [Gomis RR, Gawrzak S (2017)] Tumor cell dormancy. Mol Oncol; 11(1):62-78. [Kisqali USPI (2022)] Kisqali (ribociclib) tablets, for oral use. US Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Revised 10/2022. [Kisqali SmPC (2023)] Kisqali 200 mg film-coated tablets. Summary of product characteristics. Novartis Europharm Limited, Dublin, Ireland. Updated 31-Mar-2023. [Lynparza USPI (2023)] Lynparza ( olaparib) 100/150 mg tablets - US Prescribing Information (USPI). AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA. Last updated November 2023. [National Comprehensive Cancer Network (2019)] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Breast Cancer Risk Reduction. Version 1.2019-December 11, 2018. [Pan H, Gray R, Braybrooke J, et al (2017)] 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med; 377(19)1836-46. 181 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Investigator Study No. Cente r No. Amount Disclosed Category of Disclosure Dr 2301C >$25,000 Research Grant Dr 2301C >$25,000 Honorarium Dr 2301C >$25,000 Research Grant Dr 2301C >$25,000 Honorarium Dr 2301C $28,820 Speaker Grant Dr 2301C >$50,000 Equity Ownership Dr 2301C >$50,000 Equity Ownership Dr 2301C $40,000 Support on electronic platform development Dr 2301C $50,000 Project Support Any bias resulting from these arrangements is minimized by independent data monitoring by Novartis and CRO (TRIO) and multiple investigators used in the study. Covered Clinical Study (Name and/or Number):* CLEE011O12301C Was a list of clinical investigators provided: Yes No (Request list from Applicant) Total number of investigators identified: 4538 Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0 Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 17 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0 Significant payments of other sorts: 15 Proprietary interest in the product tested held by investigator: 0 Significant equity interest held by investigator in study: 2 Sponsor of covered study: 0 Is an attachment provided with details of the disclosable financial interests/arrangements: Yes No (Request details from Applicant) Is a description of the steps taken to minimize potential bias provided: Yes No (Request information from Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) NA Is an attachment provided with the reason: Yes No (Request explanation from Applicant) The table above should be filled by the applicant, and confirmed/edited by the FDA. The FDA’s Assessment: The financial disclosure information was reviewed with no concerns identified. 19.3 Nonclinical Pharmacology/Toxicology The Applicant’s Position: No new information is provided in the current submission. The FDA’s Assessment: (b) (6) (b) (6) 187 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Covariate Category N BW# <50kg 8 50-60kg 24 60-70kg 34 70-80kg 26 80-90kg 19 >=90kg 12 Menopausal status Premenopausal women and men 42 Postmenopausal women 81 Anatomic stage group Stage group II 68 Stage group III 55 #: Subjects with missing records were excluded from the summary. Source: [SCP Study O12301C-Table 6-1] Table 36: Summary of steady-state ribociclib PK parameters across populations and studies Stud y Popul ation Riboci clib Dose (mg) Dose regimen Cmax (ng/m L) geo- mean (Geo- CV% ) Tmax (hr) media n (min, max) AUC0- 24h (ng∙hr/ mL) geo- mean (Geo- CV%) Ctrou gh (ng/m L) geo- mean (Geo- CV%) CL/Fss (L/hr) (Geo- CV%) PopPK simulated data[a] Updat ed O123 01C popP K model eBC 400 Multiple doses (C1D15) with NSAI 952 (39.5) 3.79 (24.4) 10388 (41.0) 263 (52.8) 38.4 (95%CI: 35.5 – 41.9) Data are presented as geometric mean (CV% geo mean) for all parameters except for Tmax which is presented as median (range). Formulation of ribociclib used in the studies was capsule unless specified. [a] population PK parameters are presented as population mean (95%CI) Source: [SCP Study O12301C-Table 3-2] Table 37: Simulated C1D1 and steady-state ribociclib PK parameters at the dose of 400 mg QD in HR-positive, HER2-negative eBC patients in Study O12301C 188 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Statistic C1D1 Steady-state Ctrough (Cmin) (ng/mL) Geometric mean (CV%) 108 (50.7) 263 (52.8) Arithmetic mean (90% CI) 121 (115, 128) 297 (281, 313) 5th percentile (90% CI) 48.9 (48.9, 48.9) 118 (118, 118) 95th percentile (90% CI) 227 (227, 227) 583 (583. 583) Cmax (ng/mL) Geometric mean (CV%) 671 (51.9) 952 (39.5) Arithmetic mean (90% CI) 751 (705, 796) 1023 (974, 1073) 5th percentile (90% CI) 298 (298, 298) 514 (514, 514) 95th percentile (90% CI) 1423 (1423, 1423) 1767 (1767, 1767) AUC0-24 (hr∙ng/mL) Geometric mean (CV%) 5296 (39.5) 10388 (41.0) Arithmetic mean (90% CI) 5691 (5429, 5953) 11224 (10706, 11724) 5th percentile (90% CI) 2863 (2863, 2863) 5510 (5510, 5510) 95th percentile (90% CI) 9752 (9752, 9752) 19702 (19702, 19702) Tmax (hr) Geometric mean (CV%) 3.79 (24.4) 3.79 (24.4) Arithmetic mean (90% CI) 3.90 (3.77, 4.04) 3.90 (3.77, 4.04) 5th percentile (90% CI) 2.57 (2.57, 2.57) 2.57 (2.57, 2.57) 95th percentile (90% CI) 5.71 (5.71, 5.71) 5.71 (5.71, 5.71) Source: [SCP Study O12301C-Table 2-2] 189 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Figure 5: Prediction-corrected visual predictive check (VPC) of the updated popPK model compared with observed PK concentrations in Study O12301C Dots represent the observed concentrations in the PK-iDFS dataset. Upper and lower borders of the blue area represent the 90% CI of the 5th and 95th percentiles of the simulations, while the red area represents the 90% CI of the median. Similarly, the upper and lower dashed line represent the 5th and 95th percentile of the observations, while the solid line represents the median of the observations. Source: [SCP Study O12301C-Figure 6-2] The FDA’s Assessment: The Applicant’s population PK analysis is acceptable. Overall, the final population PK model is adequate to characterize the PK profile of ribociclib in patients with early breast cancer as indicated in the Applicant’s diagnostic plots. The FDA reviewer repeated and verified the Applicant’s analysis with no significant discordance identified. The proposed labeling statements related to PK parameters in Section 12.3 are acceptable. 200 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. baseline QTcF) + combination + population + combination log(concentration/median concentration + 1). Horizontal dotted lines are the reference lines at 30 ms and 60 ms. Source: SCP Study O12301C Appendix 1-Figure 3-1.2 The FDA’s Assessment: The Applicant’s E-R analyses for ribociclib and neutropenia are considered acceptable for the purpose of exploring the relationship between ribociclib exposure and neutropenia in patients with early breast cancer. 19.4.2.5 ER Review Issues The FDA’s Assessment: No substantive issue. 19.4.2.6 Reviewer’s Independent Analysis The FDA’s Assessment: Reviewer’s independent analysis was not performed. 19.4.2.7 Overall benefit-risk evaluation based on E-R analyses The Applicant’s Position: Efficacy in patients with eBC was demonstrated by the statistically significant improvement of both the primary endpoint of iDFS and the secondary endpoints of RFS and DDFS. Due to limited sample size of patients with iDFS events, exposure-efficacy relationship cannot be characterized. The PK-QT modeling confirmed the exposure-QTcF relationship in eBC patients, and patient population is a significant covariate where eBC patients showed less QTcF response than aBC patients. In Study O12301C, the ribociclib Ctrough values of eBC patients with vs. without Grade ≥ 3 neutropenia largely overlap with no apparent difference, which might be due to limited sample size and variability of Ctrough. Both neutropenia and QTcF prolongation, the adverse events related to ribociclib PK exposure, are lower in eBC patients in Study O12301C at the dose of 400 mg than in aBC patients at the dose of 600 mg, supporting improved tolerability of 400 mg dose in eBC patients Collectively, the exposure response analyses and the safety and efficacy result of NATALEE support the use of ribociclib 400 mg in combination with ET (letrozole or anastrozole) in patients with HR-positive, HER2-negative eBC [CO Study O12301-Section 3.2 and 3.3]. The FDA’s Assessment: Refer to other clinical pharmacology sections of the Assessment Aid for the FDA review. 19.4.3 Physiologically based Pharmacokinetic Modeling Review The FDA’s Assessment: 205 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Source: PBPK Report DMPK R2300859, Table 6-1. Data analysis: For DDI predictions, the AUC and Cmax ratios were defined as the geometric mean and 90% confidence interval (CI). Prediction error (PE) was calculated as PE = (predicted value -observed value)/observed value × 100. 3. Results 3.1 Predictive performance of ribociclib PBPK model for DDI in healthy subjects Using the updated ribociclib PBPK model and the “adapted healthy volunteer” population model, the predicted DDI effect of ribociclib, as a CYP3A perpetrator and CYP3A victim agreed with the observed data in healthy subjects. The DDI effect of the strong CYP3A4 inhibitor ritonavir and the strong CYP3A inducer rifampicin on the PK of ribociclib was reasonably described (PE <±35%). Furthermore, the ribociclib model recovered the interaction effect of ribociclib, as a strong inhibitor of CYP3A4, on the PK of the CYP3A substrate midazolam (PE<±12%) (Table 40). 210 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. HV 600 SD 61.1 (44.4) 16 A2117 HV 600 SD 49.8 (60) 24 A2111(DiC, fasting) HV 600 SD 42 (32.3) 23 A2111(Tablet, fasting) HV 600 SD 67.1 (51.4) 24 A2101 HV 600 SD 61.1 (44.4) 16 A2117 Late cancer3 400 QD 35.3 (59.2) 4 X2101 Metastatic breast cancer 400 QD 24.4 (51.8) 17 A2207 Late cancer3 600 QD 25.5 (65.7) 53 X2101 Metastatic breast cancer 600 QD 21.0 (50.0) 13 A2207 Late cancer3 600 QD 26.5 (53.2) 20 X2107 Early breast cancer 400 QD Population PK Early breast cancer 600 QD Population PK (M3/7 model) Metastatic breast cancer 600 QD Population PK (M3/7 model) %CV, percent coefficient of variance; CP, cancer population; DiC: drug in capsule; HV, healthy volunteer; N, number of subjects; QD, once a day; SD, single dose 1 The PBPK simulated trials consisted of 10 trials of 10 subjects (n=100) with an age range of 20-55 years, and 100% female. The population model used was the “adapted healthy volunteer (HV)” or “metastatic breast cancer patient (CP)” population model. 2 CL/F value calculated by dose (400 mg) divided by geometric mean AUC0-24h 400 mg QD (10600 ng.h/mL, A2106-Table 11-13). 3 “Late cancer” refers to patients with advanced solid tumor or lymphomas. Source: Reviewer modified from Table 6-2 of PBPK Report DMPK R2300859. The Reviewer did not consider the proposed “metastatic breast cancer patient” population model sufficiently justified based on the following reasons: • Currently, there is no consensus on the clinical effect of cancer on CYP3A abundance. The default cancer population model (Simcyp V22) assumes no alterations on CYP3A abundance in patients with cancer compared to healthy subjects, based on analysis of literature data by the software’s developer (data not shown). Additionally, research from Cheeti et al. (2013) suggested that CYP3A activity is not altered in patients with cancer based on PBPK modeling of midazolam exposure. This finding is supported by Baker et al. (2004), which examined CYP3A activity in 134 patients with cancer and found no significant changes related to age, sex, or body size. In contrast, CYP3A downregulation has been reported in patients with cancer during an acute inflammatory response (Coutant et al., 2015). This alteration (30% reduction in hepatic and intestinal CYP3A4 abundance) has been investigated in a PBPK study demonstrating a better prediction of exposure to sensitive CYP3A4 substrates (midazolam and simvastatin) in patients with cancer (Schwenger et al., 2018). (b) (4) 212 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. 3.3 Model Application: Prediction of the effect of CYP3A modulators on the PK of ribociclib PBPK simulations were conducted to predict the DDI effect of moderate (erythromycin) and strong CYP3A inhibitors (ritonavir) and moderate (efavirenz) and strong CYP3A inducers (rifampicin) on the PK of ribociclib in early and metastatic breast cancer patients (Table 43 and Table 44). A slightly dose and time-dependent (i.e., single dose vs steady state) interaction effect on the PK of ribociclib was predicted with CYP3A inhibitors due to autoinhibition effect of ribociclib on CYP3A4. Following administration of the strong CYP3A4 inhibitor ritonavir (100 mg BID, for 14 days) with a single dose of 400 mg ribociclib, the model predicted similar increase in ribociclib exposure (predicted AUCinf and Cmax ratios of 3.1- and 1.4-fold, respectively) as observed in the clinical DDI study in healthy subjects (observed AUCinf and Cmax ratios of 3.2 and 1.7, respectively). Administering ribociclib 400 mg QD for 8 days in the presence of ritonavir, a lower DDI effect was predicted with AUCtau and Cmax ratios of 1.84 and 1.47, respectively. The predicted Cmax and AUCtau of ribociclib in presence of ritonavir was 1322 ng/mL and 19401 ng.h/mL. Following administration of ribociclib 200 mg QD in the presence of ritonavir, a slightly higher DDI effect compared to ribociclib 400 mg QD was predicted due to less autoinhibition of CYP3A4. The predicted AUCtau and Cmax ratios are 2.51 and 1.76, respectively. Consequently, the predicted ribociclib exposure at 200 mg QD in the presence of ritonavir (AUCtau=9695 ng.h/mL) was comparable to the predicted exposure at 400 mg QD without inhibitor (AUCtau=10523 ng.h/mL) (Table 43). Also, the predicted exposure of ribociclib at 400 mg QD dose in presence of ritonavir (AUCtau and Cmax of 19401 ng.h/mL and 1322 ng/mL, respectively) is lower than its reported exposure at the 600 mg QD dose (standard dose for metastatic breast cancer therapy) in patients with late cancer (AUCtau and Cmax of 23800 ng.h/mL and 1820 ng/mL, Study X2101). Therefore, for patients with early breast cancer, a dose reduction from 400 mg QD to 200 mg QD in the presence of a strong CYP3A inhibitor is justified. Administering ribociclib 600 mg QD for 8 days in the presence of ritonavir, the predicted AUCtau and Cmax ratios were 1.56 and 1.33, respectively (Table 43). The predicted ribociclib exposure at 400 mg QD in the presence of ritonavir (AUCtau=19401 ng.h/mL) was comparable to the predicted exposure at 600 mg QD without inhibitor (AUCtau=18696 ng.h/mL). Therefore, for patients with metastatic breast cancer, a dose reduction from 600 mg QD to 400 mg QD in the presence of a strong CYP3A inhibitor is justified and in agreement with conclusions from the original submission (FDA Multidiscipline Review Ribociclib, 2017). No clinically meaningful interaction was predicted with the coadministration of the moderate CYP3A4 inhibitor erythromycin (500 mg BID, for 8 days) with ribociclib 400 mg QD (predicted AUCtau and Cmax ratios of 1.23 and 1.13, respectively) and ribociclib 600 mg QD (predicted AUCtau and Cmax ratios of 1.13 and 1.08, respectively) (Table 43). 213 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Table 43: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inhibitors Source: Table 6-6 of PBPK Report. Following administration of the strong CYP3A4 inducer rifampin (600 mg QD, for 13 days) with a single 600 mg dose of ribociclib, the model predicted a comparable decrease in ribociclib AUCinf (77%) as observed in the clinical DDI study in healthy subjects (decrease in AUCinf by 89%). A similar decrease in ribociclib AUCtau (around 83-80%) was predicted following administration of ribociclib 400 mg QD or 600 mg QD at steady state (Table 44). Therefore, concomitant use of ribociclib with strong CYP3A4 inducers should be avoided. Following administration of the moderate CYP3A4 inducer efavirenz (600 mg BID, for 14 days) with ribociclib 400 mg QD or 600 mg QD dose, a moderate interaction effect was predicted. The predicted decreases in AUCtau and Cmax of ribociclib were 74% and 55%, respectively, for 400 mg QD and 71% and 52%, respectively, for 600 mg QD. These 214 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. decrease in ribociclib exposure in the presence of efavirenz was comparable to the predictions for a single 400 mg or 600 mg dose of ribociclib (AUCinf decreased by 69%. Table 44: PBPK predicted AUC and Cmax of ribociclib in the absence and presence of CYP3A4 inducers Source: Table 6-7 of PBPK Report. 4. Conclusions A previously developed ribociclib PBPK model was updated in a newer version of the modeling software (Simcyp version V22) and used to support the revised labeling regarding DDI effects (USPI section 12.3). The Applicant proposed updating the DDI results with moderate CYP3A modulators using the updated PBPK model of ribociclib and their modified versions of the healthy volunteer (‘adapted healthy volunteer’) and cancer (‘metastatic breast cancer patient’) population models. The reviewer identified limitations in the ‘metastatic breast cancer patient’ population model and concluded that it was 215 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. inadequate to be used to support the proposed labeling edits. Consequently, predictions using the updated ribociclib model and the ‘adapted healthy volunteer’ population model were used in the USPI section 12.3. PBPK analyses were adequate to predict the interaction effect of a strong CYP3A inhibitor (ritonavir) and a moderate CYP3A inhibitor (erythromycin) on ribociclib exposure at steady state. The model predicted that coadministration of ritonavir may increase ribociclib AUCtau by 1.8-fold and 1.6-fold, respectively, for 400 mg QD and 600 mg QD doses of ribociclib, respectively. Coadministration of erythromycin is not expected to meaningfully change ribociclib exposure. PBPK analyses were adequate to predict the interaction effect of a moderate CYP3A inducer (efavirenz) on ribociclib exposure at steady state. The model predicted that coadministration of efavirenz may decrease ribociclib AUCtau by around 70% for 400 mg QD and 600 mg QD doses. 5. References Baker SD, van Schaik RHN, Rivory LP, et al (2004). Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res. 10: 8341-8350. Cheeti S, Budha NR, Rajan S, et al. (2013). A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer. Biopharm Drug Dispos. 34: 141-154. Coutant DE, Kulanthaivel P, Turner PK, et al. (2015). Understanding Disease-Drug Interactions in Cancer Patients: Implications for Dosing within the Therapeutic Window. Clin Pharmacol Ther. 98: 76-78. Cubitt HE, Yeo KR, Howgate EM, et al (2011). Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model. Xenobiotica. 41:623-638. FDA Multi-discipline Review and Evaluation NDA 209092. KISQALI (ribociclib). 2017. Accessed at: https://www.accessdata.fda.gov/drugsatfda docs/nda/2017/209092orig1s000multidiscipline r.pdf KISQALI (ribociclib) 200 mg tablets, for oral use. US Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Revised 10/2022. 216 Version date: August 2023 Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Samant TS, Huth F, Umehara K, et al (2020). Ribociclib Drug-Drug Interactions: Clinical Evaluations and Physiologically-Based Pharmacokinetic Modeling to Guide Drug Labeling. Clin Pharm Ther. 108: 575-585. Schwenger E, Reddy VP, Moorthy G, et al (2018). Harnessing meta-analysis to refine an oncology patient population for physiology-based pharmacokinetic modeling of drugs. Clin Pharmacol Ther. 103:271-280. 19.5 Additional Safety Analyses Conducted by FDA The FDA’s Assessment: Not applicable.	custom-source	2025-02-12T15:46:47.277655	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/209092s018,209935s027MultidisciplineR.pdf', 'application_number': 209935, 'submission_type': 'SUPPL ', 'submission_number': 27}
80,228	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use STELARA® safely and effectively. See full prescribing information for STELARA®. STELARA® (ustekinumab) injection, for subcutaneous or intravenous use Initial U.S. Approval: 2009 -----------------------------INDICATIONS AND USAGE-------------------------- STELARA® is a human interleukin-12 and -23 antagonist indicated for the treatment of: Adult patients with: • moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. (1.1) • active psoriatic arthritis (PsA). (1.2) • moderately to severely active Crohn’s disease (CD). (1.3) • moderately to severely active ulcerative colitis. (1.4) Pediatric patients 6 years and older with: • moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy. (1.1) • active psoriatic arthritis (PsA). (1.2) ------------------------DOSAGE AND ADMINISTRATION---------------------- Psoriasis Adult Subcutaneous Recommended Dosage (2.1): Weight Range (kilograms) Dose less than or equal to 100 kg 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks greater than 100 kg 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended Dosage (2.1): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg greater than 100 kg 90 mg Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2): • The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks. • For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks. Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co 90 mg existent moderate-to-severe plaque psoriasis Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage (2.3): A single intravenous infusion using weight- based dosing: Weight Range (kilograms) Recommended Dosage up to 55 kg 260 mg (2 vials) greater than 55 kg to 85 kg 390 mg (3 vials) greater than 85 kg 520 mg (4 vials) Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Subcutaneous Injection (3) • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe • Injection: 45 mg/0.5 mL solution in a single-dose vial Intravenous Infusion (3) • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial (3) -----------------------------CONTRAINDICATIONS-------------------------------- Clinically significant hypersensitivity to ustekinumab or to any of the excipients in STELARA®. (4) -------------------------WARNINGS AND PRECAUTIONS--------------------- • Infections: Serious infections have occurred. Avoid starting STELARA® during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue STELARA® until the infection resolves. (5.1) • Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL 12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. (5.2) • Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with STELARA®. Initiate treatment of latent TB before administering STELARA®. (5.3) • Malignancies: STELARA® may increase risk of malignancy. The safety of STELARA® in patients with a history of or a known malignancy has not been evaluated. (5.4) • Hypersensitivity Reactions: If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®. (5.5) • Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly, and discontinue STELARA®. (5.6) • Immunizations: Avoid use of live vaccines in patients during treatment with STELARA®. (5.7) • Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. If diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment. (5.8) ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions are: • Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) • Crohn’s Disease, induction (≥3%): vomiting. (6.1) • Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) • Ulcerative colitis, induction (≥3%): nasopharyngitis (6.1) • Ulcerative colitis, maintenance (≥3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA 1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5479362 1 1.1 Plaque 1.2 1.3 1.4 2.1 Recommended Dosage in Plaque Psoriasis 2.2 Recommended Dosage in 2.3 Recommended Dosage in 2.4 2.5 2.6 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 6.1 6.2 6.3 7.1 7.2 7.3 8.1 8.2 8.4 8.5 12.1 12.2 12.3 13.1 13.2 14.1 Adult Plaque 14.2 14.3 14.4 14.5 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE Immunogenicity Psoriasis (PsO) Postmarketing Experience Psoriatic Arthritis (PsA) 7 DRUG INTERACTIONS Crohn’s Disease (CD) Concomitant Therapies Ulcerative Colitis CYP450 Substrates 2 DOSAGE AND ADMINISTRATION Allergen Immunotherapy 8 USE IN SPECIFIC POPULATIONS Psoriatic Arthritis Pregnancy Crohn’s Disease and Lactation Ulcerative Colitis Pediatric Use General Considerations for Administration Geriatric Use Instructions for Administration of STELARA® 10 OVERDOSAGE Prefilled Syringes Equipped with Needle Safety 11 DESCRIPTION Guard 12 CLINICAL PHARMACOLOGY Preparation and Administration of STELARA® Mechanism of Action 130 mg/26 mL (5 mg/mL) Vial for Intravenous Pharmacodynamics Infusion (Crohn’s Disease and Ulcerative Colitis) Pharmacokinetics 3 DOSAGE FORMS AND STRENGTHS 13 NONCLINICAL TOXICOLOGY 4 CONTRAINDICATIONS Carcinogenesis, Mutagenesis, Impairment of 5 WARNINGS AND PRECAUTIONS Fertility Infections Animal Toxicology and/or Pharmacology Theoretical Risk for Vulnerability to Particular 14 CLINICAL STUDIES Infections Psoriasis Pre-treatment Evaluation for Tuberculosis Pediatric Plaque Psoriasis Malignancies Psoriatic Arthritis Hypersensitivity Reactions Crohn’s Disease Posterior Reversible Encephalopathy Syndrome Ulcerative Colitis (PRES) 15 REFERENCES Immunizations 16 HOW SUPPLIED/STORAGE AND HANDLING Noninfectious Pneumonia 17 PATIENT COUNSELING INFORMATION 6 ADVERSE REACTIONS Clinical Trials Experience Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5479362 2 1.1 1.2 1.3 1.4 2.1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Plaque Psoriasis (PsO) STELARA® is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Psoriatic Arthritis (PsA) STELARA® is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis. Crohn’s Disease (CD) STELARA® is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease. Ulcerative Colitis STELARA® is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis. 2 DOSAGE AND ADMINISTRATION Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage Regimen • For patients weighing 100 kg or less, the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. • For patients weighing more than 100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies (14)]. Subcutaneous Pediatric Dosage Regimen Administer STELARA® subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of STELARA® for pediatric patients (6-17 years old) with plaque psoriasis based on body weight is shown below (Table 1). Reference ID: 5479362 3 Table 1: Recommended Dose of STELARA® for Subcutaneous Injection in Pediatric Patients (6 17 years old) with Plaque Psoriasis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg more than 100 kg 90 mg For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the single-dose vial. Table 2: Injection volumes of STELARA® 45 mg/0.5 mL single-dose vials for pediatric patients (6 17 years old) with plaque psoriasis and pediatric patients (6-17 years old) with psoriatic arthritis weighing less than 60 kg Body Weight (kg) at the time of dosing Dose (mg) Volume of injection (mL) 15 11.3 0.12 16 12.0 0.13 17 12.8 0.14 18 13.5 0.15 19 14.3 0.16 20 15.0 0.17 21 15.8 0.17 22 16.5 0.18 23 17.3 0.19 24 18.0 0.20 25 18.8 0.21 26 19.5 0.22 27 20.3 0.22 28 21.0 0.23 29 21.8 0.24 30 22.5 0.25 31 23.3 0.26 32 24 0.27 33 24.8 0.27 34 25.5 0.28 35 26.3 0.29 36 27 0.3 37 27.8 0.31 38 28.5 0.32 39 29.3 0.32 40 30 0.33 41 30.8 0.34 42 31.5 0.35 43 32.3 0.36 44 33 0.37 45 33.8 0.37 46 34.5 0.38 47 35.3 0.39 48 36 0.4 49 36.8 0.41 50 37.5 0.42 51 38.3 0.42 52 39 0.43 53 39.8 0.44 54 40.5 0.45 Reference ID: 5479362 4 2.2 2.3 55 41.3 0.46 56 42 0.46 57 42.8 0.47 58 43.5 0.48 59 44.3 0.49 * Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen. Recommended Dosage in Psoriatic Arthritis Subcutaneous Adult Dosage Regimen • The recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. • For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. Subcutaneous Pediatric Dosage Regimen Administer STELARA® subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of STELARA® for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body weight, is shown below (Table 3). Table 3: Recommended Dose of STELARA® for Subcutaneous Injection in Pediatric Patients (6 to 17 years old) with Psoriatic Arthritis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg* 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co-existent moderate-to-severe 90 mg plaque psoriasis * For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the single-dose vial. Recommended Dosage in Crohn’s Disease and Ulcerative Colitis Intravenous Induction Adult Dosage Regimen A single intravenous infusion dose of STELARA® using the weight-based dosage regimen specified in Table 4 [see Instructions for dilution of STELARA® 130 mg vial for intravenous infusion (2.6)]. Table 4: Initial Intravenous Dosage of STELARA® Body Weight of Patient at the time of Number of 130 mg/26 mL dosing Dose (5 mg/mL) STELARA® vials 55 kg or less 260 mg 2 more than 55 kg to 85 kg 390 mg 3 more than 85 kg 520 mg 4 Reference ID: 5479362 5 2.4 2.5 Subcutaneous Maintenance Adult Dosage Regimen The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. General Considerations for Administration • STELARA® is intended for use under the guidance and supervision of a healthcare provider. STELARA® should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient’s current weight at the time of dosing. In pediatric patients, it is recommended that STELARA® be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject STELARA® after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Medication Guide [see Medication Guide]. • The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to latex. • It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended. • Prior to administration, visually inspect STELARA® for particulate matter and discoloration. STELARA® is a colorless to light yellow solution and may contain a few small translucent or white particles. Do not use STELARA® if it is discolored or cloudy, or if other particulate matter is present. STELARA® does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. Instructions for Administration of STELARA® Prefilled Syringes Equipped with Needle Safety Guard Refer to the diagram below for the provided instructions. Reference ID: 5479362 6 PLUNGER NEEDLE GUARD BODY VIEWING PLUNGER HEAD ACTIVATION CLIPS WINDOW ! fl * NEE,DLE GUARD WINGS LABEL NEEDLE NEEDLE COVER To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use. • Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place. • Inject STELARA® subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)]. • Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard. • After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty Reference ID: 5479362 7 ~ · .____,-,a~ , , -~~· ' J ?': ..... __ _ ,, 1/ • ?7") 1- --~ -,~ ,10 . ___ .,.,/ 2.6 syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below: • Used syringes should be placed in a puncture-resistant container. Preparation and Administration of STELARA® 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colitis) STELARA® solution for intravenous infusion must be diluted, prepared, and infused by a healthcare professional using aseptic technique. 1. Calculate the dose and the number of STELARA® vials needed based on patient weight (Table 4). Each 26 mL vial of STELARA® contains 130 mg of ustekinumab. 2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of STELARA® to be added (discard 26 mL sodium chloride for each vial of STELARA® needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used. 3. Withdraw 26 mL of STELARA® from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix. 4. Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed. 5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag. 6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer). 7. Do not infuse STELARA® concomitantly in the same intravenous line with other agents. 8. STELARA® does not contain preservatives. Each vial is for a single-dose only. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements. Reference ID: 5479362 8 5.1 Storage If necessary, the diluted infusion solution may be kept at room temperature up to 25°C (77°F) for up to 7 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period). Do not freeze. Discard any unused portion of the infusion solution. 3 DOSAGE FORMS AND STRENGTHS STELARA® (ustekinumab) is a colorless to light yellow solution and may contain a few small translucent or white particles. Subcutaneous Injection • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe • Injection: 45 mg/0.5 mL solution in a single-dose vial Intravenous Infusion • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial 4 CONTRAINDICATIONS STELARA® is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients in STELARA® [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS Infections STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving STELARA® [see Adverse Reactions (6.1, 6.3)]. Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included the following: • Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. • Psoriatic arthritis: cholecystitis. • Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis. • Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Avoid initiating treatment with STELARA® in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of Reference ID: 5479362 9 5.2 5.3 5.4 5.5 treatment prior to initiating use of STELARA® in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with STELARA® and discontinue STELARA® for serious or clinically significant infections until the infection resolves or is adequately treated. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® may be susceptible to these types of infections. Consider appropriate diagnostic testing, (e.g., tissue culture, stool culture, as dictated by clinical circumstances). Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA®. Avoid administering STELARA® to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti-tuberculosis therapy prior to initiation of STELARA® in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving STELARA® for signs and symptoms of active tuberculosis during and after treatment. Malignancies STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA® in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)]. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving STELARA® for the appearance of non- melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1)]. Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with STELARA® [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®. Reference ID: 5479362 10 5.6 5.7 5.8 Posterior Reversible Encephalopathy Syndrome (PRES) Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis, and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab. Monitor all patients treated with STELARA® for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA®. Immunizations Prior to initiating therapy with STELARA®, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with STELARA® should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with STELARA® or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA® because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease. Noninfectious Pneumonia Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment [see Postmarketing Experience (6.3)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: • Infections [see Warnings and Precautions (5.1)] • Malignancies [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)] • Noninfectious Pneumonia [see Warnings and Precautions (5.8)] Reference ID: 5479362 11 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Subjects with Plaque Psoriasis The safety data reflect exposure to STELARA® in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the STELARA® groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)]. Table 5: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the STELARA® groups through Week 12 in Ps STUDY 1 and Ps STUDY 2 STELARA® Placebo 45 mg 90 mg Subjects treated 665 664 666 Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) Headache 23 (3%) 33 (5%) 32 (5%) Fatigue 14 (2%) 18 (3%) 17 (3%) Back pain 8 (1%) 9 (1%) 14 (2%) Dizziness 8 (1%) 8 (1%) 14 (2%) Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) Pruritus 9 (1%) 10 (2%) 9 (1%) Injection site erythema 3 (<1%) 6 (1%) 13 (2%) Myalgia 4 (1%) 7 (1%) 8 (1%) Depression 3 (<1%) 8 (1%) 4 (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions (5.6)]. Infections In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)]. Reference ID: 5479362 12 In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 per hundred subject-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated subjects during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Pediatric Subjects with Plaque Psoriasis The safety of STELARA® was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis. Psoriatic Arthritis The safety of STELARA® was assessed in 927 subjects in two randomized, double-blind, placebo- controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials. Crohn’s Disease The safety of STELARA® was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials. These 1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1 and CD-2 there were 470 subjects who received STELARA® 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), Reference ID: 5479362 13 methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease [see Clinical Studies (14.4)]. The overall safety profile of STELARA® was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 6 and 7, respectively. Table 6: Common adverse reactions through Week 8 in Trials CD-1 and CD-2 occurring in ≥3% of STELARA®-treated subjects and higher than placebo STELARA® 6 mg/kg single intravenous Placebo induction dose N=466 N=470 Vomiting 3% 4% Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%). Table 7: Common adverse reactions through Week 44 in Trial CD-3 occurring in ≥3% of STELARA®-treated subjects and higher than placebo STELARA® 90 mg subcutaneous maintenance dose every Placebo 8 weeks N=133 N=131 Nasopharyngitis 8% 11% Injection site erythema 0 5% Vulvovaginal candidiasis/mycotic infection 1% 5% Bronchitis 3% 5% Pruritus 2% 4% Urinary tract infection 2% 4% Sinusitis 2% 3% Infections In subjects with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one patient each [see Warnings and Precautions (5.1)]. Malignancies With up to one year of treatment in the Crohn’s disease clinical trials, 0.2% of STELARA®-treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non- melanoma skin cancers occurred in 0.2% of STELARA®-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects. Hypersensitivity Reactions Including Anaphylaxis In CD trials, two subjects reported hypersensitivity reactions following STELARA® administration. One patient experienced signs and symptoms consistent with anaphylaxis Reference ID: 5479362 14 6.2 (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of subjects receiving subcutaneous STELARA®). In addition, one subject experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous STELARA® dose (0.08% of subjects receiving intravenous STELARA®). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. Ulcerative Colitis The safety of STELARA® was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of STELARA® in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of STELARA®-treated subjects and at a higher rate than placebo were: • Induction (UC-1): nasopharyngitis (7% vs 4%). • Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%). Infections In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions (5.1)]. Malignancies With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of STELARA®-treated subjects (0.48 events per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non- melanoma skin cancers occurred in 0.5% of STELARA®-treated subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred patient-years). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab in the trials described below with the incidence of antibodies to other products may be misleading. Approximately 6 to 12.4% of subjects treated with STELARA® in plaque psoriasis and psoriatic arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In Reference ID: 5479362 15 6.3 7.1 7.2 plaque psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies. In Crohn’s disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab when treated with STELARA® for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. Postmarketing Experience The following adverse reactions have been reported during post-approval use of STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure. Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria). Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis). Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES). Respiratory, thoracic, and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia. Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis. 7 DRUG INTERACTIONS Concomitant Therapies In plaque psoriasis trials the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s disease and ulcerative colitis induction trials, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®. CYP450 Substrates The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or Reference ID: 5479362 16 7.3 8.1 drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates. A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology (12.3)]. Allergen Immunotherapy STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. 8 USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Limited data from observational studies, published case reports, and postmarketing surveillance on the use of STELARA® during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, STELARA® may be transferred to the developing fetus [see Clinical Considerations]. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD). The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Because ustekinumab may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to STELARA® in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab at birth and the duration of persistence of ustekinumab in infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product. Reference ID: 5479362 17 8.2 8.4 Data Animal Data Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks. In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related- effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age. Lactation Risk Summary Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available data on the effects of ustekinumab on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab are unknown. No adverse effects on the breastfed infant causally related to ustekinumab have been identified in the published literature or postmarketing experience. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for STELARA® and any potential adverse effects on the breastfed child from STELARA® or from the underlying maternal condition. Pediatric Use Plaque Psoriasis The safety and effectiveness of STELARA® have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy. Use of STELARA® in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter, randomized, 60week trial (Ps STUDY 3) that included a 12week, double-blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies (14.2)]. Use of STELARA® in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)]. Reference ID: 5479362 18 8.5 The safety and effectiveness of STELARA® have not been established in pediatric patients less than 6 years of age with plaque psoriasis. Psoriatic Arthritis The safety and effectiveness of STELARA® have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old. Use of STELARA® in these age groups is supported by evidence from adequate and well controlled trials of STELARA® in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects 12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)]. The safety and effectiveness of STELARA® have not been established in pediatric patients less than 6 years old with psoriatic arthritis. Crohn’s Disease and Ulcerative Colitis The safety and effectiveness of STELARA® have not been established in pediatric patients with Crohn’s disease or ulcerative colitis. Geriatric Use Of the 6709 subjects exposed to STELARA®, a total of 340 were 65 years of age or older (183 subjects with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn’s disease, and 34 subjects with ulcerative colitis), and 40 subjects were 75 years of age or older. Clinical trials of STELARA® did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. 10 OVERDOSAGE Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. 11 DESCRIPTION Ustekinumab, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Using DNA recombinant technology, ustekinumab is produced in a murine cell line (Sp2/0). The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons. Reference ID: 5479362 19 12.1 12.2 STELARA® (ustekinumab) injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles with pH of 5.7- 6.3. STELARA® for Subcutaneous Use Available as 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and as 45 mg of ustekinumab in 0.5 mL in a single-dose 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that contains dry natural rubber (a derivative of latex). Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg). Each 1 mL prefilled syringe delivers 90 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg). STELARA® for Intravenous Infusion Available as 130 mg of ustekinumab in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper. Each 26 mL vial delivers 130 mg ustekinumab, EDTA disodium salt dihydrate (0.52 mg), L- histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), L-methionine (10.4 mg), Polysorbate 80 (10.4 mg), and sucrose (2210 mg). 12 CLINICAL PHARMACOLOGY Mechanism of Action Ustekinumab is a human IgG1қ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab, was shown to be protective. Pharmacodynamics Plaque Psoriasis In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with plaque psoriasis. Reference ID: 5479362 20 12.3 Ulcerative Colitis In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached a plateau at the ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment [see Clinical Studies (14.5)]. Pharmacokinetics Absorption In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis. Following multiple subcutaneous doses of STELARA® in adult subjects with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks. Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn’s disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ±SD steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn’s disease, and 3.3 ± 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks. Distribution Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment was 2.7 L (95% CI: 2.69, 2.78) in subjects with Crohn’s disease and 3.0 L (95% CI: 2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady- state was 4.6 L in subjects with Crohn’s disease and 4.4 L in subjects with ulcerative colitis. Elimination The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohn’s disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohn’s disease and ulcerative colitis) populations. Reference ID: 5479362 21 These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn’s disease and ulcerative colitis. Metabolism The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Specific Populations Weight When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group. Age: Geriatric Population A population pharmacokinetic analysis (N=106/1937 subjects with plaque psoriasis greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old. Age: Pediatric Population Following multiple recommended doses of STELARA® in pediatric subjects 6 to 17 years of age with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean ±SD steady-state trough serum ustekinumab concentrations were 0.36 ± 0.26 mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric subjects 6 to 11 years of age and pediatric subjects 12 to 17 years of age. Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration of STELARA®. Drug Interaction Studies The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease [see Drug Interactions (7.2)]. Reference ID: 5479362 22 13.1 13.2 14.1 Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects with psoriatic arthritis. In subjects with Crohn’s disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted by concomitant use of these medications. 13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA®. Published literature showed that administration of murine IL-12 caused an anti- tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV- induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown. No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females. No effects on fertility were observed in female mice that were administered an analogous IL-12/IL 23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy. Animal Toxicology and/or Pharmacology In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection. 14 CLINICAL STUDIES Adult Plaque Psoriasis Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the trials. Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo Reference ID: 5479362 23 at Weeks 0 and 4 crossed over to receive STELARA® (either 45 mg or 90 mg) at Weeks 12 and 16. In both trials, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis. In both trials, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician’s Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician’s overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. Clinical Response The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below. Table 8: Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2 Ps STUDY 1 Ps STUDY 2 STELARA® STELARA® Placebo 45 mg 90 mg Placebo 45 mg 90 mg Subjects randomized 255 255 256 410 409 411 PASI 75 response 8 (3%) 171 (67%) 170 (66%) 15 (4%) 273 (67%) 311 (76%) PGA of Cleared or Minimal 10 (4%) 151 (59%) 156 (61%) 18 (4%) 277 (68%) 300 (73%) Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups. In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 9 below). Table 9: Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2 Ps STUDY 1 Ps STUDY 2 STELARA® STELARA® Placebo 45 mg 90 mg Placebo 45 mg 90 mg Subjects randomized 255 255 256 410 409 411 PASI 75 response * <100 kg 4% 74% 65% 4% 73% 78% 6/166 124/168 107/164 12/290 218/297 225/289 >100 kg 2% 54% 68% 3% 49% 71% 2/89 47/87 63/92 3/120 55/112 86/121 PGA of Cleared or Minimal * <100 kg 4% 64% 63% 5% 74% 75% 7/166 108/168 103/164 14/290 220/297 216/289 Reference ID: 5479362 24 14.2 >100 kg 3% 49% 58% 3% 51% 69% 3/89 43/87 53/92 4/120 57/112 84/121 * Subjects were dosed with trial medication at Weeks 0 and 4. Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re- randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re- randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks. Pediatric Plaque Psoriasis A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17 years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy. Subjects were randomized to receive placebo (n = 37), the recommended dose of STELARA® (n = 36), or one-half the recommended dose of STELARA® (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of STELARA® was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive STELARA® at the recommended dose or one-half the recommended dose. Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics. The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent. Clinical Response The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10. Table 10: Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3 Ps STUDY 3 Placebo STELARA®* n (%) n (%) N 37 36 PGA PGA of cleared (0) or minimal (1) 2 (5.4%) 25 (69.4%) PASI PASI 75 responders 4 (10.8%) 29 (80.6%) PASI 90 responders 2 (5.4%) 22 (61.1%) * Using the weight-based dosage regimen specified in Table 1 and Table 2. Reference ID: 5479362 25 14.3 Psoriatic Arthritis The safety and efficacy of STELARA® was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite nonsteroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the subjects, respectively, had enthesitis and dactylitis at baseline. Subjects were randomized to receive treatment with STELARA® 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of subjects continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24. In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the subjects had been previously treated with TNF blocker, of whom over 70% had discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time. Clinical Response In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70 responses were also higher in the STELARA® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with STELARA® alone or in combination with methotrexate. Responses were similar in subjects regardless of prior TNFα exposure. Table 11: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and PsA STUDY 2 at Week 24 PsA STUDY 1 PsA STUDY 2 STELARA® STELARA® Placebo 45 mg 90 mg Placebo 45 mg 90 mg Number of subjects randomized 206 205 204 104 103 105 ACR 20 response, N (%) 47 (23%) 87 (42%) 101 (50%) 21 (20%) 45 (44%) 46 (44%) ACR 50 response, N (%) 18 (9%) 51 (25%) 57 (28%) 7 (7%) 18 (17%) 24 (23%) ACR 70 response, N (%) 5 (2%) 25 (12%) 29 (14%) 3 (3%) 7 (7%) 9 (9%) Number of subjects with ≥ 3% BSAa 146 145 149 80 80 81 PASI 75 response, N (%) 16 (11%) 83 (57%) 93 (62%) 4 (5%) 41 (51%) 45 (56%) a Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline Reference ID: 5479362 26 60 .= ,...... 40 ~ ~ "' ..... 5 ·z 20 co p.. 0 Weeks• --<r Placebo -(n=206), -a- STELARA ·45 mg·(n=205), - STELARA·90mg·(n=204), The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1. Figure 1: Percent of subjects achieving ACR 20 response through Week 24 PsA STUDY 1 The results of the components of the ACR response criteria are shown in Table 12. Table 12: Mean change from baseline in ACR components at Week 24 PsA STUDY 1 STELARA® Placebo 45 mg 90 mg (N = 206) (N = 205) (N = 204) Number of swollen jointsa Baseline 15 12 13 Mean Change at Week 24 -3 -5 -6 Number of tender jointsb Baseline 25 22 23 Mean Change at Week 24 -4 -8 -9 Subject’s assessment of painc Baseline 6.1 6.2 6.6 Mean Change at Week 24 -0.5 -2.0 -2.6 Subject global assessmentc Baseline 6.1 6.3 6.4 Mean Change at Week 24 -0.5 -2.0 -2.5 Physician global assessmentc Baseline 5.8 5.7 6.1 Mean Change at Week 24 -1.4 -2.6 -3.1 Reference ID: 5479362 27 14.4 Disability index (HAQ)d Baseline 1.2 1.2 1.2 Mean Change at Week 24 -0.1 -0.3 -0.4 CRP (mg/dL)e Baseline 1.6 1.7 1.8 Mean Change at Week 24 0.01 -0.5 -0.8 a Number of swollen joints counted (0-66) b Number of tender joints counted (0-68) c Visual analogue scale; 0= best, 10=worst. d Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. e CRP: (Normal Range 0.0-1.0 mg/dL) An improvement in enthesitis and dactylitis scores was observed in each STELARA® group compared with placebo at Week 24. Physical Function STELARA®-treated subjects showed improvement in physical function compared to subjects treated with placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ DI responders (≥0.3 improvement in HAQ-DI score) was greater in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24. Crohn’s Disease STELARA® was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction trials (CD-1 and CD 2) followed by a 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker. Trials CD-1 and CD-2 In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials, subjects were randomized to receive a single intravenous administration of STELARA® at either approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended). In trial CD-1, subjects had failed or were intolerant to prior treatment with a TNF blocker: 29% subjects had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, Reference ID: 5479362 28 6-MP, MTX). The median baseline CDAI score was 319 in the STELARA® approximately 6 mg/kg group and 313 in the placebo group. In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of subjects). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial, approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the STELARA® and 290 in the placebo group. In these induction trials, a greater proportion of subjects treated with STELARA® (at the recommended dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 13 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in STELARA®-treated subjects and continued to improve through Week 8. Table 13: Induction of Clinical Response and Remission in CD-1* and CD-2** CD-1 CD-2 n = 741 n = 627 Treatment Treatment Placebo STELARA®† difference Placebo STELARA®† difference N = 247 N = 249 and 95% CI N = 209 N = 209 and 95% CI Clinical Response 53 (21%) 84 (34%)a 12% 60 (29%) 116 (56%)b 27% (100 point), Week 6 (4%, 20%) (18%, 36%) Clinical Remission, 18 (7%) 52 (21%)b 14% 41 (20%) 84 (40%)b 21% Week 8 (8%, 20%) (12%, 29%) Clinical Response 50 (20%) 94 (38%)b 18% 67 (32%) 121 (58%)b 26% (100 point), Week 8 (10%, 25%) (17%, 35%) 70 Point Response, 75 (30%) 109 (44%)a 13% 81 (39%) 135 (65%)b 26% Week 6 (5%, 22%) (17%, 35%) 70 Point Response, 67 (27%) 101 (41%)a 13% 66 (32%) 106 (51%)b 19% Week 3 (5%, 22%) (10%, 28%) Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points * Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy ** Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA, MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker. † Infusion dose of STELARA® using the weight-based dosage regimen specified in Table 4. a 0.001≤ p < 0.01 b p < 0.001 Trial CD-3 The maintenance trial (CD-3), evaluated 388 subjects who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 with either induction dose of STELARA® in trials CD-1 or CD-2. Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks or placebo for 44 weeks (see Table 14). Reference ID: 5479362 29 14.5 Table 14: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose) 90 mg STELARA® Treatment Placebo* every 8 weeks difference and N = 131† N = 128† 95% CI Clinical Remission 47 (36%) 68 (53%)a 17% (5%, 29%) Clinical Response 58 (44%) 76 (59%)b 15% (3%, 27%) Clinical Remission in subjects in remission 36/79 (46%) 52/78 (67%)a 21% (6%, 36%) at the start of maintenance therapy** Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission * The placebo group consisted of subjects who were in response to STELARA® and were randomized to receive placebo at the start of maintenance therapy. ** Subjects in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not account for any other time point during maintenance therapy. † Subjects who achieved clinical response to STELARA® at the end of the induction trial. a p < 0.01 b 0.01≤ p < 0.05 At Week 44, 47% of subjects who received STELARA® were corticosteroid-free and in clinical remission, compared to 30% of subjects in the placebo group. At Week 0 of trial CD-3, 34/56 (61%) STELARA®-treated subjects who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) subjects were in clinical remission at Week 0 while 16/61 (26%) of these subjects were in remission at Week 44. At Week 0 of trial CD-3, 46/72 (64%) STELARA®-treated subjects who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week 0 while 31/70 (44%) were in remission at Week 44. In the subset of these subjects who were also naïve to TNF blockers, 34/52 (65%) of STELARA®-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm. Subjects who were not in clinical response 8 weeks after STELARA® induction were not included in the primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg subcutaneous injection of STELARA® upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the trial. Ulcerative Colitis STELARA® was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of 52 weeks of therapy. Reference ID: 5479362 30 Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2. An endoscopy score of 2 was defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline, subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12). Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone). Trial UC-1 In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of STELARA® of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. A total of 51% had failed at least one biologic and 17% had failed both a TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or immunomodulators but were biologic-naïve and an additional 3% had previously received but had not failed a biologic. At induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates. The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo endoscopy subscore of 0 or 1 (Mayo endoscopy subscore of 0 defined as normal or inactive disease and Mayo subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability) is provided in Table 15. The secondary endpoints were clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement. Clinical response with a definition of (≥ 2 points and ≥ 30% decrease in modified Mayo score, defined as 3-component Mayo score without the Physician’s Global Assessment, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1), endoscopic improvement with a definition of Mayo endoscopy subscore of 0 or 1, and histologic-endoscopic mucosal improvement with a definition of combined endoscopic improvement and histologic improvement of the colon tissue [neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue]) are provided in Table 15. In UC-1, a significantly greater proportion of subjects treated with STELARA® (at the recommended dose of approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 15). Table 15: Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1 Endpoint Placebo N = 319 STELARA®† N = 322 Treatment difference and 97.5% CI a Reference ID: 5479362 31 N % N % Clinical Remission* 22 7% 62 19% 12% (7%, 18%) b Bio-naïve⸸ 14/151 9% 36/147 24% Prior biologic failure 7/161 4% 24/166 14% Endoscopic Improvement§ 40 13% 80 25% 12% (6%, 19%) b Bio-naïve⸸ 28/151 19% 43/147 29% Prior biologic failure 11/161 7% 34/166 20% Clinical Response† 99 31% 186 58% 27% (18%, 35%) b Bio-naïve⸸ 55/151 36% 94/147 64% Prior biologic failure 42/161 26% 86/166 52% Histologic-Endoscopic Mucosal Improvement‡ 26 8% 54 17% 9% (3%, 14%) b Bio-naïve⸸ 19/151 13% 30/147 20% Prior biologic failure 6/161 4% 21/166 13% † Infusion dose of STELARA® using the weight-based dosage regimen specified in Table 4. ⸸ An additional 7 subjects on placebo and 9 subjects on STELARA® (6 mg/kg) had been exposed to, but had not failed, biologics. * Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). § Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). † Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. ‡ Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 or 1) and histologic improvement of the colon tissue (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). a Adjusted treatment difference (97.5% CI) b p < 0.001 The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to disease progression and long-term outcomes was not evaluated during UC-1. Rectal Bleeding and Stool Frequency Subscores Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in STELARA®-treated subjects. Trial UC-2 The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following the intravenous administration of either induction dose of STELARA® in UC-1. These subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks. The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included the proportion of subjects maintaining clinical response at Week 44, the proportion of subjects with endoscopic improvement at Week 44, the proportion of subjects with corticosteroid-free clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission 8 weeks after induction. Reference ID: 5479362 32 Results of the primary and secondary endpoints at Week 44 in subjects treated with STELARA® at the recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16. Table 16: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose) Endpoint Placebo* † N = 175 90 mg STELARA® every 8 weeks N = 176 Treatment difference and 95% CI N % N % Clinical Remission** 46 26% 79 45% 19% (9%, 28%) a Bio-naïve⸸ 30/84 36% 39/79 49% Prior biologic failure 16/88 18% 37/91 41% Maintenance of Clinical Response at Week 44† 84 48% 130 74% 26% (16%, 36%) a Bio-naïve⸸ 49/84 58% 62/79 78% Prior biologic failure 35/88 40% 64/91 70% Endoscopic Improvement§ 47 27% 83 47% 20% (11%, 30%) a Bio-naïve⸸ 29/84 35% 42/79 53% Prior biologic failure 18/88 20% 38/91 42% Corticosteroid-free Clinical Remission‡ 45 26% 76 43% 17% a (8%, 27%) Bio-naïve⸸ 30/84 36% 38/79 48% Prior biologic failure 15/88 17% 35/91 38% Maintenance of Clinical Remission at Week 44 in subjects who achieved clinical remission 8 weeks after induction 18/50 36% 27/41 66% 31% (12%, 50%) b Bio-naïve⸸ 12/27 44% 14/20 70% Prior biologic failure 6/23 26% 12/18 67% ⸸ An additional 3 subjects on placebo and 6 subjects on STELARA® had been exposed to, but had not failed, biologics. * The placebo group consisted of subjects who were in response to STELARA® and were randomized to receive placebo at the start of maintenance therapy. ** Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). † Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. § Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). ‡ Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44. a p =<0.001 b p=0.004 Other Endpoints Week 16 Responders to Ustekinumab Induction Subjects who were not in clinical response 8 weeks after induction with STELARA® in UC-1 were not included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive a 90 mg subcutaneous injection of STELARA® at Week 8. Of these subjects, 55/101 Reference ID: 5479362 33 (54%) achieved clinical response eight weeks later (Week 16) and received STELARA® 90 mg subcutaneously every 8 weeks during the UC-2 trial. At Week 44, there were 97/157 (62%) subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission. Histologic-Endoscopic Mucosal Improvement at Week 44 The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2 was 75/172 (44%) among subjects on STELARA® and 40/172 (23%) in subjects on placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2. Endoscopic Normalization Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At Week 8 in UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with STELARA® and 12/319 (4%) of subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects treated with STELARA® and in 32/175 (18%) of subjects in placebo group. 15 REFERENCES 1 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEERStat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973 2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission. 16 HOW SUPPLIED/STORAGE AND HANDLING STELARA® (ustekinumab) injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials. For Subcutaneous Use Prefilled Syringes • 45 mg/0.5 mL (NDC 57894-060-03) • 90 mg/mL (NDC 57894-061-03) Each prefilled syringe is equipped with a 27-gauge fixed ½ inch needle, a needle safety guard, and a needle cover that contains dry natural rubber. Single-dose Vial • 45 mg/0.5 mL (NDC 57894-060-02) Reference ID: 5479362 34 For Intravenous Infusion Single-dose Vial • 130 mg/26 mL (5 mg/mL) (NDC 57894-054-27) Storage and Stability Store STELARA® vials and prefilled syringes refrigerated between 2ºC to 8ºC (36ºF to 46ºF). Store STELARA® vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. If needed, individual prefilled syringes may be stored at room temperature up to 30°C (86°F) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, do not return to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use STELARA® after the expiration date on the carton or on the prefilled syringe. 17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Infections Inform patients that STELARA® may lower the ability of their immune system to fight infections and to contact their healthcare provider immediately if they develop any signs or symptoms of infection [see Warnings and Precautions (5.1)]. Malignancies Inform patients of the risk of developing malignancies while receiving STELARA® [see Warnings and Precautions (5.4)]. Hypersensitivity Reactions • Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue STELARA® [see Warnings and Precautions (5.5)]. • Inform patients the needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex [see Dosage and Administration (2.4)] Posterior Reversible Encephalopathy Syndrome (PRES) Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)]. Reference ID: 5479362 35 Immunizations Inform patients that STELARA® can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.7)]. Administration Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use. Prefilled Syringe Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Baxter Pharmaceutical Solutions, Bloomington, IN 47403 and at Cilag AG, Schaffhausen, Switzerland Vial Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Cilag AG, Schaffhausen, Switzerland © 2012, 2016, 2019 Janssen Pharmaceutical Companies Reference ID: 5479362 36 MEDICATION GUIDE STELARA® (stel ar’ a) (ustekinumab) injection, for subcutaneous or intravenous use What is the most important information I should know about STELARA? STELARA is a medicine that affects your immune system. STELARA can increase your risk of having serious side effects, including: Serious infections. STELARA may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking STELARA, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection. • Your doctor should check you for TB before starting STELARA. • If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with STELARA and during treatment with STELARA. • Your doctor should watch you closely for signs and symptoms of TB while you are being treated with STELARA. You should not start taking STELARA if you have any kind of infection unless your doctor says it is okay. Before starting STELARA, tell your doctor if you: • think you have an infection or have symptoms of an infection such as: o fever, sweat, or chills o warm, red, or painful skin or sores on your body o muscle aches o diarrhea or stomach pain o cough o burning when you urinate or urinate more often than normal o shortness of breath o feel very tired o blood in phlegm o weight loss • are being treated for an infection or have any open cuts. • get a lot of infections or have infections that keep coming back. • have TB, or have been in close contact with someone with TB. After starting STELARA, call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. STELARA can make you more likely to get infections or make an infection that you have worse. People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take STELARA may also be more likely to get these infections. Cancers. STELARA may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving STELARA and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with STELARA, tell your doctor if you develop any new skin growths. Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including: o headache o confusion o seizures o vision problems What is STELARA? STELARA is a prescription medicine used to treat: • adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills). • adults and children 6 years and older with active psoriatic arthritis. • adults 18 years and older with moderately to severely active Crohn’s disease. • adults 18 years and older with moderately to severely active ulcerative colitis. It is not known if STELARA is safe and effective in children less than 6 years of age. Do not take STELARA if you are allergic to ustekinumab or any of the ingredients in STELARA. See the end of this Medication Guide for a complete list of ingredients in STELARA. 1 Reference ID: 5479362 Before you receive STELARA, tell your doctor about all of your medical conditions, including if you: • have any of the conditions or symptoms listed in the section “What is the most important information I should know about STELARA?” • ever had an allergic reaction to STELARA. Ask your doctor if you are not sure. • are allergic to latex. The needle cover on the prefilled syringe contains latex. • have recently received or are scheduled to receive an immunization (vaccine). People who take STELARA should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system, and can cause serious problems. You should not receive the BCG vaccine during the one year before receiving STELARA or one year after you stop receiving STELARA. • have any new or changing lesions within psoriasis areas or on normal skin. • are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with STELARA. STELARA may also increase your risk of having an allergic reaction to an allergy shot. • receive or have received phototherapy for your psoriasis. • are pregnant or plan to become pregnant. It is not known if STELARA can harm your unborn baby. You and your doctor should decide if you will receive STELARA. See “What should I avoid while using STELARA?” • received STELARA while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby. • are breastfeeding or plan to breastfeed. STELARA can pass into your breast milk. • Talk to your doctor about the best way to feed your baby if you receive STELARA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use STELARA? • Use STELARA exactly as your doctor tells you to. • The needle cover on the STELARA prefilled syringe contains latex. Do not handle the needle cover if you are sensitive to latex. • Adults with Crohn’s disease and ulcerative colitis will receive the first dose of STELARA through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive STELARA as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of STELARA, as described below. • Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive STELARA as an injection under the skin (subcutaneous injection) as described below. • Injecting STELARA under your skin o STELARA is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that STELARA be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of STELARA at home, you should receive training on the right way to prepare and inject STELARA. Your doctor will determine the right dose of STELARA for you, the amount for each injection, and how often you should receive it. Do not try to inject STELARA yourself until you or your caregiver have been shown how to inject STELARA by your doctor or nurse. o Inject STELARA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen). o Do not give an injection in an area of the skin that is tender, bruised, red or hard. o Use a different injection site each time you use STELARA. o If you inject more STELARA than prescribed, call your doctor right away. o Be sure to keep all of your scheduled follow-up appointments. Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of STELARA, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the rubber stopper is punctured, STELARA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of STELARA. What should I avoid while using STELARA? You should not receive a live vaccine while taking STELARA. See “Before you receive STELARA, tell your doctor about all of your medical conditions, including if you:” 2 Reference ID: 5479362 What are the possible side effects of STELARA? STELARA may cause serious side effects, including: • See “What is the most important information I should know about STELARA?” • Serious allergic reactions. Serious allergic reactions can occur with STELARA. Stop using STELARA and get medical help right away if you have any of the following symptoms of a serious allergic reaction: o feeling faint o chest tightness o swelling of your face, eyelids, tongue, or throat o skin rash • Lung inflammation. Cases of lung inflammation have happened in some people who receive STELARA, and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during treatment with STELARA. Common side effects of STELARA include: • nasal congestion, sore throat, and runny nose • redness at the injection site • upper respiratory infections • vaginal yeast infections • fever • urinary tract infections • headache • sinus infection • tiredness • bronchitis • itching • diarrhea • nausea and vomiting • stomach pain These are not all of the possible side effects of STELARA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Biotech, Inc. at 1-800 JANSSEN (1-800-526-7736). How should I store STELARA? • Store STELARA vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C). • Store STELARA vials standing up straight. • Store STELARA in the original carton to protect it from light until time to use it. • Do not freeze STELARA. • Do not shake STELARA. If needed, individual STELARA prefilled syringes may also be stored at room temperature up to 30°C (86ºF) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use STELARA after the expiration date on the carton or on the prefilled syringe. Keep STELARA and all medicines out of the reach of children. General information about the safe and effective use of STELARA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use STELARA for a condition for which it was not prescribed. Do not give STELARA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about STELARA that was written for health professionals. What are the ingredients in STELARA? Active ingredient: ustekinumab Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains L-histidine, L-histidine monohydrochloride monohydrate, Polysorbate 80, and sucrose. Single-dose vial for subcutaneous use contains L- histidine, L-histidine hydrochloride monohydrate, Polysorbate 80 and sucrose. Single-dose vial for intravenous infusion contains EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, Polysorbate 80, and sucrose. Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 © 2012, 2016, 2019 Janssen Pharmaceutical Companies For more information, go to www.stelarainfo.com or call 1-800-JANSSEN (1-800-526-7736). This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 03/2024 3 Reference ID: 5479362 INSTRUCTIONS FOR USE STELARA (stel ar’ a) (ustekinumab) injection, for subcutaneous use Instructions for injecting STELARA from a vial. Read this Instructions for Use before you start using STELARA. Your doctor or nurse should show you how to prepare, measure your dose, and give your injection of STELARA the right way. If you cannot give yourself the injection:  ask your doctor or nurse to help you, or  ask someone who has been trained by a doctor or nurse to give your injections. Do not try to inject STELARA yourself until you have been shown how to inject STELARA by your doctor, nurse or health professional. Important information:  Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor. o If your dose is 45 mg or less you will receive one 45 mg vial. o If your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself two injections, one right after the other.  Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45 mg.  Check the expiration date on the vial and carton. If the expiration date has passed, do not use it. If the expiration date has passed, call your doctor or pharmacist, or call 1-800-JANSSEN (1-800-526-7736) for help.  Check the vial for any particles or discoloration. Your vial should look clear and colorless to light yellow with few white particles.  Do not use if it is frozen, discolored, cloudy or has large particles. Get a new vial.  Do not shake the vial at any time. Shaking your vial may damage your STELARA medicine. If your vial has been shaken, do not use it. Get a new vial.  Do not use a STELARA vial more than one time, even if there is medicine left in the vial. After the rubber stopper is punctured, STELARA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused STELARA after you give your injection.  Safely throw away (dispose of) STELARA vials after use.  Do not re-use syringes or needles. See “Step 6: Dispose of needles and syringes.”  To avoid needle-stick injuries, do not recap needles. Gather the supplies you will need to prepare STELARA and to give your injection. (See Figure A) You will need:  a syringe with the needle attached, you will need a prescription from your healthcare provider to get syringes with the needles attached from your pharmacy. Reference ID: 5479362 ADHESIVE BANDAGE ANTISE?llCWIPES 0 COTTON BAU. OR GAU!E FADS ST ELAM Vll\L SYRINGE ANOATIU:HEO NEEDLE FOA<:l.EAREO SttMPS OISPOSAL CONTAINER  antiseptic wipes  cotton balls or gauze pads  adhesive bandage  your prescribed dose of STELARA  FDA-cleared sharps disposal container. See “Step 6: Dispose of needles and syringes.” Figure A Step 1: Prepare the injection.  Choose a well-lit, clean, flat work surface.  Wash your hands well with soap and warm water. Step 2: Prepare your injection site  Choose an injection site around your stomach area (abdomen), buttocks, and upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure B)  Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.  Clean the skin with an antiseptic wipe where you plan to give your injection.  Do not touch this area again before giving the injection. Let your skin dry before injecting.  Do not fan or blow on the clean area. Reference ID: 5479362 Figure B Areas in gray are recommended injection sites. Step 3: Prepare the vial.  Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber stopper. (See Figure C) Figure C  Clean the rubber stopper with an antiseptic swab. (See Figure D) Figure D  Do not touch the rubber stopper after you clean it.  Put the vial on a flat surface. Reference ID: 5479362 Step 4: Prepare the needle  Pick up the syringe with the needle attached.  Remove the cap that covers the needle. (See Figure E)  Throw the needle cap away. Do not touch the needle or allow the needle to touch anything. Figure E  Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor.  Hold the vial between your thumb and index (pointer) finger.  Use your other hand to push the syringe needle through the center of the rubber stopper. (See Figure F) Figure F  Push down on the plunger until all of the air has gone from the syringe into the vial.  Turn the vial and the syringe upside down. (See Figure G)  Hold the STELARA vial with one hand.  It is important that the needle is always in the liquid in order to prevent air bubbles forming in the syringe. Reference ID: 5479362  Pull back on the syringe plunger with your other hand.  Fill the syringe until the black tip of the plunger lines up with the mark that matches your prescribed dose. Figure G  Do not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it has any air bubbles inside.  If there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the top. (See Figure H)  Slowly press the plunger up until all of the air bubbles are out of the syringe (but none of the liquid is out).  Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch anything. Reference ID: 5479362 Figure H Step 5: Inject STELARA  Hold the barrel of the syringe in one hand, between the thumb and index fingers.  Do not pull back on the plunger at any time.  Use the other hand to gently pinch the cleaned area of skin. Hold firmly.  Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure I) Figure I  Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched.  When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J) Reference ID: 5479362 Figure J  When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary. If your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a second injection right after the first. Repeat Steps 1-5 using a new syringe. Choose a different site for the second injection. Step 6: Dispose of the needles and syringes.  Do not re-use a syringe or needle.  To avoid needle-stick injuries, do not recap a needle.  Put your needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.  If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright and stable during use o leak-resistant, o and properly labeled to warn of hazardous waste inside the container.  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.  Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.  Throw away the vial into the container where you put the syringes and needles. Reference ID: 5479362  If you have any questions, talk to your doctor or pharmacist. Keep STELARA and all medicines out of the reach of children. Vial Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Cilag AG, Schaffhausen, Switzerland This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2019 © 2012, 2016 Janssen Pharmaceutical Companies Reference ID: 5479362 INSTRUCTIONS FOR USE STELARA (stel ar’ a) (ustekinumab) injection, for subcutaneous use Instructions for injecting STELARA using a prefilled syringe. Read this Instructions for Use before you start using STELARA. Your doctor or nurse should show you how to prepare and give your injection of STELARA the right way. If you cannot give yourself the injection:  ask your doctor or nurse to help you, or  ask someone who has been trained by a doctor or nurse to give your injections. Do not try to inject STELARA yourself until you have been shown how to inject STELARA by your doctor, nurse or health professional. Important information:  Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor. o If your dose is 45 mg, you will receive one 45 mg prefilled syringe. o If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other.  Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use a prefilled syringe.  Check the expiration date on the prefilled syringe and carton. If the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 30ºC (86ºF) for longer than a maximum single period of 30 days or if the prefilled syringe has been stored above 30ºC (86ºF), do not use it. If the expiration date has passed or if the prefilled syringe has been stored above 30ºC (86ºF), call your doctor or pharmacist, or call 1-800-JANSSEN (1-800-526-7736) for help.  Make sure the syringe is not damaged.  The needle cover on the prefilled syringe contains latex. Do not handle the needle cover on the STELARA prefilled syringe if you are allergic to latex.  Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should look clear and colorless to light yellow with few white particles.  Do not use if it is frozen, discolored, cloudy or has large particles. Get a new prefilled syringe.  Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may damage your STELARA medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe.  To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger at any time. Reference ID: 5479362 0 oono!i !,Ill CllGIIJllPNJ!. PLUNGER NEEDLE GUARD BODY VIEWING WINDOW PLUNGER HEAD ACTIVATION CLIPS I NEEDLE GUARD WINGS LABEL ~H• •ii >i;F '5lB..M';!I ~=tu..EDSWUMGE NEEDLE fl».-Cl.EAltED SH.filPS ~CONTltNEJI NEEDLE COVER Gather the supplies you will need to prepare and to give your injection. (See Figure A) You will need:  antiseptic wipes  cotton balls or gauze pads  adhesive bandage  your prescribed dose of STELARA (See Figure B)  FDA-cleared sharps disposal container. See “Step 4: Dispose of the syringe.” Figure A Figure B To prevent early activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use. Step 1: Prepare the injection.  Choose a well-lit, clean, flat work surface.  Wash your hands well with soap and warm water.  Hold the prefilled syringe with the covered needle pointing upward. Step 2: Prepare your injection site  Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure C)  Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.  Clean the skin with an antiseptic wipe where you plan to give your injection. Reference ID: 5479362 . ) <r---1  Do not touch this area again before giving the injection. Let your skin dry before injecting.  Do not fan or blow on the clean area. Figure C *Areas in gray are recommended injection sites. Step 3: Inject STELARA  Remove the needle cover when you are ready to inject your STELARA.  Do not touch the plunger while removing the needle cover.  Hold the body of the prefilled syringe with one hand, and pull the needle cover straight off. (see Figure D)  Put the needle cover in the trash.  You may also see a drop of liquid at the end of the needle. This is normal.  Do not touch the needle or let it touch anything.  Do not use the prefilled syringe if it is dropped without the needle cover in place. Call your doctor, nurse or health professional for instructions. Figure D Reference ID: 5479362  Hold the body of the prefilled syringe in one hand between the thumb and index fingers. (See Figure E) Figure E  Do not pull back on the plunger at any time.  Use the other hand to gently pinch the cleaned area of skin. Hold firmly.  Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure F) Figure F  Inject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. (See Figure G) Reference ID: 5479362 NEEDLE GUARD WINGS Figure G  When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and let go of the skin.  Slowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure H) Figure H  When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary. Reference ID: 5479362 If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1-3 for the second injection using a new syringe. Choose a different site for the second injection. Step 4: Dispose of the syringe.  Put the syringe in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes in your household trash.  If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic. o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out. o upright and stable during use, o leak-resistant, o and properly labeled to warn of hazardous waste inside the container.  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.  Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.  If you have any questions, talk to your doctor or pharmacist. Keep STELARA and all medicines out of the reach of children. Prefilled Syringe Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Baxter Pharmaceutical Solutions, Bloomington, IN 47403 and at Cilag AG, Schaffhausen, Switzerland This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 03/2020 © 2012 Janssen Pharmaceutical Companies Reference ID: 5479362	custom-source	2025-02-12T15:46:47.972511	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125261s166,761044s014lbl.pdf', 'application_number': 125261, 'submission_type': 'SUPPL ', 'submission_number': 166}
80,247	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLUDARABINE PHOSPHATE INJECTION safely and effectively. See full prescribing information for FLUDARABINE PHOSPHATE INJECTION. FLUDARABINE PHOSPHATE injection, for intravenous use Initial U.S. Approval: 1991 ----------------------------RECENT MAJOR CHANGES-------------------------- Boxed Warning (removed) 11/2024 Indications and Usage (1) 11/2024 Dosage and Administration, Recommended Dosage (2.1) 11/2024 Warnings and Precautions (5) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- Fludarabine Phosphate Injection is a nucleoside metabolic inhibitor indicated: • as a component of a combination regimen for the treatment of adults with B-cell chronic lymphocytic leukemia (CLL); (1) • for the treatment of adults with B-cell CLL who have not responded to, or whose disease has progressed during treatment with at least one alkylating- agent containing regimen. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------- • The recommended dosage is: o In Combination with Cyclophosphamide and Rituximab: The recommended dosage is 25 mg/m2 administered intravenously over 30 minutes daily for the first three days (Days 1 to 3) of each 28-day cycle for 6 cycles in combination with cyclophosphamide 250 mg/m2 administered intravenously daily for three days (Days 1 to 3), and rituximab 375 mg/m2 administered intravenously on Day 1 of the first cycle, followed by rituximab 500 mg/m2 on Day 1 of subsequent cycles. (2.1) o Single Agent: The recommended dosage is 25 mg/m2 administered intravenously over approximately 30 minutes daily for five consecutive days (Days 1 to 5) of each 28-day cycle. (2.1) • Renal impairment: Reduce the dosage for patients with creatinine clearance (CLcr) 30 to 79 mL/min. (2.2, 8.6) • See the Full Prescribing Information for instructions for preparation and administration. (2.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Injection: 50 mg/2 mL (25 mg/mL) (3) -------------------------------CONTRAINDICATIONS------------------------------ None. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ Neurological Toxicities: Coma, seizures, agitation and confusion can occur and are dose dependent. Monitor patients for signs and symptoms of neurologic toxicity. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. (5.1, 10) Myelosuppression: Severe anemia, thrombocytopenia, neutropenia, or pancytopenia can occur and are dose dependent. Monitor blood counts before and during treatment. Consider dose delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle. (5.2, 10) Autoimmune Cytopenias: Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/ thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur. Closely monitor patients for hemolysis and manage as clinically indicated. (5.3) Transfusion-Associated Graft-Versus-Host Disease: Use only irradiated blood products for transfusions. (5.4) Tumor Lysis Syndrome (TLS): Closely monitor patients at risk for TLS, consider appropriate prophylaxis including hydration, and manage as clinically indicated. (5.5) Pulmonary Toxicity in Patients with CLL when Fludarabine Phosphate is Used with Pentostatin: Severe and sometimes fatal pulmonary toxicity when used concomitantly with pentostatin. Concomitant use is not recommended. (5.6, 7.1) Vaccination: Avoid live attenuated vaccines during or after treatment with Fludarabine Phosphate Injection. (5.7) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.8, 8.1) ------------------------------ADVERSE REACTIONS------------------------------- The most common adverse reactions (≥ 20%) are myelosuppression (neutropenia, thrombocytopenia, or anemia), fever, infection, nausea and vomiting, weakness, and pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS------------------------ • Lactation: Advise not to breastfeed. (8.2) • Infertility: May impair fertility. (8.3) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Recommended Dosage for Patients with Renal Impairment 2.3 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Neurologic Toxicities 5.2 Myelosuppression 5.3 Autoimmune Cytopenias 5.4 Transfusion Associated Graft-Versus-Host Disease 5.5 Tumor Lysis Syndrome 5.6 Pulmonary Toxicity in Patients with CLL when Fludarabine Phosphate is Used with Pentostatin 5.7 Vaccination 5.8 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Pentostatin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Fludarabine Phosphate Injection is indicated: • as a component of a combination regimen for the treatment of adults with B-cell chronic lymphocytic leukemia (CLL); • for the treatment of adults with B-cell CLL who have not responded to or whose disease has progressed during treatment with at least one alkylating-agent containing regimen. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage In Combination with Cyclophosphamide and Rituximab The recommended dosage of Fludarabine Phosphate Injection is 25 mg/m2 administered intravenously over 30 minutes daily for the first three days (Days 1 to 3) of each 28-day cycle for 6 cycles or until unacceptable toxicity or disease progression, in combination with cyclophosphamide 250 mg/m2 administered intravenously daily for three days (Days 1 to 3), and rituximab 375 mg/m2 administered intravenously on Day 1 of the first cycle, followed by rituximab 500 mg/m2 on Day 1 of subsequent cycles. Refer to the cyclophosphamide and rituximab prescribing information for additional dosing information as appropriate. Single Agent The recommended dosage of Fludarabine Phosphate Injection is 25 mg/m2 administered intravenously over 30 minutes daily for five consecutive days (Days 1 to 5) of each 28-day cycle. 2.2 Recommended Dosage for Patients with Renal Impairment Reduce the Fludarabine Phosphate Injection dosage for patients with renal impairment as shown in Table 1. Closely monitor patients with renal impairment for adverse reactions. Table 1: Dosage Modifications for Renal Impairment Creatinine Clearance (Estimated by Cockcroft-Gault equation) Recommended Dosage 50 – 79 mL/min 20 mg/m2 30 – 49 mL/min 15 mg/m2 < 30 mL/min A dosage has not been established. 2.3 Preparation and Administration Fludarabine Phosphate Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 Dilute Fludarabine Phosphate Injection in 100 mL to 125 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Infuse diluted Fludarabine Phosphate Injection intravenously over 30 minutes. Fludarabine Phosphate Injection contains no antimicrobial preservative. If not used immediately, discard the unused portion within 8 hours after opening the single-dose vial. Do not mix Fludarabine Phosphate Injection with other drugs. 3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg/2 mL (25 mg/mL) fludarabine phosphate supplied as a a clear, colorless to almost colorless sterile solution in single-dose vials. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Neurologic Toxicities Severe central nervous system (CNS) adverse reactions, including coma, seizures, agitation and confusion, can occur in patients treated with Fludarabine Phosphate Injection. CNS adverse reactions may occur either early or late after the initiation of Fludarabine Phosphate Injection (range 7 to 225 days). CNS adverse reactions are dose dependent and occur at greater incidence and severity in patients treated at doses higher than the recommended dose of Fludarabine Phosphate Injection [see Overdosage (10)]. Monitor patients for signs and symptoms of neurologic toxicity during and after treatment with Fludarabine Phosphate Injection. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. Do not administer Fludarabine Phosphate Injection at doses higher than the recommended dose. Advise patients that Fludarabine Phosphate Injection may reduce the ability to drive or use mechanical equipment, since fatigue, weakness, visual disturbances, confusion, agitation, or seizures may occur. 5.2 Myelosuppression Fludarabine phosphate can cause severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia, or anemia. Cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. The median time to nadir of counts was approximately 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. The duration of the cytopenia in reported cases has ranged from approximately 2 months to approximately 1 year. Monitor complete blood counts at baseline, prior to and during each treatment cycle, and as clinically needed. Consider dosage delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle. 5.3 Autoimmune Cytopenias Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur in patients treated with fludarabine phosphate with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test. The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Closely monitor patients during treatment with Fludarabine Phosphate Injection for autoimmune cytopenias and manage as clinically indicated. 5.4 Transfusion Associated Graft-Versus-Host Disease Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in patients treated with fludarabine phosphate. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludarabine Phosphate Injection should receive irradiated blood only. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) can occur in patients treated with Fludarabine Phosphate Injection. TLS has been reported in patients with CLL who have large tumor burdens and can occur as early as the first week of treatment. Closely monitor patients at risk for TLS, consider appropriate prophylaxis including hydration, and manage as clinically indicated. 5.6 Pulmonary Toxicity in Patients with CLL When Fludarabine Phosphate is Used with Pentostatin In clinical trials, patients experienced fatal pulmonary toxicity when treated with fludarabine phosphate and pentostatin for refractory CLL. Avoid concomitant use of Fludarabine Phosphate Injection with pentostatin [see Drug Interactions (7.1)]. 5.7 Vaccination During and after treatment with Fludarabine Phosphate Injection, avoid vaccination with live vaccines. 5.8 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Neurologic Toxicities [see Warnings and Precautions (5.1)] • Myelosuppression [see Warnings and Precautions (5.2)] • Autoimmune Cytopenias [see Warnings and Precautions (5.3)] • Transfusion Associated Graft-Versus-Host Disease [see Warnings and Precautions (5.4)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. B-cell Chronic Lymphocytic Leukemia Combination with Cyclophosphamide and Rituximab The safety of Fludarabine Phosphate Injection for the treatment of adults with B-cell CLL as a component of a combination regimen was derived from the published literature [see Clinical Studies (14)]. The safety of Fludarabine Phosphate Injection for the treatment of adults with B-cell CLL as a component of a combination regimen was consistent with the known safety profile of fludarabine phosphate. Single Agent The safety of fludarabine phosphate was evaluated in two single-arm open-label studies (MDAH and SWOG) in adult patients (n=133) with CLL refractory to at least one prior alkylating-agent containing regimen [see Clinical Studies (14)]. In these two clinical trials, 22% of the patients treated with fludarabine phosphate had fatal adverse reactions, with approximately 50% of these due to infection. Serious and fatal infections, including opportunistic and reactivation of latent viral infections such as Varicella-Zoster Virus (VZV; herpes zoster), Epstein-Barr Virus (EPV), and John Cunningham (JC) virus (progressive multifocal leukoencephalopathy) occurred in patients treated with fludarabine phosphate. Hematologic adverse reactions, including neutropenia (Grade 4: 59%), thrombocytopenia (55%), and anemia (55%) occurred in a majority of the CLL patients treated with fludarabine phosphate. The most common adverse reactions (> 20%) occurring in patients treated with fludarabine in the MDAH and SWOG trials (n=133) were myelosuppression (neutropenia, thrombocytopenia, or anemia), fever, infection, nausea and vomiting, weakness, and pain. Table 2 summarizes the non-hematologic adverse reactions in the MDAH and SWOG studies. Table 2: Non-Hematologic Adverse Reactions (> 5%) in CLL Patients Treated with Fludarabine in the MDAH and SWOG Studies Adverse Reactions MDAH (N=101) % SWOG (N=32) % General Fever 60 69 Pain 20 22 Fatigue 10 38 Chills 11 19 Malaise 8 6 Diaphoresis 1 13 Infection Infection 33 44 Pneumonia 16 22 Upper respiratory infection 2 16 Urinary infection 2 15 Sinusitis 5 0 Pharyngitis 0 9 Gastrointestinal Nausea/Vomiting 36 31 Anorexia 7 34 Diarrhea 15 13 Stomatitis 9 0 Gastrointestinal bleeding 3 13 Neurological Weakness 9 65 Paresthesia 4 12 Adverse Reactions MDAH (N=101) % SWOG (N=32) % Visual disturbance 3 15 Hearing loss 2 6 Pulmonary Cough 10 44 Dyspnea 9 22 Allergic pneumonitis 0 6 Hemoptysis 1 6 Skin and Subcutaneous Rash 15 15 Cardiovascular Edema 8 19 Angina 0 6 Musculoskeletal Myalgia 4 16 Endocrine Hyperglycemia 1 6 Clinically relevant adverse reactions in < 5% of patients who received fludarabine phosphate included the following: General: Headache, hemorrhage, tumor lysis syndrome (hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, flank pain, renal failure) Blood and Lymphatic: Bone marrow fibrosis, thrombocytopenia/ITP, Evans syndrome, acquired hemophilia Cardiovascular: Congestive heart failure, arrhythmia, supraventricular tachycardia, myocardial infarction, transient ischemic attack, pericardial effusion Gastrointestinal: Esophagitis, mucositis, constipation, dysphagia, pancreatic enzyme increase Genitourinary: Dysuria, hematuria, renal failure, abnormal renal function test, proteinuria, hesitancy, hemorrhagic cystitis Hepatobiliary: Liver failure, ALT/AST elevation, cholelithiasis Immune System: Anaphylaxis Infection: VZR (herpes zoster), EBV (lymphoproliferative disorders), JC virus (progressive multifocal leukoencephalopathy) Musculoskeletal: Osteoporosis, arthralgia, Neoplasms: tumor flare, skin cancer Neurological: Sleep disorder, depression, cerebellar syndrome, impaired mentation, agitation, confusion, seizures, optic neuritis, optic neuropathy, blindness and coma, peripheral neuropathy, cerebral hemorrhage Pulmonary: Epistaxis, bronchitis, hypoxia, interstitial pulmonary infiltrate Renal &Urinary: Dehydration Skin and Subcutaneous Tissue: Alopecia, pruritis, seborrhea; erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis, pemphigus (some fatal cases) Vascular: Deep venous thrombosis, phlebitis, aneurysm, cerebrovascular accident 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fludarabine phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic: Bone marrow hypoplasia or aplasia resulting in pancytopenia (range: 2 months to 12 months after treatment initiation; some fatal); myelodysplastic syndrome and acute myeloid leukemia Infection: Progressive multifocal leukoencephalopathy (range: 3 weeks to one year after treatment initiation; some fatal) Pulmonary: Acute Respiratory Distress Syndrome (ARDS), respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis, respiratory failure 7 DRUG INTERACTIONS 7.1 Pentostatin Avoid use of Fludarabine Phosphate Injection in combination with pentostatin due to the risk of severe and fatal pulmonary toxicity [see Warnings and Precautions (5.6)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. There are no available data on Fludarabine Phosphate Injection use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended human intravenous dose (25 mg/m2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human intravenous dose, and was limited to slight body weight decreases at 7.2 times the human intravenous dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human intravenous dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.5 times the human intravenous dose). 8.2 Lactation Risk Summary There are no data on the presence of fludarabine phosphate or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with Fludarabine Phosphate Injection, and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiation of Fludarabine Phosphate Injection [see Use in Specific Populations (8.1)]. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings in animals and humans, Fludarabine Phosphate Injection may impair male fertility. Fludarabine phosphate may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The reversibility of this effect is unknown [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of Fludarabine Phosphate Injection have not been established in pediatric patients. Safety and effectiveness were assessed, but not established for Fludarabine Phosphate Injection in pediatric patients 1 year to < 17 years with refractory acute leukemia or solid tumors. No new safety signals were observed in pediatric patients across these studies. 8.5 Geriatric Use Among patients with CLL evaluated in two randomized active-controlled trials treated with fludarabine, cyclophosphamide, and rituximab, 36% were 65 years of age or older; of these, 15% were 70 years of age or older. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving fludarabine in combination with cyclophosphamide and rituximab who were 70 years or older compared to younger patients for neutropenia, febrile neutropenia, anemia, thrombocytopenia, pancytopenia, and infections. Clinical studies of fludarabine as a single agent for patients with B-cell CLL did not include a sufficient numbers of younger adults to determine if patients with B-cell CLL who are 65 years of age and older respond differently from younger adults. 8.6 Renal Impairment Reduce the dosage in patients with CLcr 30 to 79 mL/min. A dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) [see Dosage and Administration (2.2)]. The total body clearance of 2-fluoro-ara-A is correlated with the creatinine clearance [see Clinical Pharmacology (12.3)]; however, the effect of varying degrees of renal impairment on the pharmacokinetics of this metabolite has not been fully characterized. 10 OVERDOSAGE Severe myelosuppression, including thrombocytopenia, neutropenia, anemia, and pancytopenia has occurred in patients treated with doses that exceed the recommended dosage of Fludarabine Phosphate Injection [see Warnings and Precautions (5.3)]. Severe, irreversible, central nervous system effects including blindness, coma, and death have occurred in patients treated at doses approximately four times greater (96 mg/m2/day for 5 to 7 days) than the recommended dose for fludarabine phosphate [see Warnings and Precautions (5.4)]. There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy. 11 DESCRIPTION Fludarabine Phosphate Injection contains fludarabine phosphate, a nucleoside metabolic inhibitor. The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-β-D- arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C10H13FN5O7P (MW 365.2) and has the following chemical structure: Each mL contains 25 mg of the active ingredient fludarabine phosphate (equivalent to 19.5 mg Fludarabine), 1.78 mg disodium phosphate dihydrate, water for injection and sodium hydroxide to adjust pH to 7.5. The pH range for the final product is 7.3 to 7.7. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fludarabine phosphate is rapidly converted to active 2-fluoro-ara-ATP [see Clinical Pharmacology (12.3)], which appears to inhibit DNA synthesis through inhibition of DNA polymerase alpha, ribonucleotide reductase and DNA primase. 12.2 Pharmacodynamics The degree of absolute granulocyte count nadir is correlated with increased area under the concentration x time curve (AUC); however, the exposure-response relationship and time-course of pharmacodynamic response of fludarabine have not been fully characterized. 12.3 Pharmacokinetics Fludarabine phosphate is a prodrug. It is rapidly converted to its active metabolite, 2-fluoro-ara-A which is the focus of the pharmacokinetic characterization. 2-fluoro-ara-A plasma trough concentration accumulated 2-fold. Distribution Plasma protein binding ranged between 19% and 29% in vitro. Elimination The terminal half-life of 2-fluoro-ara-A was approximately 20 hours. The total body clearance of 2-fluoro-ara-A correlated with the creatinine clearance. Renal clearance represents approximately 40% of the total body clearance. Metabolism Fludarabine phosphate is dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No animal carcinogenicity studies with fludarabine have been conducted. Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation) and induced sister chromatid exchanges both with and without metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice). Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay in Chinese hamster ovary cells) either in the presence or absence of metabolic activation. Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive system. Observations consisted of a decrease in mean testicular weights in mice and rats with a trend toward decreased testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs. 14 CLINICAL STUDIES B-cell Chronic Lymphocytic Leukemia In Combination with Cyclophosphamide and Rituximab The efficacy of Fludarabine Phosphate Injection for treatment of adults with B-cell CLL as a component of a combination regimen was derived from studies of fludarabine phosphate in the published literature. Fludarabine phosphate as a component of a combination regimen was evaluated in two randomized clinical trials (NCT00090051 and NCT00281918). In both trials, the major efficacy outcome measure was progression-free survival. Single Agent The efficacy of fludarabine phosphate was evaluated in two single-arm open-label studies in adult patients with CLL refractory to at least one prior alkylating-agent containing regimen. The first study (MDAH) included 48 patients treated with a dose of 22 to 40 mg/m2 for 5 days every 28 days daily (0.9 – 1.6 times the recommended dose). The second study (SWOG) included 31 patients treated with a dose of 15 to 25 mg/m2 daily for 5 days every 28 days daily (0.6 – 1.0 times the recommended dose). Patients in the SWOG trial had a median age of 63 years and a baseline median performance status of 1. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group. The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks), respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with fludarabine phosphate was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively. Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline. 15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. https://www.osha.gov/hazardous-drugs 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Fludarabine Phosphate Injection is supplied as a clear, colorless to almost colorless sterile solution in a single- dose vial containing 50 mg/2 mL (25 mg/mL) of fludarabine phosphate. NDC 66758-046-01 one carton containing 1 vial of Fludarabine Phosphate Injection. Storage Store in a refrigerator between 2° and 8°C (36° to 46°F). Handling and Disposal Fludarabine Phosphate Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or mucous membranes. 17 PATIENT COUNSELING INFORMATION Neurologic Toxicities Inform patients that Fludarabine Phosphate Injection can cause severe CNS adverse reactions, including coma, seizures, agitation, and confusion. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider immediately if they experience signs or symptoms of CNS adverse reactions [see Warnings and Precautions (5.1)]. Myelosuppression Inform patients Fludarabine Phosphate Injection can cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Autoimmune Cytopenias Inform patients that Fludarabine Phosphate Injection can cause autoimmune hemolytic anemia, autoimmune thrombocytopenia/ITP, Evans syndrome, and acquired hemophilia. Advise patients to seek immediate medical attention if any signs or symptoms of autoimmune cytopenias occur [see Warnings and Precautions (5.3)]. Tumor Lysis Syndrome Inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. Advise patients to notify their healthcare provider if they experience these symptoms [see Warnings and Precautions (5.5)]. Vaccination Advise patients they should avoid vaccinations with live vaccines during and after treatment [see Warnings and Precautions (5.7)]. Nausea and Vomiting Advise patients that Fludarabine Phosphate Injection may cause nausea and/or vomiting. Inform patients to report nausea and vomiting so that symptomatic treatment may be provided when this occurs [see Adverse Reactions (6.1)]. Rash Advise patients that a rash or itching may occur during treatment with Fludarabine Phosphate Injection. Advise patients to immediately report severe or worsening rash or itching [see Adverse Reactions (6.1)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients to contact their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose [see Use in Specific Populations (8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment and for 1 week after the last dose of Fludarabine Phosphate Injection [see Use in Specific Populations (8.2)]. Infertility Advise males of reproductive potential that Fludarabine Phosphate Injection may impair fertility [see Use in Specific Populations (8.3)]. Manufactured for: SANDOZ Princeton, NJ 08540 Manufactured by: EBEWE Pharma Ges.m.b.H. Nfg.KG A-4866 Unterach, AUSTRIA	custom-source	2025-02-12T15:46:47.988783	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022137s015lbl.pdf', 'application_number': 22137, 'submission_type': 'SUPPL ', 'submission_number': 15}
80,237	Vial & Carton Label – Pemetrexed Injection 100mg/10mL (10mg/mL) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Vial & Carton Label - Pemetrexed Injection 500 mg/50 mL (10 mg/mL) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Vial & Container Label - Pemetrexed Injection 1,000 mg/100 mL (10 mg/mL) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PEMETREXED INJECTION safely and effectively. See full prescribing information for PEMETREXED INJECTION PEMETREXED INJECTION, for intravenous use Initial US Approval: 2004 -------------------------RECENT MAJOR CHANGES-------------------------- Dosage and Administration, Preparation for Administration (2.7) 11/2024 --------------------------INDICATIONS AND USAGE--------------------------- Pemetrexed Injection is a folate analog metabolic inhibitor indicated: • in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non- small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. (1.1) • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. (1.1) • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1) • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (1.1) Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (1.1) • initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (1.2) -----------------------DOSAGE AND ADMINISTRATION------------------- • The recommended dose of Pemetrexed Injection administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day 1 of each 21-day cycle. (2.1) • The recommended dose of Pemetrexed Injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (2.1, 2.2) • Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed Injection and continue until 21 days after the last dose of Pemetrexed Injection. (2.4) • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles. (2.4) • Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS------------------- • Injection: 100 mg/10 mL, 500 mg/50 mL, 1,000 mg/100 mL in single dose vials (3) ------------------------------CONTRAINDICATIONS---------------------------- History of severe hypersensitivity reaction to pemetrexed. (4) -----------------------WARNINGS AND PRECAUTIONS---------------------- • Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer Pemetrexed Injection when the absolute neutrophil count is less than 1500 cells/mm3 and platelets are less than 100,000 cells/mm3. Initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection. (2.4, 5.1) • Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. (2.3, 5.2) • Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. (5.3) • Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. (5.4) • Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. (5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.7, 8.1, 8.3) ------------------------------ADVERSE REACTIONS---------------------------- • The most common adverse reactions (incidence ≥ 20%) of pemetrexed injection, when administered as a single agent are fatigue, nausea, and anorexia. (6.1) • The most common adverse reactions (incidence ≥20%) of pemetrexed injection when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) • The most common adverse reactions (incidence ≥20%) of pemetrexed injection when administered in combination with pembrolizumab and platinum chemotherapy are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Shilpa Medicare Limited at 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS---------------------------- Ibuprofen increased risk of Pemetrexed Injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. (2.5, 5.6, 7) ------------------------USE IN SPECIFIC POPULATIONS-------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling Revised:11/2024 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* 1. INDICATIONS AND USAGE 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) 1.2 Mesothelioma 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Non-Squamous NSCLC 2.2 Recommended Dosage for Mesothelioma 2.3 Renal Impairment 2.4 Premedication and Concomitant Medications to Mitigate Toxicity 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed Injection 2.6 Dosage Modifications for Adverse Reactions 2.7 Preparation for Administration 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation 5.2 Renal Failure 5.3 Bullous and Exfoliative Skin Toxicity 5.4 Interstitial Pneumonitis 5.5 Radiation Recall 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment 5.7 Embryo-Fetal Toxicity 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7. DRUG INTERACTIONS 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Renal Impairment 10. OVERDOSAGE 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14. CLINICAL STUDIES 14.1 Non-Squamous NSCLC 14.2 Mesothelioma 15. REFERENCES 16. HOW SUPPLIED/STORAGE AND HANDLING 17. PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Pemetrexed Injection is indicated: • in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non- squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies (14.1)]. 1.2 Mesothelioma Pemetrexed Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Non-Squamous NSCLC • The recommended dose of Pemetrexed Injection when administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, treatment with Pemetrexed Injection with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin. • The recommended dose of Pemetrexed Injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity. • The recommended dose of Pemetrexed Injection for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • The recommended dose of Pemetrexed Injection for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Recommended Dosage for Mesothelioma • The recommended dose of Pemetrexed Injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment • Pemetrexed Injection dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Administration (2.1, 2.2)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)]. 2.4 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of Pemetrexed Injection and continuing until 21 days after the last dose of Pemetrexed Injection [see Warnings and Precautions (5.1)]. • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pemetrexed Injection [see Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Corticosteroids • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed Injection administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed Injection In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.6 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer Pemetrexed Injection if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of Pemetrexed Injection until: • recovery of non-hematologic toxicity to Grade 0-2, • absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and • platelet count is 100,000 cells/mm3 or higher. Upon recovery, modify the dosage of Pemetrexed Injection in the next cycle as specified in Table 1. For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information. Table 1: Recommended Dosage Modifications for Adverse Reactionsa Toxicity in Most Recent Treatment Cycle Pemetrexed Injection Dose Modification for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions (5.1)] ANC less than 500/mm3 and platelets greater than or equal to 50,000/mm3 OR Platelet count less than 50,000/mm3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm3 with bleeding 50% of previous dose Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions Discontinue Non-hematologic toxicity Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose Renal toxicity [see Warnings and Precautions (5.2)] Withhold until creatinine clearance is 45 mL/min or greater Grade 3 or 4 neurologic toxicity Permanently discontinue Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions Permanently discontinue Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinue Interstitial Pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2). 2.7 Preparation for Administration Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Calculate the dose of Pemetrexed Injection and determine the volume of needed Pemetrexed Injection. Each vial contains an excess of Pemetrexed Injection to facilitate delivery of labeled amount. • Withdraw the calculated dose of Pemetrexed Injection from the vial(s) and discard the vial(s) with any unused portion. • Transfer the calculated dose into an empty intravenous bag. Do NOT further dilute Pemetrexed Injection. • Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed. • Immediately administer Pemetrexed Injection undiluted, as an intravenous infusion over 10 minutes using an infusion pump. • If not used immediately, store undiluted Pemetrexed Injection solution in infusion bag for no more than 24 hours at controlled room temperature of 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Discard the infusion bag solution if not used within 24 hours. 3. DOSAGE FORMS AND STRENGTHS Injection: Pemetrexed Injection is a sterile clear colorless to pale yellow to greenish yellow solution available as follows: • 100 mg/10 mL (10 mg/mL) single-dose vial • 500 mg/50 mL (10 mg/mL) single-dose vial • 1,000 mg/100 mL (10 mg/mL) single-dose vial 4. CONTRAINDICATIONS Pemetrexed Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions (6.1)]. 5. WARNINGS AND PRECAUTIONS 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation Pemetrexed Injection can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of Pemetrexed Injection; continue vitamin supplementation during treatment and for 21 days after the last dose of Pemetrexed Injection to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection [see Dosage and Administration (2.4)]. Obtain a complete blood count at the beginning of each cycle. Do not administer Pemetrexed Injection until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce Pemetrexed Injection in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%. 5.2 Renal Failure Pemetrexed Injection can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions (6.1)]. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with Pemetrexed Injection. Withhold Pemetrexed Injection in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)]. 5.3 Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with Pemetrexed Injection. Permanently discontinue Pemetrexed Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity. 5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with Pemetrexed Injection treatment. Withhold Pemetrexed Injection for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue Pemetrexed Injection. 5.5 Radiation Recall Radiation recall can occur with Pemetrexed Injection in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue Pemetrexed Injection for signs of radiation recall. 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to Pemetrexed Injection is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of Pemetrexed Injection. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for Pemetrexed Injection adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.1)]. 6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions (5.1)] • Renal failure [see Warnings and Precautions (5.2)] • Bullous and exfoliative skin toxicity [see Warning and Precautions (5.3)] • Interstitial pneumonitis [see Warnings and Precautions (5.4)] • Radiation recall [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥ 20 %) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia. Non-Squamous NSCLC First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy The safety of pemetrexed, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received pemetrexed, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies (14.1)]. The median duration of exposure to pemetrexed was 7.2 months (range: 1 day to 1.7 years). Seventy- two percent of patients received carboplatin. The study population characteristics were: median age of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline. Pemetrexed was discontinued for adverse reactions in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed occurred in 49% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥ 2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed, pembrolizumab, and platinum. Table 2: Adverse Reactions Occurring in ≥ 20% of Patients in KEYNOTE-189 Pemetrexed Pembrolizumab Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 Adverse Reaction All Gradesa (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal Disorders Nausea 56 3.5 52 3.5 Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24 3.7 23 3.0 General Disorders and Administration Site Conditions Fatigueb 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition Disorders Decreased appetite 28 1.5 30 0.5 Skin and Subcutaneous Tissue Disorders Rashc 25 2.0 17 2.5 Respiratory, Thoracic and Mediastinal Disorders Cough 21 0 28 0 Dyspnea 21 3.7 26 5 a Graded per NCI CTCAE version 4.03. b Includes asthenia and fatigue. c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed, pembrolizumab, and platinum. Table 3: Laboratory Abnormalities Worsened from Baseline in ≥ 20% of Patients in KEYNOTE-189 Pemetrexed Pembrolizumab Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy Laboratory Testa All Gradesb % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 63 9 60 7 Increased ALT 47 3.8 42 2.6 Increased AST 47 2.8 40 1.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypoalbuminemia 39 2.8 39 1.1 Increased creatinine 37 4.2 25 1.0 Hyponatremia 32 7 23 6 Hypophosphatemia 30 10 28 14 Increased alkaline phosphatase 26 1.8 29 2.1 Hypocalcemia 24 2.8 17 0.5 Hyperkalemia 24 2.8 19 3.1 Hypokalemia 21 5 20 5 Hematology Anemia 85 17 81 18 Lymphopenia 64 22 64 25 Neutropenia 48 20 41 19 Thrombocytopenia 30 12 29 8 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Pemetrexed /pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/Pemetrexed /platinum chemotherapy (range: 184 to 197 patients). b Graded per NCI CTCAE version 4.03. Initial Treatment in Combination with Cisplatin The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12. Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White, 16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed. Table 4 provides the frequency and severity of adverse reactions that occurred in ≥ 5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 4. Table 4: Adverse Reactions Occurring in ≥ 5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Adverse Reactiona Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactiona Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Thrombocytopenia 10 4 27 13 Renal Elevated creatinine 10 1 7 1 Clinical Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/heartburn 5 0 6 0 Constitutional symptoms Fatigue 43 7 45 5 Dermatology/Skin Alopecia 12 0 21 1 Rash/Desquamation 7 0 8 1 Neurology Sensory neuropathy 9 0 12 1 Taste disturbance 8 0 9 0 a NCI CTCAE version 2.0. The following additional adverse reactions were observed in patients assigned to receive pemetrexed. Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal —renal failure Eye Disorder — conjunctivitis Incidence <1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy In Study JMEN, the safety of pemetrexed was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed. Table 5 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 438 pemetrexed-treated patients in Study JMEN. Table 5: Adverse Reactions Occurring in ≥ 5% of Patients Receiving Pemetrexed in Study JMEN Adverse Reactiona Pemetrexed (N=438) Placebo (N=218) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Dermatology/Skin Rash/desquamation 10 0 3 0 Neurology Sensory neuropathy 9 1 4 0 Infection 5 2 2 0 a NCI CTCAE version 3.0. The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm. The following additional adverse reactions were observed in patients who received pemetrexed. Incidence 1% to<5% Dermatology/Skin — alopecia, pruritus/itching Gastrointestinal — constipation General Disorders — edema, fever Hematologic — thrombocytopenia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation Incidence <1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexed in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B12 supplementation. PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for pemetrexed and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Table 6 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 333 pemetrexed- treated patients in PARAMOUNT. Table 6: Adverse Reactions Occurring in ≥ 5% of Patients Receiving Pemetrexed in PARAMOUNT Adverse Reactiona Pemetrexed (N=333) Placebo (N=167) All Grades (%) Grade 3-4 (%) All Grades (%) Grades 3-4 (%) All adverse reactions 53 17 34 4.8 Laboratory Hematologic Anemia 15 4.8 4.8 0.6 Neutropenia 9 3.9 0.6 0 Clinical Constitutional symptoms Fatigue 18 4.5 11 0.6 Gastrointestinal Nausea 12 0.3 2.4 0 Vomiting 6 0 1.8 0 Mucositis/stomatitis 5 0.3 2.4 0 General disorders This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Edema 5 0 3.6 0 a NCI CTCAE version 3.0. The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm. Incidence 1% to <5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence <1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of pemetrexed was evaluated in Study JMEI, a randomized (1:1), open-label, active- controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed arm received folic acid and vitamin B12 supplementation. Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0. Table 7 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 265 pemetrexed- treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table 7 below. Table 7: Adverse Reactions Occurring in ≥ 5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactiona Pemetrexed (N=265) Docetaxel (N=276) All Grades (%) Grades 3-4 (%) All Grade (%) Grades 3-4 (%) Laboratory Hematologic Anemia 19 4 22 4 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Constitutional symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Dermatology/Skin Rash/desquamation 14 0 6 0 Pruritus 7 0 2 0 Alopecia 6 1 38 2 a NCI CTCAE version 2.0. The following additional adverse reactions were observed in patients assigned to receive pemetrexed injection. Incidence 1% to <5% Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin — erythema multiforme Neurology — motor neuropathy, sensory neuropathy Incidence <1% Cardiovascular — supraventricular arrhythmias Renal — renal failure Mesothelioma The safety of pemetrexed was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received pemetrexed 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle administered until disease progression or unacceptable toxicity. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 74% (n=168) received full supplementation with folic acid and vitamin B12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented. Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study. The data described below reflect exposure to pemetrexed in 168 patients that were fully supplemented with folic acid and vitamin B12. Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and <1% were other ethnicities; 54% had KPS of 90-100. The median number of treatment cycles administered was 6 in the pemetrexed /cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented group. Patients receiving pemetrexed in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia. Table 8 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed- treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the table below. Table 8: Adverse Reactions Occurring in ≥ 5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCHa Adverse Reactionb Pemetrexed /cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Laboratory Hematologic Neutropenia 56 23 13 3 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Elevated creatinine 11 1 10 1 Decreased creatinine clearance 16 1 18 2 Clinical Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Dermatology/Skin Rash 16 1 5 0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactionb Pemetrexed /cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Alopecia 11 0 6 0 Neurology Sensory neuropathy 10 0 10 1 Taste disturbance 8 0 6 0 Metabolism and Nutrition Dehydration 7 4 1 1 Eye Disorder Conjunctivitis 5 0 1 0 a In Study JMCH, 226 patients received at least one dose of pemetrexed in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 8 provides the ADRs for subgroup of patients treated with pemetrexed in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. b NCI CTCAE version 2.0. The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin: Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia Dermatology/Skin — urticaria General Disorders — chest pain Metabolism and Nutrition — increased AST, increased ALT, increased GGT Renal — renal failure Incidence <1% Cardiovascular — arrhythmia Neurology — motor neuropathy Exploratory Subgroup Analyses based on Vitamin Supplementation Table 9 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in Study JMCH (fully-supplemented). Table 9: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa Grade 3-4 Adverse Reactions Fully Supplemented Patients N=168 (%) Never Supplemented Patients N=32 (%) Neutropenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a NCI CTCAE version 2.0. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented: • hypertension (11% versus 3%), • chest pain (8% versus 6%), • thrombosis/embolism (6% versus 3%). Additional Experience Across Clinical Trials Sepsis, with or without neutropenia, including fatal cases: 1% Severe esophagitis, resulting in hospitalization: <1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis 7. DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed [see Clinical Pharmacology (12.3)]. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection [see Dosage and Administration (2.5)]. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on Pemetrexed Injection use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2 [see Data]. Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). 8.2 Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from Pemetrexed Injection, advise women not to breastfeed during treatment with Pemetrexed Injection and for one week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating Pemetrexed Injection [see Use in Specific Populations (8.1)]. Contraception Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose of Pemetrexed Injection. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Nonclinical Toxicology (13.1)]. Infertility Males Pemetrexed Injection may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of pemetrexed in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473 N=32 and NCT00520936 N=72). Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. 8.6 Patients with Renal Impairment Pemetrexed is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function [Warnings and Precautions (5.2, 5.6) and Clinical Pharmacology (12.3)]. No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration (2.3)]. 10. OVERDOSAGE No drugs are approved for the treatment of Pemetrexed Injection overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage. It is not known whether pemetrexed is dialyzable. 11. DESCRIPTION Pemetrexed is a folate analog metabolic inhibitor. The drug substance, Pemetrexed Disodium Hemipentahydrate, has the chemical name disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid hemipentahydrate, with a molecular formula of C20H19N5Na2O6•2.5 H2O and a molecular weight of 516.41. The structural formula is as follows: Pemetrexed Injection is a sterile clear, colorless to pale yellow to green-yellow ready-to-use solution in single-dose vials. Each milliliter of solution contains 10 mg of pemetrexed (equivalent to 12.1 mg pemetrexed disodium hemipentahydrate), 10 mg of mannitol, 9 mg of sodium chloride, 1 mg of L- cysteine hydrochloride, sodium hydroxide and/or hydrochloric acid to adjust pH and water for injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate- dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. 12.2 Pharmacodynamics Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. 12.3 Pharmacokinetics Absorption The pharmacokinetics of pemetrexed when Pemetrexed Injection was administered as a single agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles. Distribution Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins. Elimination The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases. Metabolism Pemetrexed is not metabolized to an appreciable extent. Excretion Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Specific Populations Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses. Racial Groups The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups. Patients with Hepatic Impairment Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies. Patients with Renal Impairment Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Third-Space Fluid The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known. Drug Interaction Studies Drugs Inhibiting OAT3 Transporter Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min). In Vitro Studies Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent. [see Drug Interactions (7)]. Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations. Aspirin Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. Cisplatin Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Vitamins Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 Enzymes In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay). Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy. 14. CLINICAL STUDIES 14.1 Non-Squamous NSCLC Initial Treatment in Combination with Pembrolizumab and Platinum The efficacy of pemetrexed in combination with pembrolizumab and platinum chemotherapy was investigated in Study KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in patients with metastatic non-squamous NSCLC, regardless of PD- L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never versus former/current), choice of platinum (cisplatin versus carboplatin), and tumor PD-L1 status (TPS <1% [negative] versus TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms: • Pemetrexed 500 mg/m2, pembrolizumab 200 mg, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. Pemetrexed was administered after pembrolizumab and prior to platinum chemotherapy on Day 1. • Placebo, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks. Treatment with pemetrexed continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients randomized to placebo, pemetrexed, and platinum chemotherapy were offered pembrolizumab as a single agent at the time of disease progression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. A total of 616 patients were randomized: 410 patients to the pemetrexed, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, pemetrexed, and platinum chemotherapy arm. The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1%. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo, pemetrexed, and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to pemetrexed in combination with pembrolizumab and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy (see Table 10 and Figure 1). Table 10: Efficacy Results of KEYNOTE-189 Endpoint Pemetrexed Pembrolizumab Platinum Chemotherapy n=410 Placebo Pemetrexed Platinum Chemotherapy n=206 OS Number (%) of patients with event 127 (31%) 108 (52%) Median in months (95% CI) NR (NR, NR) 11.3 (8.7, 15.1) Hazard ratioa (95% CI) 0.49 (0.38, 0.64) p-valueb <0.0001 PFS Number of patients with event (%) 245(60%) 166 (81%) Median in months (95% CI) 8.8 (7.6, 9.2) 4.9 (4.7, 5.5) Hazard ratioa (95% CI) 0.52 (0.43, 0.64) p-valueb <0.0001 ORR Overall response ratec (95% CI) 48% (43, 53) 19% (14, 25) Complete response 0.5% 0.5% Partial response 47% 18% p-valued <0.0001 Duration of Response Median in months (range) 11.2 (1.1+, 18.0+) 7.8 (2.1+, 16.4+) a Based on the stratified Cox proportional hazard model. b Based on stratified log-rank test. c Response: Best objective response as confirmed complete response or partial response. d Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status. NR = not reached At the protocol specified final OS analysis, the median in the pemetrexed in combination with pembrolizumab and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189 *Based on the protocol-specified final OS analysis Initial Treatment in Combination with Cisplatin The efficacy of pemetrexed was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS 0 versus 1), gender, disease stage, basis for pathological diagnosis (histopathological/cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival. A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes. Efficacy results in Study JMDB are presented in Table 11 and Figure 2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 11: Efficacy Results in Study JMDB Efficacy Parameter Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Overall Survival Median (months) (95% CI) 10.3 (9.8-11.2) 10.3 (9.6-10.9) Hazard ratio (HR)a,b (95% CI) 0.94 (0.84-1.05) Progression-Free Survival Median (months) (95% CI) 4.8 (4.6-5.3) 5.1 (4.6-5.5) Hazard ratio (HR)a,b (95% CI) 1.04 (0.94-1.15) Overall Response Rate (95% CI) 27.1% (24.2-30.1) 24.7% (21.8-27.6) a Unadjusted for multiple comparisons. b Adjusted for gender, stage, basis of diagnosis, and performance status. Figure 2: Kaplan-Meier Curves for Overall Survival in Study JMDB In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 12 and Figures 3 and 4. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI. Table 12: Overall Survival in NSCLC Histologic Subgroups in Study JMDB Histologic Subgroups Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Non-squamous NSCLC (N=1252) Median (months) (95% CI) 11.0 (10.1-12.5) 10.1 (9.3-10.9) HRa,b (95% CI) 0.84 (0.74-0.96) Adenocarcinoma (N=847) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Histologic Subgroups Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Median (months) (95% CI) 12.6 (10.7-13.6) 10.9 (10.2-11.9) HRa,b (95% CI) 0.84 (0.71-0.99) Large Cell (N=153) Median (months) (95% CI) 10.4 (8.6-14.1) 6.7 (5.5-9.0) HRa,b (95% CI) 0.67 (0.48-0.96) Non-squamous, not otherwise specified (N=252) Median (months) (95% CI) 8.6 (6.8-10.2) 9.2 (8.1-10.6) HRa,b (95% CI) 1.08 (0.81-1.45) Squamous Cell (N=473) Median (months) (95% CI) 9.4 (8.4-10.2) 10.8 (9.5-12.1) HRa,b (95% CI) 1.23 (1.00-1.51) a Unadjusted for multiple comparisons. b Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological). Figure 3: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDB This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 4: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo- controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN. A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies. Efficacy results are presented in Table 13 and Figure 5. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 13: Efficacy Results in Study JMEN Efficacy Parameter Pemetrexed Placebo Overall survival N=441 N=222 Median (months) (95% CI) 13.4 (11.9-15.9) 10.6 (8.7-12.0) Hazard ratioa (95% CI) 0.79 (0.65-0.95) p-value p=0.012 Progression-free survival per independent review N=387 N=194 Median (months) (95% CI) 4.0 (3.1-4.4) 2.0 (1.5-2.8) Hazard ratioa (95% CI) 0.60 (0.49-0.73) p-value p<0.00001 a Hazard ratios are adjusted for multiplicity but not for stratification variables. Figure 5: Kaplan-Meier Curves for Overall Survival in Study JMEN The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 14 and Figures 6 and 7. Table 14: Efficacy Results in Study JMEN by Histologic Subgroup Efficacy Parameter Overall Survival Progression-Free Survival Per Independent Review Pemetrexed (N=441) Placebo (N=222) Pemetrexed (N=387) Placebo (N=194) Non-squamous NSCLC (n=481) Median (months) 15.5 10.3 4.4 1.8 HRa 0.70 0.47 (95% CI) (0.56-0.88) (0.37-0.60) Adenocarcinoma (n=328) Median (months) 16.8 11.5 4.6 2.7 HRa 0.73 0.51 (95% CI) (0.56-0.96) (0.38-0.68) Large cell carcinoma (n=20) Median (months) 8.4 7.9 4.5 1.5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Efficacy Parameter Overall Survival Progression-Free Survival Per Independent Review Pemetrexed (N=441) Placebo (N=222) Pemetrexed (N=387) Placebo (N=194) HRa 0.98 0.40 (95% CI) (0.36-2.65) (0.12-1.29) Otherb (n=133) Median (months) 11.3 7.7 4.1 1.6 HRa 0.61 0.44 (95% CI) (0.40-0.94) (0.28-0.68) Squamous cell NSCLC (n=182) Median (months) 9.9 10.8 2.4 2.5 HRa 1.07 1.03 (95% CI) (0.77-1.50) (0.71-1.49) a Hazard ratios are not adjusted for multiplicity b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. Figure 6: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN Figure 7: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization. A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies. Efficacy results for PARAMOUNT are presented in Table 15 and Figure 8. Table 15: Efficacy Results in PARAMOUNT Efficacy Parameter Pemetrexed (N=359) Placebo (N=180) Overall survival Median (months) (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) Hazard ratio (HR)a (95% CI) 0.78 (0.64-0.96) p-value p=0.02 Progression-free survivalb Median (months) (95% CI) 4.1 (3.2-4.6) 2.8 (2.6-3.1) Hazard ratio (HR) a (95% CI) 0.62 (0.49-0.79) p-value p<0.0001 a Hazard ratios are adjusted for multiplicity but not for stratification variables. b Based on investigator's assessment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 8: Kaplan-Meier Curves for Overall Survival in PARAMOUNT Treatment of Recurrent Disease After Prior Chemotherapy The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure. A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC. The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 16 and 17, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)]. Table 16: Efficacy Results in Study JMEI Efficacy Parameter Pemetrexed (N=283) Docetaxel (N=288) Overall survival Median (months) (95% CI) 8.3 (7.0-9.4) 7.9 (6.3-9.2) Hazard ratioa (95% CI) 0.99 (0.82-1.20) Progression-free survival Median (months) (95% CI) 2.9 (2.4-3.1) 2.9 (2.7-3.4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Efficacy Parameter Pemetrexed (N=283) Docetaxel (N=288) Hazard ratioa (95% CI) 0.97 (0.82-1.16) Overall response rate (95% CI) 8.5% (5.2-11.7) 8.3% (5.1-11.5) a Hazard ratios are not adjusted for multiplicity or for stratification variables. Table 17: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI Histologic Subgroups Pemetrexed (N=283) Docetaxel (N=288) Non-squamous NSCLC (N=399) Median (months) (95% CI) 9.3 (7.8-9.7) 8.0 (6.3-9.3) HRa (95% CI) 0.89 (0.71-1.13) Adenocarcinoma (N=301) Median (months) (95% CI) 9.0 (7.6-9.6) 9.2 (7.5-11.3) HRa (95% CI) 1.09 (0.83-1.44) Large Cell (N=47) Median (months) (95% CI) 12.8 (5.8-14.0) 4.5 (2.3-9.1) HRa (95% CI) 0.38 (0.18-0.78) Otherb (N=51) Median (months) (95% CI) 9.4 (6.0-10.1) 7.9 (4.0-8.9) HRa (95% CI) 0.62 (0.32-1.23) Squamous NSCLC (N=172) Median (months) (95% CI) 6.2 (4.9-8.0) 7.4 (5.6-9.5) HRa (95% CI) 1.32 (0.93-1.86) a Hazard ratio unadjusted for multiple comparisons. b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. 14.2 Mesothelioma The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m2 intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m2 intravenously over 2 hours on Day 1 of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1000 mcg daily beginning 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B12 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration. A total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed, 74% received full supplementation with folic acid and vitamin B12 during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had a baseline KPS score of 90-100% and 46% had a KPS score of 70-80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population. The efficacy results from Study JMCH are summarized in Table 18 and Figure 9. Table 18: Efficacy Results in Study JMCH Efficacy Parameter All Randomized and Treated Patients (N=448) Fully Supplemented Patients (N=331) Pemetrexed /Cisplatin (N=226) Cisplatin (N=222) Pemetrexed /Cisplatin (N=168) Cisplatin (N=163) Median overall survival (months) 12.1 9.3 13.3 10.0 (95% CI) (10.0-14.4) (7.8-10.7) (11.4-14.9) (8.4-11.9) Hazard ratioa 0.77 0.75 Log rank p-value 0.020 NAb a Hazard ratios are not adjusted for stratification variables. b Not a pre-specified analysis. Figure 9: Kaplan-Meier Curves for Overall Survival in Study JMCH This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm. 15. REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. [https://www.osha.gov/hazardous-drugs] 16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied Pemetrexed Injection is a sterile clear, colorless to pale yellow to green-yellow ready-to-use solution packaged in a USP type-I glass vial with rubber stopper and aluminium flip-off cap. NDC 63759-3048-1: Carton containing one single-dose vial, 100 mg/10 mL. NDC 63759-3049-1: Carton containing one single-dose vial, 500 mg/50 mL. NDC 63759-3050-1: Carton containing one single-dose vial, 1,000 mg/100 mL. Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Premedication and Concomitant Medication: Instruct patients to take folic acid as directed and to keep appointments for vitamin B12 injections to reduce the risk of treatment-related toxicity. Instruct patients of the requirement to take corticosteroids to reduce the risks of treatment-related toxicity [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Myelosuppression: Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, fever, bleeding, or symptoms of anemia [see Warnings and Precautions (5.1)]. Renal Failure: Inform patients of the risks of renal failure, which may be exacerbated in patients with dehydration arising from severe vomiting or diarrhea. Instruct patients to immediately contact their healthcare provider for a decrease in urine output [see Warnings and Precautions (5.2)]. Bullous and Exfoliative Skin Disorders: Inform patients of the risks of severe and exfoliative skin disorders. Instruct patients to immediately contact their healthcare provider for development of bullous lesions or exfoliation in the skin or mucous membranes [see Warnings and Precautions (5.3)]. Interstitial Pneumonitis: Inform patients of the risks of pneumonitis. Instruct patients to immediately contact their healthcare provider for development of dyspnea or persistent cough [see Warnings and Precautions (5.4)]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Radiation Recall: Inform patients who have received prior radiation of the risks of radiation recall. Instruct patients to immediately contact their healthcare provider for development of inflammation or blisters in an area that was previously irradiated [see Warnings and Precautions (5.5)]. Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Advise patients with mild to moderate renal impairment of the risks associated with concomitant ibuprofen use and instruct them to avoid use of all ibuprofen containing products for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection [see Dosage and Administration (2.5), Warnings and Precautions (5.6), and Drug Interactions (7)]. Embryo-Fetal Toxicity: Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Advise females to inform their prescriber of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Warnings and Precautions (5.7) and Use in Specific Populations (8.3)]. Lactation: Advise women not to breastfeed during treatment with Pemetrexed Injection and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Manufactured by: Zydus Lifesciences Limited, Ahmedabad, India. Manufactured for: Shilpa Medicare Limited, Jadcherla-509301, India. Revised: 11/2024 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION Pemetrexed (pem-e-TREX-ed) Injection for intravenous use What is Pemetrexed Injection? Pemetrexed Injection is a prescription medicine used to treat: • a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). Pemetrexed Injection is used: ○ as the first treatment in combination with pembrolizumab and platinum chemotherapy when your lung cancer with no abnormal EGFR or ALK gene has spread (advanced NSCLC). ○ as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC). ○ alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed. ○ alone when your lung cancer has returned or spread after prior chemotherapy. Pemetrexed Injection is not for use for the treatment of people with squamous cell non-small cell lung cancer. • a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed Injection is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery. Pemetrexed Injection has not been shown to be safe and effective in children. Do not take Pemetrexed Injection if you have had a severe allergic reaction to any medicine that contains pemetrexed. Before taking Pemetrexed Injection, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems. • have had radiation therapy. • are pregnant or plan to become pregnant. Pemetrexed Injection can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with Pemetrexed Injection. You should use effective birth control (contraception) during treatment with Pemetrexed Injection and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Pemetrexed Injection. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Pemetrexed Injection and for 3 months after the last dose. • are breastfeeding or plan to breastfeed. It is not known if Pemetrexed Injection passes into breast milk. Do not breastfeed during treatment with Pemetrexed Injection and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with Pemetrexed Injection. How is Pemetrexed Injection given? • It is very important to take folic acid and vitamin B12 during your treatment with Pemetrexed Injection to lower your risk of harmful side effects. o Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of Pemetrexed Injection and continue taking folic acid until 21 days (3 weeks) after your last dose of Pemetrexed Injection. o Your healthcare provider will give you vitamin B12 injections during treatment with Pemetrexed Injection. You will get your first vitamin B12 injection 7 days (1 week) before your first dose of Pemetrexed Injection, and then every 3 cycles. • Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with Pemetrexed Injection. • Pemetrexed Injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes. • Pemetrexed Injection is usually given once every 21 days (3 weeks). What are the possible side effects of Pemetrexed Injection? Pemetrexed Injection can cause serious side effects, including: • Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda blood tests to check your blood cell counts regularly during your treatment with Pemetrexed Injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with Pemetrexed Injection. • Kidney problems, including kidney failure. Pemetrexed Injection can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in amount of urine. • Severe skin reactions. Severe skin reactions that may lead to death can happen with Pemetrexed Injection. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area. • Lung problems (pneumonitis). Pemetrexed Injection can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever. • Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiation treatment in the past and are treated with Pemetrexed Injection. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation. The most common side effects of Pemetrexed Injection when given alone are: • tiredness • nausea • loss of appetite The most common side effects of Pemetrexed Injection when given with cisplatin are: • vomiting • swelling or sores in your mouth or sore throat • constipation • low white blood cell counts (neutropenia) • low platelet counts (thrombocytopenia) • low red blood cell counts (anemia) The most common side effects of Pemetrexed Injection when given with pembrolizumab and platinum chemotherapy are: • tiredness and weakness • constipation • loss of appetite • vomiting • shortness of breath • nausea • diarrhea • rash • cough • fever Pemetrexed Injection may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you. Your healthcare provider will do blood tests to check for side effects during treatment with Pemetrexed Injection. Your healthcare provider may change your dose of Pemetrexed Injection, delay treatment, or stop treatment if you have certain side effects. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of Pemetrexed Injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Pemetrexed Injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Pemetrexed Injection that is written for health professionals. What are the ingredients in Pemetrexed Injection? Active ingredient: pemetrexed Inactive ingredients: mannitol, sodium chloride, L-cysteine hydrochloride, sodium hydroxide and/or hydrochloric acid to adjust pH, and water for injection. Manufactured by: Zydus Lifesciences Limited, Ahmedabad, India. Manufactured for: Shilpa Medicare Limited, Jadcherla-509301, India. For more information, call 1-888-557-1212. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: November 2024 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ramesh Raghavachari Digitally signed by Ramesh Raghavachari Date: 11/15/2024 01:48:10PM GUID: 502d0913000029f375128b0de8c50020 ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:48.519044	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215179Orig1s002lbl.pdf', 'application_number': 215179, 'submission_type': 'SUPPL ', 'submission_number': 2}
80,248	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BELEODAQ safely and effectively. See full prescribing information for BELEODAQ. BELEODAQ® (belinostat) for injection, for intravenous use Initial U.S. Approval: 2014 ---------------------------RECENT MAJOR CHANGES--------------------------- Dosage and Administration (2.3, 2.4, 2.6) M/202Y -------------------------INDICATIONS AND USAGE------------------------------ Beleodaq is a histone deacetylase inhibitor indicated for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. (1) ---------------------DOSAGE AND ADMINISTRATION------------------------- • Recommended dosage of Beleodaq is 1,000 mg/m2 administered over 30 minutes by intravenous infusion once daily on days 1 through 5 of a 21-day cycle. Cycles can be repeated until disease progression or unacceptable toxicity. (2.1) • Treatment discontinuation or interruption with or without dosage reductions by 25% may be needed to manage adverse reactions (2.2) • Reduce dosage in patients with moderate hepatic or renal impairment. (2.3, 2.4, 8.6, 8.7) • Avoid use in patients with severe hepatic or renal impairment. (2.3, 2.4, 8.6, 8.7) • Modify dosage in patients known to be homozygous for the UGT1A128 allele. (2.5) • See the full prescribing information for preparation and administration instructions. (2.7) --------------------DOSAGE FORMS AND STRENGTHS----------------------- For injection: 500 mg, lyophilized powder in single-dose vial for reconstitution (3) ---------------------------CONTRAINDICATIONS---------------------------------- None. (4) ---------------------WARNINGS AND PRECAUTIONS-------------------------- • Hematologic Toxicity: Thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia: Monitor blood counts and modify dosage for hematologic toxicities. (2.2, 5.1) • Infection: Serious and fatal infections (e.g., pneumonia and sepsis). (5.2) • Hepatotoxicity: Beleodaq may cause hepatic toxicity and liver function test abnormalities. Monitor liver function tests and omit or modify dosage for hepatic toxicities. (2.2, 5.3) • Tumor lysis syndrome: Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions (5.4) • Gastrointestinal Toxicity: Nausea, vomiting, and diarrhea occur with Beleodaq and may require antiemetic and antidiarrheal medications. (5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. (5.6) ------------------------------ADVERSE REACTIONS------------------------------- The most common adverse reactions (>25%) are nausea, fatigue, pyrexia, anemia, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Acrotech Biopharma Inc at 1-888-292-9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------------------DRUG INTERACTIONS-------------------------- UGT1A1 Inhibitors: Avoid use or modify dosage if use is unavoidable. (2.6, 7.1) ---------------------USE IN SPECIFIC POPULATIONS-------------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Dosage Modification for Hematologic and Non-Hematologic Toxicities 2.3 Recommended Dosage in Patients with Hepatic Impairment 2.4 Recommended Dosage in Patients with Renal Impairment 2.5 Dosage Modification for Patients with Reduced UGT1A1 Activity 2.6 Dosage Modification for Concomitant Use with UGT1A1 Inhibitors 2.7 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Toxicity 5.2 Infections 5.3 Hepatotoxicity 5.4 Tumor Lysis Syndrome 5.5 Gastrointestinal Toxicity 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 UGT1A1 Inhibitors 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Use in Patients with Hepatic Impairment 8.7 Use in Patients with Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Beleodaq is indicated for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14)]. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of Beleodaq is 1,000 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1 through 5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. 2.2 Dosage Modification for Hematologic and Non-Hematologic Toxicities Table 1 displays the recommended Beleodaq dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy. • Absolute neutrophil count (ANC) should be greater than or equal to 1 x 109/L and the platelet count should be greater than or equal to 50 x 109/L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Beleodaq according to the guidelines described in Table 1 below. Discontinue Beleodaq in patients who have recurrent ANC nadirs less than 0.5 x 109/L and/or recurrent platelet count nadirs less than 25 x 109/L after two dosage reductions. • Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment. Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle. Table 1: Dosage Modifications for Hematologic and Non-Hematologic Toxicities Dosage Modification Dosage Modifications due to Hematologic Toxicities Platelet count ≥ 25 x 109/L and nadir ANC ≥ 0.5 x 109/L No Change Nadir ANC < 0.5 x 109/L (any platelet count) Decrease dosage by 25% (750 mg/m2) Platelet count < 25 x 109/L (any nadir ANC) Dosage Modifications due to Non-Hematologic Toxicities Any CTCAE Grade 3 or 4 adverse reactiona Decrease dosage by 25% (750 mg/m2) Recurrence of CTCAE Grade 3 or 4 adverse reaction after two dosage reductions Discontinue Beleodaq a For nausea, vomiting, and diarrhea, dose modification may not be necessary if the duration is less than 7 days with supportive management 2.3 Recommended Dosage in Patients with Hepatic Impairment Beleodaq dosage in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN, any aspartate aminotransferase (AST)) is 500 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1 through 5 of a 21-day cycle. Avoid use of Beleodaq in patients with severe hepatic impairment (total bilirubin > 3 x ULN, any AST). No dosage adjustment is recommended for patients with mild hepatic Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda impairment (total bilirubin ≤ 1.5 x ULN, any AST). Hepatic impairment is defined per the National Cancer Institute Organ Dysfunction Working Group. 2.4 Recommended Dosage in Patients with Renal Impairment Beleodaq dosage in patients with moderate renal impairment (creatine clearance [CLcr] 30 to <60 mL/min) is 500 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1 through 5 of a 21-day cycle. Avoid use of Beleodaq in patients with severe renal impairment (CLcr < 30 mL/min). No dosage adjustment is recommended for patients with mild renal impairment (CLcr 60 to < 90 mL/min). 2.5 Dosage Modification for Patients with Reduced UGT1A1 Activity Reduce the starting dose of Beleodaq to 750 mg/m2 in patients known to be homozygous for the UGT1A128 allele [see Clinical Pharmacology (12.5)]. 2.6 Dosage Modification for Concomitant Use with UGT1A1 Inhibitors Avoid concomitant use of Beleodaq with UGT1A1 inhibitors. If concomitant use of a UGT1A1 inhibitor is unavoidable, reduce the Beleodaq dosage by 25% as shown in Table 2. Table 2: Dosage Modifications for Concomitant Use with a UGT1A1 Inhibitor Beleodaq Starting Dosage Beleodaq Modified Dosage 1,000 mg/m2 750 mg/m2 750 mg/m2 562.5 mg/m2 500 mg/m2 Interrupt Beleodaq treatment for the duration of UGT1A1 inhibitor use. After discontinuation of a UGT1A1 inhibitor of 5 half-lives, resume the Beleodaq dosage that was taken prior to initiating the UGT1A1 inhibitor. 2.7 Preparation and Administration Beleodaq is a hazardous drug. Follow applicable special handling and disposal procedures.1 Preparation: • Aseptically reconstitute each vial of Beleodaq by adding 9 mL of Sterile Water for Injection into the Beleodaq vial with a suitable syringe to achieve a concentration of 50 mg of belinostat per mL. Swirl the contents of the vial until there are no visible particles in the resulting solution. If not used immediately, the reconstituted product may be stored for up to 12 hours at room temperature (15°C to 25°C; 59°F to 77°F). • Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient’s BSA [m2]) and transfer to an infusion bag containing 250 mL of 0.9 % Sodium Chloride Injection. If not used immediately, the infusion bag with drug solution may be stored at room temperature (15°C to 25°C; 59°F to 77°F) for up to 36 hours including infusion time. • Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed. Administration: • Connect the infusion bag containing drug solution to an infusion set with a 0.22 micron in-line filter for administration. • Infuse intravenously over 30 minutes. If infusion site pain or other symptoms potentially attributable to the infusion occur, the infusion time may be extended to 45 minutes. Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DOSAGE FORMS AND STRENGTHS For injection: 500 mg, lyophilized powder in single-dose vial for reconstitution 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Toxicity Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.2 Infections Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections [see Adverse Reactions (6.1)]. 5.3 Hepatotoxicity Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL [see Clinical Studies (14)]. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see Adverse Reactions (6.1)]. 5.5 Gastrointestinal Toxicity Nausea, vomiting and diarrhea occur with Beleodaq [see Adverse Reactions (6.1)] and may require the use of antiemetic and antidiarrheal medications. 5.6 Embryo-Fetal Toxicity Based on its mechanism of action and findings of genotoxicity, Beleodaq can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with Beleodaq and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in more detail in other sections of the prescribing information. • Hematologic Toxicity [see Warnings and Precautions (5.1)] • Infection [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] • Gastrointestinal Toxicity [see Warnings and Precautions (5.5)] Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Beleodaq may not reflect the rates observed in practice. Adverse Reactions in Patients with Peripheral T-Cell Lymphoma The safety of Beleodaq was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Beleodaq at a dosage of 1,000 mg/m2 administered over 30 minutes by IV infusion once daily on Days 1 through 5 of a 21-day cycle [see Clinical Studies (14)]. The median duration of treatment was 2 cycles (range 1 – 33 cycles). The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with Beleodaq were nausea, fatigue, pyrexia, anemia, and vomiting [see Clinical Studies (14)]. Table 3 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL. Table 3: Adverse Reactions Occurring in ≥ 10% of Patients with Relapsed or Refractory PTCL (NCI-CTC Grade 1-4) Adverse Reactions Percentage of Patients (%) (N=129) All Grades Grade 3 or 4 All Adverse Reactions 97 61 Nausea 42 1 Fatigue 37 5 Pyrexia 35 2 Anemia 32 11 Vomiting 29 1 Constipation 23 1 Diarrhea 23 2 Dyspnea 22 6 Rash 20 1 Peripheral Edema 20 0 Cough 19 0 Thrombocytopenia 16 7 Pruritus 16 3 Chills 16 1 Increased Blood Lactate Dehydrogenase 16 2 Decreased Appetite 15 2 Headache 15 0 Infusion Site Pain 14 0 Hypokalemia 12 4 Prolonged QT 11 4 Abdominal pain 11 1 Hypotension 10 3 Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions Percentage of Patients (%) (N=129) All Grades Grade 3 or 4 Phlebitis 10 1 Dizziness 10 0 Note: Adverse reactions are listed by order of incidence in the “All Grades” category first, then by incidence in “ the Grade 3 or 4” category; Measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 Serious Adverse Reactions Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq . The most common serious adverse reactions (> 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial. One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with Beleodaq. ECG analysis did not identify QTc prolongation. Discontinuations due to Adverse Reactions Twenty-five patients (19.4%) discontinued treatment with Beleodaq due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure. Dosage Modifications due to Adverse Reactions In the trial, dosage adjustments due to adverse reactions occurred in 12% of Beleodaq-treated patients. 7 DRUG INTERACTIONS 7.1 UGT1A1 Inhibitors Avoid concomitant administration of Beleodaq with UGT1A1inhibitors. If concomitant use of a UGT1A1 inhibitor is unavoidable, modify the Beleodaq dose [see Dosage and Administration (2.6)]. Belinostat is primarily metabolized by UGT1A1. Concomitant use with a UGT1A1 inhibitor increases belinostat exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Beleodaq adverse reactions. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, Beleodaq can cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. There are no available data on Beleodaq use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. No animal reproduction studies were conducted with Beleodaq. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 8.2 Lactation Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Risk Summary There are no data on the presence of belinostat in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with Beleodaq, and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Beleodaq can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating Beleodaq. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Beleodaq and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings from animal studies, Beleodaq may impair male fertility. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of Beleodaq in pediatric patients have not been established. 8.5 Geriatric Use In the single-arm trial, 48% of patients (N = 62) were ≥ 65 years of age and 10% of patients (N=13) were ≥ 75 years of age [see Clinical Studies (14)]. The median age of the trial population was 63 years. Patients ≥ 65 years of age had a higher response rate to Beleodaq treatment than patients < 65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients ≥ 75 years of age and those < 75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age (< 65 years compared with ≥ 65 years or < 75 years of age compared with ≥ 75 years of age). 8.6 Use in Patients with Hepatic Impairment No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ 1.5 x ULN, any AST). Reduce the Beleodaq dosage in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN, any AST) [see Dosage and Administration (2.3)]. Avoid use of Beleodaq in patients with severe hepatic impairment (total bilirubin > 3 x ULN, any AST) [see Clinical Pharmacology (12.3)]. Belinostat is metabolized in the liver, moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN, any AST) and severe hepatic impairment (total bilirubin > 3 x ULN, any AST) increases belinostat exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Beleodaq adverse reactions. 8.7 Use in Patients with Renal Impairment No dosage adjustment is recommended for patients with mild renal impairment (CLcr 60 to < 90 mL/min). Reduce the Beleodaq dosage in in patients with moderate renal impairment (CLcr 30 to <60 mL/min) [see Dosage and Administration (2.4)]. Avoid use of Beleodaq in patients with severe renal impairment (CLcr < 30 mL/min). Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Moderate renal impairment (CLcr 30 to <60 mL/min) increases belinostat exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Beleodaq adverse reactions. The effect of severe renal impairment (CLcr < 30 mL/min) on belinostat pharmacokinetics is unknown [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of Beleodaq. There is no antidote for Beleodaq and it is not known if Beleodaq is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The elimination half-life of belinostat is 1.1 hours [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION Beleodaq is a histone deacetylase inhibitor with a sulfonamide-hydroxamide structure. The chemical name of belinostat is (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide. The structural formula is as follows: H N S H N OH O O O The molecular formula is C15H14N2O4S and the molecular weight is 318.35 g/mol. Belinostat is a white to off-white powder. It is slightly soluble in distilled water (0.14 mg/mL) and polyethylene glycol 400 (about 1.5 mg/mL), and is freely soluble in ethanol (> 200 mg/mL). The pKa values are 7.87 and 8.71 by potentiometry and 7.86 and 8.59 by UV. Beleodaq (belinostat) for injection is supplied as a sterile lyophilized yellow powder containing 500 mg belinostat as the active ingredient. Each vial also contains 1000 mg L-Arginine, USP as an inactive ingredient. The drug product is supplied in a single-dose clear glass vial with a coated stopper and aluminum crimp seal with “flip-off” cap. Beleodaq is intended for intravenous administration after reconstitution with 9 mL Sterile Water for injection, and the reconstituted solution is further diluted with 250 mL of sterile 0.9% Sodium Chloride injection prior to infusion [see Dosage and Administration (2)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Beleodaq is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM). 12.2 Pharmacodynamics Belinostat exposure-response relationships and the time course of pharmacodynamic response are not fully characterized. Cardiac Electrophysiology Multiple clinical trials have been conducted with Beleodaq, in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Beleodaq on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes. Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12.3 Pharmacokinetics The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m2 (0.15 to 1.2 times the approved recommended dosage). Distribution The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL. Elimination Belinostat elimination half-life is 1.1 hours with a total mean plasma clearance of 1240 mL/min. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent). Metabolism Belinostat is primarily metabolized by hepatic UGT1A1. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes. Excretion Following a single dose of radiolabeled belinostat (100 μCi, 1500 mg) administered as a 30-minute intravenous infusion in patients with recurrent or progressive malignancy, fecal excretion accounted for a mean (± SD) of 9.7% (± 6.5%) of the administered radioactive belinostat dose over 168 hours. The mean (± SD) of the administered radioactive belinostat dose that was excreted in urine over 168 hours was 84.8% (± 9.8%), of which unchanged belinostat accounted for only 1.7%. Specific Populations Hepatic Impairment Belinostat steady state clearance decreased and AUC increased as a function of the degree of liver dysfunction, but were unchanged for Cmax, half‐life and apparent volume of distribution. Mean belinostat clearance was reduced by 18% in mild (total bilirubin ≤ ULN and AST >ULN, or total bilirubin ˃1 to 1.5 x ULN), 24% in moderate (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) and 33% in severe hepatic impairment (total bilirubin ˃ 3 to 10 times ULN and any value for AST). Increases in belinostat exposure were correlated with worsening liver function, but there was no obvious relationship between exposure and DLTs during the first cycle of therapy. Renal Impairment Belinostat Cmax increased by 1.7-fold, AUC0-∞ by 1.3-fold and CLtot was unchanged in patients with mild renal impairment (CLcr 60 to <90 ml/min). Belinostat Cmax and AUC0-∞ increased by 1.7-fold and CLtot decreased by 26% in patients with moderate renal impairment (CLcr 30 < 60 ml/min). The effect of severe renal impairment (CLcr < 30 mL/min) on belinostat pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches UGT1A1 inhibitors: Belinostat t1/2 increased by 1.5-fold, AUC0-inf increased by 1.4-fold, Cmax decreased by 33%, and renal excretion increased by 2.5-fold following concomitant administration with atazanavir (UGT1A1 inhibitor), but there was minimal change in steady state clearance. There was minimal change in belinostat glucuronide Cmax, AUC0-24; however, belinostat glucuronide excretion decreased by 48%. Warfarin: No clinically significant differences in the pharmacokinetics of R- or S-warfarin were observed when used concomitantly with belinostat. Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Vitro Studies CYP450 Enzymes: Belinostat and its metabolites are CYP2C8 and CYP2C9 inhibitors. Transporter Systems: Belinostat is a glycoprotein (P-gp) substrate but is not a P-gp inhibitor. 12.5 Pharmacogenomics UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A128 polymorphism. Approximately 20% of the Black population, 10% of the White population, and 2% of the Asian population are homozygous for the UGT1A128 allele. Additional reduced function alleles may be more prevalent in specific populations. Because belinostat is primarily (80-90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A128 allele). Reduce the starting dose of Beleodaq to 750 mg/m2 in patients known to be homozygous for the UGT1A128 allele to minimize dose limiting toxicities [see Dosage and Administration (2.5)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with belinostat. Belinostat was genotoxic in a bacterial reverse mutation test (AMES assay), an in vitro mouse lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay. Beleodaq may impair male fertility. Fertility studies using belinostat were not conducted. However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose dog toxicology study included reduced organ weights of the testes/epididymides that correlated with a delay in testicular maturation. 14 CLINICAL STUDIES Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL) In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Beleodaq 1,000 mg/m2 administered over 30 minutes via IV infusion once daily on Days 1 through 5 of a 21-day cycle. There were 120 patients who had histologically confirmed PTCL by central review evaluable for efficacy. Patients were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity. Efficacy was evaluated using response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC) (Cheson 2007). Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. Response and progression of disease were evaluated by the IRC using the IWC. Table 4 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy. Table 4: Baseline Patient Characteristics (PTCL Population) Characteristics Evaluable Patients (N=120) Age (years) Median (range) 64 (29 - 81) Sex, % Male 52 Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Characteristics Evaluable Patients (N=120) Female 48 Race, % White Black Asian Latin Other 88 6 3 3 2 PTCL Subtype Based on Central Diagnosis, % PTCL Unspecified (NOS) Angioimmunoblastic T-cell lymphoma (AITL) ALK-1 negative anaplastic large cell lymphoma (ALCL) Other 64 18 11 7 Baseline Platelet Count, % ≥100,000/μL <100,000/μL 83 17 ECOG Performance Status, % 0 1 2 3 34 43 22 1 Median Time (months) from Initial PTCL Diagnosis (Range) 12 (2.6 - 266.4) Median Number of Prior Systemic Therapies (Range) 2 (1 - 8) In all evaluable patients (N = 120) treated with Beleodaq, the overall response rate per central review using IWC was 25.8% (N = 31) (Table 5) with rates of 23.4% for PTCL, NOS and 45.5% for AITL, the two largest subtypes enrolled. Table 5: Response Analysis per Central Assessment Using IWC in Patients with Relapsed or Refractory PTCL Evaluable Patients (N=120) Response Rate N (%) (95% CI) CR+PR 31 (25.8) 18.3 - 34.6 CR 13 (10.8) 5.9 - 17.8 PR 18 (15.0) 9.1 - 22.7 CI=confidence interval, CR=complete response, PR=partial response The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 - 29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3 - 50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Beleodaq. 15 REFERENCES 1 OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Beleodaq (belinostat) for injection is supplied in single vial cartons; each clear vial contains sterile, lyophilized powder equivalent to 500 mg belinostat. NDC 72893-002-01: Individual carton of Beleodaq single-dose vial containing 500 mg belinostat. Storage and Handling Store Beleodaq (belinostat) for injection at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Retain in original package until use. [see USP Controlled Room Temperature]. Beleodaq is a hazardous drug. Follow special handling and disposal procedures.1 17 PATIENT COUNSELING INFORMATION Physicians should discuss the FDA approved Patient Information Leaflet with patients prior to treatment with Beleodaq. Instruct patients to read the Patient Information Leaflet carefully. Advise the patient or the caregiver to read the FDA-approved patient labeling (Patient Information). Advise patients or their caregivers: • To report symptoms of nausea, vomiting and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered [see Warnings and Precautions (5.5)]. • To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia [see Warnings and Precautions (5.1)]. • To immediately report symptoms of infection (e.g., pyrexia) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. • Of the potential risk to the fetus and for women to avoid pregnancy and use effective contraception while receiving Beleodaq and for 6 months after the last dose [see Warnings and Precautions (5.6)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose. • To avoid breastfeeding while receiving Beleodaq and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]. • To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. Manufactured by: Cenexi Laboratories Thissen SA Braine I'Alleud, 1420, Belgium Manufactured for: Acrotech Biopharma Inc East Windsor, NJ 08520 USA Beleodaq is a registered trademark of Acrotech Biopharma Inc. All rights are reserved. U.S. Patent: 6,888,027 Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION BELEODAQ® (Bē-lēo-dak) (belinostat) for injection, for intravenous use Read this Patient Information before you receive treatment with Beleodaq and each time you receive Beleodaq. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. What is Beleodaq? Beleodaq is a prescription medicine used to treat people with a type of cancer called peripheral T-cell Lymphoma (PTCL) that comes back or does not respond to cancer treatment. It is not known if Beleodaq is safe and effective in children. What should I tell my doctor before receiving Beleodaq? Before receiving Beleodaq, tell your doctor about all of your medical conditions, including if you: • have an infection • have had chemotherapy treatment • have liver or kidney problems • have nausea, vomiting, or diarrhea • are pregnant or plan to become pregnant. Beleodaq can harm your unborn baby. You should not become pregnant while receiving Beleodaq. Tell your doctor right away if you become pregnant while receiving Beleodaq. • are breastfeeding or plan to breastfeed. It is not known if Beleodaq passes into your breast milk. You and your doctor should decide if you will receive Beleodaq or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive Beleodaq? • Beleodaq will be given to you by intravenous (IV) injection into your vein, usually over 30 minutes. • Beleodaq is given one time a day on Days 1 through 5 of a 21-day cycle of treatment. • You should have regular blood tests before and during your treatment with Beleodaq. • Your doctor may change your dose of Beleodaq, change when you receive your treatment, or stop treatment if you have certain side effects while receiving Beleodaq. What are the possible side effects of Beleodaq? Beleodaq may cause serious side effects, including: • Low blood cell counts. Your doctor will do blood tests to check your blood counts during your treatment with Beleodaq. o Low platelet counts can cause unusual bleeding or bruising under your skin. o Low red blood cell counts may make you feel weak, tired, or you get tired easily, you look pale, or you feel short of breath. o Low white blood cell counts can cause you to get infections, which may be serious. • Serious infections. People receiving Beleodaq may develop serious infections that can sometimes lead to death. You may have a greater risk of life-threatening infections if you have had chemotherapy in the past. Tell your doctor right away if you have any of the following signs or symptoms of an infection: fever, flu-like symptoms, cough, shortness of breath, burning with urination, muscle aches, or worsening skin problems. • Liver problems. Beleodaq may cause liver problems which can lead to death. Your doctor will do blood tests during your treatment with Beleodaq to check for liver problems. Tell your doctor right away if you have any of the following signs or symptoms of liver problems: yellowing of the skin or the white part of your eyes (jaundice), dark urine, itching, or pain in the right upper stomach area. • Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. Your doctor will check you for TLS during treatment with Beleodaq. • Nausea, vomiting, and diarrhea are common with Beleodaq and can sometimes be serious. Tell your doctor if you develop nausea, vomiting or diarrhea. Your doctor may prescribe medicines to help prevent or treat these side effects. Common side effects of Beleodaq include fatigue, fever, and low red blood cell count. Tell your doctor if you have any side effect that bothers you or that does not go away. Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda These are not all the possible side effects of Beleodaq. Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088. General information about Beleodaq Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or doctor for information about Beleodaq that is written for health professionals. What are the ingredients in Beleodaq? Active ingredient: belinostat Inactive ingredients: L-Arginine Manufactured by: Cenexi Laboratories Thissen SA, Braine l'Alleud, 1420, Belgium Manufactured for: Acrotech Biopharma Inc, East Windsor, NJ 08520 USA Beleodaq is a registered trademark of Acrotech Biopharma Inc. All rights reserved. For more information, go to www.Beleodaq.com or call 1-888-292-9617. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11 2024 Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ NICHOLAS C RICHARDSON 11/19/2024 04:57:01 PM Signature Page 1 of 1 Reference ID: 5481092 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:48.941218	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206256Orig1s006lbl.pdf', 'application_number': 206256, 'submission_type': 'SUPPL ', 'submission_number': 6}
80,235	® Cetirizine HCl orally disintegrating tablets 10 mg/antihistamine 0 00000 00000 0 Active ingredient made in Switzerland Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI XXXX Pat. www.jjcipats.com 00000000/000-00-00000.00 www.zyrtec.com DISSOLVE TABS Sugar-Free • Dye-Free DISSOLVE TABS Sugar-Free • Dye-Free ® ALLERGY Citrus Flavor Melts in your mouth Orally Disintegrating Tablets 12 10 mg each ALLERGY Indoor & Outdoor Allergies yrs & older 6 24 HOUR DISSOLVE TABS Sneezing Runny Nose Actual Size Relief of Itchy, Watery Eyes Itchy Throat or Nose Sugar-Free • Dye-Free NDC 00000-000-00 Original Prescription Strength New look Same relief 00000000 00000000 Citrus Flavor The trade dress of this ZYRTEC® package is subject to trademark protection. 00000000 00000000 Drug Facts (cont nued) Drug Facts Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg ............................................ Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ sneezing ■ itchy, watery eyes ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions Tablet melts in mouth. Can be taken with or without water. Other information ■ store between 20° to 25°C (68° to 77°F). Avoid high humidity. ■ do not use if blister unit is torn or broken Inactive ingredients amino methacrylate copolymer, anhydrous citric acid, colloidal silicon dioxide, crospovidone, ﬂavors, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, sodium bicarbonate, sodium starch glycolate, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect) one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. ask a doctor ask a doctor ask a doctor adults and children 6 years and over consumers with liver or kidney disease adults 65 years and over children under 6 years of age ® ALLERGY HelveticaNeueLTStd Cond, Bold Cond, Bold Cond Obl 11.00 8.00 6.00 6.00 6.50 8.00 5.00 2.50 0.50 82% -10 Cetirizine HCl Cetirizine HCl Cetirizine HCl Cetirizine HCl Reference ID: 5479297 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ® Cetirizine HCl orally disintegrating tablets 10 mg/antihistamine 0 00000 00000 0 Active ingredient made in Switzerland Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI XXXX Pat. www.jjcipats.com 00000000/000-00-00000.00 www.zyrtec.com Citrus Flavor Melts in your mouth Orally Disintegrating Tablets 24 10 mg each ALLERGY Indoor & Outdoor Allergies yrs & older 6 24 HOUR DISSOLVE TABS Sneezing Runny Nose Actual Size Relief of Itchy, Watery Eyes Itchy Throat or Nose Sugar-Free • Dye-Free NDC 00000-000-00 Original Prescription Strength New look Same relief Citrus Flavor The trade dress of this ZYRTEC® package is subject to trademark protection. 00000000 00000000 DISSOLVE TABS Sugar-Free • Dye-Free ® ALLERGY ® ALLERGY DISSOLVE TABS Sugar-Free • Dye-Free Drug Facts (cont nued) Drug Facts Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg ............................................ Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ sneezing ■ itchy, watery eyes ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions Tablet melts in mouth. Can be taken with or without water. Other information ■ store between 20° to 25°C (68° to 77°F). Avoid high humidity. ■ do not use if blister unit is torn or broken Inactive ingredients amino methacrylate copolymer, anhydrous citric acid, colloidal silicon dioxide, crospovidone, ﬂavors, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, sodium bicarbonate, sodium starch glycolate, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect) one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. ask a doctor ask a doctor ask a doctor adults and children 6 years and over consumers with liver or kidney disease adults 65 years and over children under 6 years of age HelveticaNeueLTStd Cond, Bold Cond, Bold Cond Obl 11.00 8.00 6.00 6.00 6.50 8.00 5.00 2.50 0.50 82% -10 Cetirizine HCl Cetirizine HCl Cetirizine HCl Cetirizine HCl Reference ID: 5479297 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine 00000000/000000 00000000/000000 00000000/000000 00000000/000000 00000000/ 000000 00000000/ 000000 LOT EXP LOT EXP LOT EXP LOT EXP LOT EXP LOT EXP 1E 1F 1C 1D 1B 1A Reference ID: 5479297 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Citrus Flavor Melts in your mouth 10 mg each 0 00000 00000 0 Active Ingredient Made in Switzerland Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI XXXX Pat. www.jjcipats.com 00000000/000-00-00000.00 www.zyrtec.com ALLERGY NDC 00000-000-00 ® DISSOLVE TABS Dye-Free Original Prescription Strength New look Same relief DISSOLVE TABS Dye-Free Orally Disintegrating Tablets 24 Sneezing Relief of Runny Nose Itchy,Watery Eyes Itchy Throat or Nose Actual Size Dye-Free 24 HOUR DISSOLVE TABS Indoor & Outdoor Allergies 10 mg The trade dress of this ZYRTEC® package is subject to trademark protection. 00000000 00000000 Citrus Flavor Drug Facts (cont nued) Drug Facts Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg ............................................ Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ sneezing ■ itchy, watery eyes ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions Tablet melts in mouth. Can be taken with or without water. Other information ■ store between 20° to 25°C (68° to 77°F). Avoid high humidity. ■ do not use if blister unit is torn or broken Inactive ingredients amino methacrylate copolymer, anhydrous citric acid, colloidal silicon dioxide, crospovidone, ﬂavors, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, sodium bicarbonate, sodium starch glycolate, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect) one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. ask a doctor ask a doctor ask a doctor adults and children 6 years and over consumers with liver or kidney disease adults 65 years and over children under 6 years of age ALLERGY ® ALLERGY ® Cetirizine HCl orally disintegrating tablets 10 mg/antihistamine HelveticaNeueLTStd Cond, Bold Cond, Bold Cond Obl 11.00 8.00 6.00 6.00 6.50 8.00 5.00 2.50 0.50 82% -10 Cetirizine HCl Cetirizine HCl Cetirizine HCl Cetirizine HCl Reference ID: 5479297 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD ON DOTTED LINE AND TEAR OR USE SCISSORS FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR FOLD \| TEAR 00000000/000000 00000000/000000 00000000/000000 00000000/000000 00000000/ 000000 00000000/ 000000 LOT EXP LOT EXP LOT EXP LOT EXP LOT EXP LOT EXP 1E 1F 1C 1D 1B 1A Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Active ingredient made in Switzerland Dist. by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 20XX Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Cetirizine HCl orally disintegrating tablets 10mg/antihistamine Reference ID: 5479297 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ NUSHIN F TODD 11/15/2024 04:29:53 PM Signature Page 1 of 1 Reference ID: 5479297 ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:49.065170	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022578Orig1s014lbl.pdf', 'application_number': 22578, 'submission_type': 'SUPPL ', 'submission_number': 14}
80,249	1 (Rifabutin) Capsules, USP DESCRIPTION MYCOBUTIN Capsules for oral administration contain 150 mg of the rifamycin antimycobacterial agent rifabutin, USP, per capsule, along with the inactive ingredients, microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink. The chemical name for rifabutin is 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1- oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9S,12E,14S,15R, 16S,17R,18R,19R,20S,21S,22E, 24Z)-6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy- 7,9,15,17,19,21,25-heptamethyl-spiro [9,4-(epoxypentadeca[1,11,13]trienimino)-2H- furo[2',3':7,8]naphth[1,2-d] imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-trione-16-acetate. Rifabutin has a molecular formula of C46H62N4O11, a molecular weight of 847.02 and the following structure: Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water). CLINICAL PHARMACOLOGY Pharmacokinetics Absorption: Following a single oral dose of 300 mg to nine healthy adult volunteers, rifabutin was readily absorbed from the gastrointestinal tract with mean (±SD) peak plasma levels (Cmax) of 375 (±267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (±0.9) hours (Tmax range: 2 to 4 hours). Absolute bioavailability assessed in five HIV-positive patients, who received both oral Reference ID: 5482092 2 and intravenous doses, averaged 20%. Total recovery of radioactivity in the urine indicates that at least 53% of the orally administered rifabutin dose is absorbed from the gastrointestinal tract. The bioavailability of rifabutin from the capsule dosage form, relative to an oral solution, was 85% in 12 healthy adult volunteers. High-fat meals slow the rate without influencing the extent of absorption from the capsule dosage form. Plasma concentrations post-Cmax declined in an apparent biphasic manner. Pharmacokinetic dose-proportionality was established over the 300 mg to 600 mg dose range in nine healthy adult volunteers (crossover design) and in 16 early symptomatic human immunodeficiency virus (HIV)-positive patients over a 300 mg to 900 mg dose range. Distribution: Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Following intravenous dosing, estimates of apparent steady-state distribution volume (9.3 ± 1.5 L/kg) in five HIV-positive patients exceeded total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung-to-plasma concentration ratio, obtained at 12 hours, was approximately 6.5 in four surgical patients who received an oral dose. Mean rifabutin steady-state trough levels (Cp,minss; 24-hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive patients and in healthy adult volunteers. About 85% of the drug is bound in a concentration-independent manner to plasma proteins over a concentration range of 0.05 to 1 µg/mL. Binding does not appear to be influenced by renal or hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven healthy adult volunteers, presumably because of distribution-limited elimination, with a mean terminal half-life of 45 (±17) hours (range: 16 to 69 hours). Although the systemic levels of rifabutin following multiple dosing decreased by 38%, its terminal half-life remained unchanged. Metabolism: Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite:parent area under the curve ratio of 0.10 and 0.07, respectively. The former has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity. Excretion: A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Mean systemic clearance (CLs/F) in healthy adult volunteers following a single oral dose was 0.69 (±0.32) L/hr/kg (range: 0.46 to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute approximately 5% to CLs/F. Pharmacokinetics in Special Populations Geriatric: Compared to healthy volunteers, steady-state pharmacokinetics of MYCOBUTIN are more variable in elderly patients (>70 years). Pediatric: The pharmacokinetics of MYCOBUTIN have not been studied in subjects under 18 years of age. Reference ID: 5482092 3 Renal Impairment: The disposition of rifabutin (300 mg) was studied in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) increased by about 71% in patients with severe renal impairment (creatinine clearance below 30 mL/min) compared to patients with creatinine clearance (Crcl) between 61–74 mL/min. In patients with mild to moderate renal impairment (Crcl between 30–61 mL/min), the AUC increased by about 41%. In patients with severe renal impairment, carefully monitor for rifabutin associated adverse events. A reduction in the dosage of rifabutin is recommended for patients with Crcl <30 mL/min if toxicity is suspected (see DOSAGE AND ADMINISTRATION). Hepatic Impairment: Mild hepatic impairment does not require a dose modification. The pharmacokinetics of rifabutin in patients with moderate and severe hepatic impairment is not known. Malabsorption in HIV-Infected Patients: Alterations in gastric pH due to progressing HIV disease has been linked with malabsorption of some drugs used in HIV-positive patients (e.g., rifampin, isoniazid). Drug serum concentrations data from AIDS patients with varying disease severity (based on CD4+ counts) suggests that rifabutin absorption is not influenced by progressing HIV disease. Drug-Drug Interactions (see also PRECAUTIONS-Drug Interactions) Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutin’s predominant metabolite (25-desacetyl rifabutin: LM565), may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a decrease in plasma concentrations of concomitantly administered drugs that are primarily metabolized by the CYP3A enzymes. Similarly concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin. CLINICAL STUDIES Two randomized, double-blind clinical trials (Study 023 and Study 027) compared MYCOBUTIN (300 mg/day) to placebo in patients with CDC-defined AIDS and CD4 counts ≤200 cells/µL. These studies accrued patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median CD4 cell count at study entry of 42 cells/µL (mean 61). Study 027 enrolled 556 patients with a median CD4 cell count at study entry of 40 cells/µL (mean 58). Endpoints included the following: (1) MAC bacteremia, defined as at least one blood culture positive for Mycobacterium avium complex (MAC) bacteria. (2) Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including one or more of the following: fever, night sweats, rigors, weight loss, worsening anemia, and/or elevations in alkaline phosphatase. (3) Survival. Reference ID: 5482092 4 MAC Bacteremia Participants who received MYCOBUTIN were one-third to one-half as likely to develop MAC bacteremia as were participants who received placebo. These results were statistically significant (Study 023: p<0.001; Study 027: p = 0.002). In Study 023, the one-year cumulative incidence of MAC bacteremia, on an intent to treat basis, was 9% for patients randomized to MYCOBUTIN and 22% for patients randomized to placebo. In Study 027, these rates were 13% and 28% for patients receiving MYCOBUTIN and placebo, respectively. Most cases of MAC bacteremia (approximately 90% in these studies) occurred among participants whose CD4 count at study entry was ≤100 cells/µL. The median and mean CD4 counts at onset of MAC bacteremia were 13 cells/µL and 24 cells/µL, respectively. These studies did not investigate the optimal time to begin MAC prophylaxis. Clinically Significant Disseminated MAC Disease In association with the decreased incidence of bacteremia, patients on MYCOBUTIN showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic dysfunction. Survival The one-year survival rates in Study 023 were 77% for the group receiving MYCOBUTIN and 77% for the placebo group. In Study 027, the one-year survival rates were 77% for the group receiving MYCOBUTIN and 70% for the placebo group. These differences were not statistically significant. Microbiology Mechanism of Action Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli, rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC). Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. In Vitro Studies Rifabutin has demonstrated in vitro activity against M. avium complex (MAC) organisms isolated from both HIV-positive and HIV-negative people. While-gene probe techniques may be used to identify these two organisms, many reported studies did not distinguish between these two species. The vast majority of isolates from MAC-infected, HIV-positive people are M. avium, whereas in HIV-negative people, about 40% of the MAC isolates are M. intracellulare. Reference ID: 5482092 5 Various in vitro methodologies employing broth or solid media, with and without polysorbate 80 (Tween 80), have been used to determine rifabutin MIC values for mycobacterial species. In general, MIC values determined in broth are several fold lower than that observed with methods employing solid media. Utilization of Tween 80 in these assays has been shown to further lower MIC values. However, MIC values were substantially higher for egg-based compared to agar-based solid media. Rifabutin activity against 211 MAC isolates from HIV-positive people was evaluated in vitro utilizing a radiometric broth and an agar dilution method. Results showed that 78% and 82% of these isolates had MIC99 values of ≤0.25 µg/mL and ≤1.0 µg/mL, respectively, when evaluated by these two methods. Rifabutin was also shown to be active against phagocytized, M. avium complex in a mouse macrophage cell culture model. Rifabutin has in vitro activity against many strains of Mycobacterium tuberculosis. In one study, utilizing the radiometric broth method, each of 17 and 20 rifampin-naive clinical isolates tested from the United States and Taiwan, respectively, were shown to be susceptible to rifabutin concentrations of ≤0.125 µg/mL. Cross-resistance between rifampin and rifabutin is commonly observed with M. tuberculosis and M. avium complex isolates. Isolates of M. tuberculosis resistant to rifampin are likely to be resistant to rifabutin. Rifampicin and rifabutin MIC99 values against 523 isolates of M. avium complex were determined utilizing the agar dilution method (Heifets, Leonid B. and Iseman, Michael D. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 1985; 132(3):710–711). Table 1 Susceptibility of M. Avium Complex Strains to Rifampin and Rifabutin % of Strains Susceptible/Resistant to Different Concentrations of Rifabutin (μg/mL) Susceptibility to Rifampin (μg/mL) Number of Strains Susceptible to 0.5 Resistant to 0.5 only Resistant to 1.0 Resistant to 2.0 Susceptible to 1.0 30 100.0 0.0 0.0 0.0 Resistant to 1.0 only 163 88.3 11.7 0.0 0.0 Resistant to 5.0 105 38.0 57.1 2.9 2.0 Resistant to 10.0 225 20.0 50.2 19.6 10.2 TOTAL 523 49.5 36.7 9.0 4.8 Rifabutin in vitro MIC99 values of ≤0.5 µg/mL, determined by the agar dilution method, for M. kansasii, M. gordonae and M. marinum have been reported; however, the clinical significance of these results is unknown. INDICATIONS AND USAGE MYCOBUTIN Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Reference ID: 5482092 6 CONTRAINDICATIONS MYCOBUTIN Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins. MYCOBUTIN Capsules are contraindicated in patients being treated with cabotegravir/rilpivirine prolonged-release injectable suspension (see PRECAUTIONS-Drug Interactions, Table 2). WARNINGS Tuberculosis MYCOBUTIN Capsules must not be administered for MAC prophylaxis to patients with active tuberculosis. Patients who develop complaints consistent with active tuberculosis while on prophylaxis with MYCOBUTIN should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of MYCOBUTIN as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to MYCOBUTIN and to rifampin. There is no evidence that MYCOBUTIN is an effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently. Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. In addition to chest X-ray and sputum culture, the following studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood culture, urine culture, or biopsy of a suspicious lymph node. MAC Treatment with Clarithromycin When MYCOBUTIN is used concomitantly with clarithromycin for MAC treatment, a decreased dose of MYCOBUTIN is recommended due to the increase in plasma concentrations of MYCOBUTIN (see PRECAUTIONS-Drug Interactions, Table 2). Hypersensitivity and Related Reactions Hypersensitivity reactions may occur in patients receiving rifamycins. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis with the use of rifamycins. Monitor patients receiving MYCOBUTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue MYCOBUTIN. Reference ID: 5482092 7 Uveitis Due to the possible occurrence of uveitis, patients should also be carefully monitored when MYCOBUTIN is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds (see PRECAUTIONS-Drug Interactions, Table 2). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with MYCOBUTIN should be suspended (see also ADVERSE REACTIONS). Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MYCOBUTIN (rifabutin) Capsules, USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Severe Cutaneous Adverse Reactions There have been reports of severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) associated with MYCOBUTIN (see ADVERSE REACTIONS). If patients develop a skin rash they should be monitored closely, and MYCOBUTIN discontinued if lesions progress. Specifically, for DRESS, a multi-system potential life-threatening SCAR, time to onset of the first symptoms may be prolonged. DRESS is a clinical diagnosis, and its clinical presentation remains the basis for decision making. An early withdrawal of MYCOBUTIN is essential because of the syndrome’s mortality and visceral involvement (e.g., liver, bone marrow or kidney). Antiretroviral and Anti-HCV Drug Interactions Protease inhibitors act as substrates or inhibitors of CYP3A4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and a patient-specific drug profile. The concomitant use of protease inhibitors may require at least a 50% reduction in rifabutin dose, and depending on the protease inhibitor, an adjustment of the antiretroviral drug Reference ID: 5482092 8 dose. Increased monitoring for adverse events is recommended when using these drug combinations (see PRECAUTIONS-Drug Interactions). MYCOBUTIN is a CYP3A inducer. Co-administration with antiretroviral drugs metabolized by CYP3A, including but not limited to products containing bictegravir, elvitegravir, oral rilpivirine, or doravirine and anti-HCV drugs including but not limited to sofosbuvir (alone or in combination) may decrease plasma concentrations of those drugs, which may lead to loss of virologic response and possible development of resistance. Therefore, co-administration with antiretroviral and anti-HCV drugs metabolized by CYP3A is not recommended or there may be a need to increase the dose of antiretroviral or anti-HCV drugs (see PRECAUTIONS-Drug Interactions). For further recommendations, please refer to the most recent prescribing information of the antiretrovirals or anti-HCV drugs or contact the specific manufacturer. PRECAUTIONS General Because treatment with MYCOBUTIN Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with MYCOBUTIN. Information for Patients Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since MYCOBUTIN may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders. Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with MYCOBUTIN should be made aware of these possibilities. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes, after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible. Drug Interactions Effect of Rifabutin on the Pharmacokinetics of Other Drugs: Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir. Effect of Other Drugs on Rifabutin Pharmacokinetics: Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Therefore, carefully monitor for Reference ID: 5482092 9 rifabutin associated adverse events in those patients also receiving CYP3A inhibitors, which include fluconazole and clarithromycin. In some cases, the dosage of MYCOBUTIN may need to be reduced when it is co-administered with CYP3A inhibitors. Table 2 summarizes the results and magnitude of the pertinent drug interactions assessed with rifabutin. The clinical relevance of these interactions and subsequent dose modifications should be judged in light of the population studied, severity of the disease, patient’s drug profile, and the likely impact on the risk/benefit ratio. Table 2 Rifabutin Interaction Studies Co-administere d drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation ANTIRETROVIRALS Amprenavir 1200 mg twice a day for 10 days 300 mg once a day for 10 days Healthy male subjects (6) ↑ AUC by 193%, ↑ Cmax by 119% ↔ Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. Atazanavir/ Ritonavir 300/100 mg once daily 150 mg twice weekly Healthy adult subjects 48% in AUC, 149% ↑ Cmax of rifabutin. 990% in AUC, 677% ↑ Cmax of 25-O-desac etyl- rifabutin. No significant change in pharmacokinetic s. A reduction in the dose of rifabutin (to 150 mg every other day or 3 times a week) is recommended. Increased monitoring for adverse reactions is warranted. Bictegravir 75 mg once a day 300 mg once a day (fasted) Healthy subjects ND ↓AUC 38% ↓Cmin 56% ↓Cmax 20% Co-administration of rifabutin with Biktarvy (bictegravir/emtricitabin e/tenofovir alafenamide) is not recommended due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in bictegravir. Refer to Biktarvy prescribing information for additional information Darunavir/Ritona vir 600/100 mg twice a day for 12 days 150 mg every other day for 12 days Healthy HIV negative adults No significant change in rifabutin pharmacoki netics. 57% in AUC, 42% ↑ Cmax of darunavir. 66% in AUC, 68% ↑ Cmax of ritonavir. A reduction in the dose of rifabutin (to 150 mg every other day or 3 times a week) is recommended. Increased monitoring for adverse reactions is warranted. Reference ID: 5482092 10 Co-administere d drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation 881% in AUC, 377% ↑ Cmax of 25-O-desac etyl- rifabutin. Delavirdine 400 mg three times a day 300 mg once a day HIV- infected patients (7) ↑ AUC by 230%, ↑ Cmax by 128% ↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17% CONTRAINDICATED Didanosine 167 or 250 mg twice a day for 12 days 300 or 600 mg once a day for 12 days HIV- infected patients (11) ↔ ↔ Dolutegravir 50 mg daily for 14 days 300 mg daily for 14 days Healthy adult subjects ND No significant change in dolutegravir pharmacokinetic s at steady state. Doravirine 100 mg single dose 300 mg once a day for 16 days Healthy subjects (12) ND ↓50% in AUC, ↓68% in C24 ↔ in Cmax If concomitant use is necessary, increase the doravirine dosage as instructed in doravirine-containing product prescribing information. Elvitegravir/ Cobicistat 150/50 mg daily 300 mg daily Or 150 mg every other day Healthy subjects (12) No significant change in rifabutin pharmacoki netics. 6.3-fold  in AUC, 4.8-fold ↑ Cmax of 25-O-desac etyl- rifabutin. No change in elvitegravir except 67% ↓ Ctrough of elvitegravir. No change in cobicistat exposure. Co-administration of rifabutin with elvitegravir/ cobicistat is not recommended due to an expected decrease in elvitegravir exposure. Etravirine 800 mg twice daily for 21 days 300 mg daily on days 8 to 21 Healthy volunteers (18) No significant change in rifabutin pharmacoki netics. 37% in AUC, 37% in Cmax and 35% in Cmin No dose adjustment of rifabutin is required when etravirine is not co-administered with protease inhibitor/ritonavir. Rifabutin should not be co-administered with Reference ID: 5482092 11 Co-administere d drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation etravirine and boosted PIs due to potential for decreased effectiveness of etravirine. Fosamprenavir/ ritonavir 700 mg twice a day plus ritonavir 100 mg twice a day for 2 weeks 150 mg every other day for 2 weeks Healthy subjects (15) ↔ AUCa ↓ Cmax by 15% ↑ AUC by 35%b, ↑ Cmax by 36%, ↑ Cmin by 36% Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. Indinavir 800 mg three times a day for 10 days 300 mg once a day for 10 days Healthy subjects (10) ↑ AUC by 173%, ↑ Cmax by 134% ↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39% Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg three times a day. Lopinavir/ ritonavir 400/100 mg twice a day for 20 days 150 mg once a day for 10 days Healthy subjects (14) ↑ AUC by 203% c ↓ Cmax by 112% ↔ Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. Saquinavir/ ritonavir 1000/100 mg twice a day for 14 or 22 days 150 mg every 3 days for 21-22 day s Healthy subjects ↑ AUC by 53% d ↑ Cmax by 88% (n=11) ↓ AUC by 13%, ↓ Cmax by 15%, (n=19) Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. Rilpivirine 25 mg once a day 300 mg once a day Healthy subjects (18) ND AUC by 42% Cmin by 48% Cmax by 31% Co-administration of rifabutin with Odefsey (rilpivirine/tenofovir alafenamide/emtricitabin e) is not recommended, due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in rilpivirine. Refer to Odefsey prescribing information for additional information. Co-administration of Reference ID: 5482092 12 Co-administere d drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation rifabutin with cabotegravir/rilpivirine prolonged-release injectable suspension is contraindicated. Ritonavir 500 mg twice a day for 10 days 150 mg once a day for 16 days Healthy subjects (5) ↑ AUC by 300%, ↑ Cmax by 150% ND Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. Tipranavir/ ritonavir 500/200 twice a day for 15 doses 150 mg single dose Healthy subjects (20) ↑ AUC by 190%, ↑ Cmax by 70% ↔ Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. Nelfinavir 1250 mg twice a day for 7-8 days 150 mg once a day for 8 days HIV- infected patients (11) ↑ AUC by 83%, e ↑ Cmax by 19% ↔ Reduce rifabutin dose by 50% (to 150 mg once a day) and increase the nelfinavir dose to 1250 mg twice a day. Zidovudine 100 or 200 mg every four hours 300 or 450 mg once a day HIV- infected patients (16) ↔ ↓ AUC by 32%, ↓ Cmax by 48%, Because zidovudine levels remained within the therapeutic range during co-administration of rifabutin, dosage adjustments are not necessary. ANTI-HCV DRUGS Sofosbuvir 400 mg on day 1 and day 21 300 mg daily on day 10 to day 29 Healthy subjects (20) ND 36% in Cmax and 24% AUC Co-administration of rifabutin with sofosbuvir (alone or in combination) is not recommended. Reference ID: 5482092 13 Co-administere d drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation ANTIFUNGALS Fluconazole 200 mg once a day for 2 weeks 300 mg once a day for 2 weeks HIV- infected patients (12) ↑ AUC by 82%, ↑ Cmax by 88% ↔ Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected. Posaconazole 200 mg once a day for 10 days 300 mg once a day for 17 days Healthy subjects (8) ↑ AUC by 72%, ↑ Cmax by 31% ↓AUC by 49%, ↓ Cmax by 43% If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. Itraconazole 200 mg once a day 300 mg once a day HIV- Infected patients (6) ↑f ↓ AUC by 70%, ↓ Cmax by 75%, If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg once a day) with itraconazole (600-900 mg once a day). Voriconazole 400 mg twice a day for 7 days (maintenance dose) 300 mg once a day for 7 days Healthy male subjects (12) ↑ AUC by 331%, ↑ Cmax by 195% ↑ AUC by ~100%, ↑ Cmax by ~100%g CONTRAINDICATED ANTI-PCP (Pneumocystis carinii pneumonia) Dapsone 50 mg once a day 300 mg once a day HIV- infected patients (16) ND ↓ AUC by 27 -40% Sulfamethoxazol e-Trimethoprim 800/160 mg 300 mg once a day HIV- infected patients (12) ↔ ↓ AUC by 15-20% ANTI-MAC (Mycobacterium avium intracellulare complex) Azithromycin 500 mg once a day for 1 day, then 250 mg once a day for 9 days 300 mg once a day Healthy subjects (6) ↔ ↔ Clarithromycin 500 mg twice a 300 mg HIV- ↑ AUC by ↓ AUC by 50% Monitor for rifabutin Reference ID: 5482092 14 Co-administere d drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation day once a day infected patients (12) 75% associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin ANTI-TB (Tuberculosis) Ethambutol 1200 mg 300 mg once a day for 7 days Healthy subjects (10) ND ↔ Isoniazid 300 mg 300 mg once a day for 7 days Healthy subjects (6) ND ↔ Bedaquiline 400 mg daily on day 1 and day 29 300 mg daily Healthy subjects (17) ND No change in bedaquiline pharmacokinetic s. 1.4-fold in M2 and approximately 3.0-fold in M3 metabolites of bedaquiline. Avoid bedaquiline co-administration with rifabutin due to the adverse reactions associated with increased bedaquiline metabolite concentrations. OTHER Methadone 20 – 100 mg once a day 300 mg once a day for 13 days HIV- infected patients (24) ND ↔ Ethinylestradiol (EE)/ Norethindrone (NE) 35 mg EE / 1 mg NE for 21 days 300 mg once a day for 10 days Healthy female subjects (22) ND EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46% Patients should be advised to use additional or alternative methods of contraception. Theophylline 5 mg/kg 300 mg for 14 days Healthy subjects (11) ND ↔ ↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change ND - No Data AUC - Area under the Concentration vs. Time Curve; Cmax - Maximum serum concentration; Cmin – Minimum serum concentration a compared to rifabutin 300 mg once a day alone b compared to historical control (fosamprenavir/ritonavir 700/100 mg twice a day) c also taking zidovudine 500 mg once a day d compared to rifabutin 150 mg once a day alone e compared to rifabutin 300 mg once a day alone f data from a case report g compared to voriconazole 200 mg twice a day alone Reference ID: 5482092 15 Other drugs: The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although a weaker enzyme inducer than rifampin, rifabutin may be expected to have some effect on those drugs as well. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies were conducted with rifabutin in mice and in rats. Rifabutin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose. Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in Schizosaccharomyces pombe P1 and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo. Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose). Pregnancy Rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant or breastfeeding women. Reproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (about 6 to 13 times the recommended human daily dose based on body surface area comparisons). No teratogenicity was observed in either species. In rats, given 200 mg/kg/day, (about 6 times the recommended human daily dose based on body surface area comparisons), there was a decrease in fetal viability. In rats, at 40 mg/kg/day (approximately equivalent to the recommended human daily dose based on body surface area comparisons), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80 mg/kg/day (about 5 times the recommended human daily dose based on body surface area comparisons), rifabutin caused maternotoxicity and increase in fetal skeletal anomalies. Because animal reproduction studies are not always predictive of human response, rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of rifabutin for prophylaxis of MAC in children have not been established. Limited safety data are available from treatment use in 22 HIV-positive children with MAC who received MYCOBUTIN in combination with at least two other Reference ID: 5482092 16 antimycobacterials for periods from 1 to 183 weeks. Mean doses (mg/kg) for these children were: 18.5 (range 15.0 to 25.0) for infants 1 year of age, 8.6 (range 4.4 to 18.8) for children 2 to 10 years of age, and 4.0 (range 2.8 to 5.4) for adolescents 14 to 16 years of age. There is no evidence that doses greater than 5 mg/kg daily are useful. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia, and rash. In addition, corneal deposits have been observed in some patients during routine ophthalmologic surveillance of HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple-drug regimen for MAC prophylaxis. These are tiny, almost transparent, asymptomatic peripheral and central corneal deposits which do not impair vision. Geriatric Use Clinical studies of MYCOBUTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS Adverse Reactions from Clinical Trials MYCOBUTIN Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving MYCOBUTIN, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of MYCOBUTIN were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%). The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with MYCOBUTIN in studies 023 and 027. Reference ID: 5482092 17 Table 3 Clinical Adverse Experiences Reported in ≥1% of Patients Treated With MYCOBUTIN Adverse event MYCOBUTIN (n = 566) % Placebo (n = 580) % Body as a whole Abdominal pain 4 3 Asthenia 1 1 Chest pain 1 1 Fever 2 1 Headache 3 5 Pain 1 2 Blood and lymphatic system Leucopenia 10 7 Anemia 1 2 Digestive System Anorexia 2 2 Diarrhea 3 3 Dyspepsia 3 1 Eructation 3 1 Flatulence 2 1 Nausea 6 5 Nausea and vomiting 3 2 Vomiting 1 1 Musculoskeletal system Myalgia 2 1 Nervous system Insomnia 1 1 Skin and appendages Rash 11 8 Special senses Taste perversion 3 1 Urogenital system Discolored urine 30 6 CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED MYCOBUTIN Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN appears to be a likely cause of the following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, skin discoloration, thrombocytopenia, pancytopenia and jaundice. The following adverse events have occurred in more than one patient receiving MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued. Reference ID: 5482092 18 Mild to severe, reversible uveitis has been reported less frequently when MYCOBUTIN is used at 300 mg as monotherapy in MAC prophylaxis versus MYCOBUTIN in combination with clarithromycin for MAC treatment (see also WARNINGS). Uveitis has been infrequently reported when MYCOBUTIN is used at 300 mg/day as monotherapy in MAC prophylaxis of HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibacterials. However, if higher doses of MYCOBUTIN are administered in combination with these agents, the incidence of uveitis is higher. Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops; in some severe cases, however, resolution of symptoms occurred after several weeks. When uveitis occurs, temporary discontinuance of MYCOBUTIN and ophthalmologic evaluation are recommended. In most mild cases, MYCOBUTIN may be restarted; however, if signs or symptoms recur, use of MYCOBUTIN should be discontinued (Morbidity and Mortality Weekly Report, September 9, 1994). Corneal deposits have been reported during routine ophthalmologic surveillance of some HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision. The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in Studies 023 and 027. Table 4 Percentage of Patients With Laboratory Abnormalities Laboratory abnormalities MYCOBUTIN (n = 566) % PLACEBO (n = 580) % Chemistry Increased alkaline phosphatase 1 <1 3 Increased SGOT 2 7 12 Increased SGPT 2 9 11 Hematology Anemia 3 6 7 Eosinophilia 1 1 Leukopenia 4 17 16 Neutropenia 5 25 20 Thrombocytopenia 6 5 4 Includes grades 3 or 4 toxicities as specified: 1 All values >450 U/L 2 All values >150 U/L 3 All hemoglobin values <8.0 g/dL 4 All WBC values <1,500/mm3 5 All ANC values <750/mm3 6 All platelet count values <50,000/mm3 The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with MYCOBUTIN in these trials, Reference ID: 5482092 19 MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN. Adverse Reactions from Post-Marketing Experience Adverse reactions identified through post-marketing surveillance by system organ class (SOC) are listed below: Blood and lymphatic system disorders: White blood cell disorders (including agranulocytosis, lymphopenia, granulocytopenia, neutropenia, white blood cell count decreased, neutrophil count decreased), platelet count decreased. Immune system disorders: Hypersensitivity, bronchospasm, rash, and eosinophilia. Gastrointestinal disorders: Clostridioides difficile colitis/Clostridioides difficile associated diarrhea. Pyrexia, rash and other hypersensitivity reactions such as eosinophilia and bronchospasm might occur, as has been seen with other antibacterials. A limited occurrence of skin discoloration has been reported. Severe cutaneous adverse reactions (SCARs): MYCOBUTIN has been associated with the occurrence of DRESS as well as other SCARs such as SJS, TEN, and AGEP (see WARNINGS). Rifamycin hypersensitivity reactions: Hypersensitivity to rifamycins have been reported including flu-like symptoms, bronchospasm, hypotension, urticaria, angioedema, conjunctivitis, thrombocytopenia or neutropenia. ANIMAL TOXICOLOGY Liver abnormalities (increased bilirubin and liver weight) occurred in mice, rats and monkeys at doses (respectively) 0.5, 1, and 3 times the recommended human daily dose based on body surface area comparisons. Testicular atrophy occurred in baboons at doses 2 times the recommended human dose based on body surface area comparisons, and in rats at doses 6 times the recommended human daily dose based on body surface area comparisons. OVERDOSAGE No information is available on accidental overdosage in humans. Treatment While there is no experience in the treatment of overdose with MYCOBUTIN Capsules, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help absorb any remaining drug from the gastrointestinal tract. Reference ID: 5482092 20 Rifabutin is 85% protein bound and distributed extensively into tissues (Vss:8 to 9 L/kg). It is not primarily excreted via the urinary route (less than 10% as unchanged drug); therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifabutin from the body in a patient with an overdose of MYCOBUTIN. DOSAGE AND ADMINISTRATION It is recommended that MYCOBUTIN Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of MYCOBUTIN at doses of 150 mg twice daily taken with food may be useful. Doses of MYCOBUTIN may be administered mixed with foods such as applesauce. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), consider reducing the dose of MYCOBUTIN by 50%, if toxicity is suspected. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of MYCOBUTIN may also be needed for patients receiving concomitant treatment with certain other drugs (see PRECAUTIONS-Drug Interactions). Mild hepatic impairment does not require a dose modification. The pharmacokinetics of rifabutin in patients with moderate and severe hepatic impairment is not known. HOW SUPPLIED MYCOBUTIN (rifabutin) Capsules, USP are supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with MYCOBUTIN/PHARMACIA & UPJOHN in white ink, each containing 150 mg of rifabutin, USP. MYCOBUTIN is available as follows: NDC 0013-5301-17 Bottles of 100 capsules Keep tightly closed and dispense in a tight container as defined in the USP. Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. LAB-0217-11.3 Revised 11/2024 Reference ID: 5482092	custom-source	2025-02-12T15:46:49.097462	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/050689s027lbl.pdf', 'application_number': 50689, 'submission_type': 'SUPPL ', 'submission_number': 27}
80,250	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BIMZELX safely and effectively. See full prescribing information for BIMZELX. BIMZELX® (bimekizumab-bkzx) injection, for subcutaneous use Initial U.S. Approval: 2023 --------------------------RECENT MAJOR CHANGES----------------------------- Indications and Usage (1.2, 1.3, 1.4, 1.5) 11/2024 Dosage and Administration (2.3, 2.4, 2.5, 2.6, 2.7) 11/2024 Warnings and Precautions (5.1, 5.2) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- BIMZELX is a humanized interleukin-17A and F antagonist indicated for the treatment of: • Moderate to severe plaque psoriasis (PSO) in adults who are candidates for systemic therapy or phototherapy. (1.1) • Adults with active psoriatic arthritis (PsA). (1.2) • Adults with active non-radiographic axial spondyloarthritis (nr- axSpA) with objective signs of inflammation. (1.3) • Adults with active ankylosing spondylitis (AS). (1.4) • Adults with moderate to severe hidradenitis suppurativa (HS). (1.5) ----------------------DOSAGE AND ADMINISTRATION----------------------- • Prior to treatment: (2.1) o Evaluate patients for tuberculosis infection. o Test liver enzymes, alkaline phosphatase, and bilirubin. o Complete all age-appropriate vaccinations as recommended by current immunization guidelines. • Plaque Psoriasis o Administer 320 mg by subcutaneous injection at Weeks 0, 4, 8, 12, and 16, then every 8 weeks thereafter. For patients weighing 120 kg or more, consider a dose of 320 mg every 4 weeks after Week 16. (2.2) • Psoriatic Arthritis o Administer 160 mg by subcutaneous injection every 4 weeks. (2.3) o For patients with coexisting moderate to severe plaque psoriasis, use the dosage and administration for plaque psoriasis. (2.2) • Non-Radiographic Axial Spondyloarthritis o Administer 160 mg by subcutaneous injection every 4 weeks. (2.4) • Ankylosing Spondylitis o Administer 160 mg by subcutaneous injection every 4 weeks. (2.5) • Hidradenitis Suppurativa o Administer 320 mg by subcutaneous injection at Week 0, 2, 4, 6, 8, 10, 12, 14 and 16, then every 4 weeks thereafter. (2.6) • See full prescribing information for recommendations regarding missed doses, preparation and administration instructions. (2.7, 2.8, 2.9) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- • Injection: 160 mg/mL in a single-dose prefilled syringe or single-dose prefilled autoinjector. (3) • Injection: 320 mg/2 mL (160 mg/mL) in a single-dose prefilled syringe or single-dose prefilled autoinjector. (3) -------------------------------CONTRAINDICATIONS------------------------------ None. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ • Suicidal Ideation and Behavior (SI/B): May increase risk of SI/B. Advise patients, their caregivers, and families to monitor for the emergence or worsening of depression, suicidal ideation, or other mood changes. If such changes occur, instruct patients to promptly seek medical attention or call the National Suicide and Crisis Lifeline at 988. Carefully weigh risks and benefits of treatment with BIMZELX in patients with a history of severe depression and/or suicidal ideation or behavior. (5.1) • Infections: May increase risk of infection. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If such an infection develops, do not administer BIMZELX until the infection resolves. (5.2) • Tuberculosis (TB): Avoid use in patients with active TB. Initiate treatment of latent TB prior to BIMZELX treatment. (5.3) • Liver Biochemical Abnormalities: Elevated serum transaminases were reported in clinical trials. Test liver enzymes, alkaline phosphatase, and bilirubin at baseline and according to routine patient management. Permanently discontinue use of BIMZELX in patients with causally - associated combined elevations of transaminases and bilirubin. (5.4) • Inflammatory Bowel Disease (IBD): Cases of IBD were reported in clinical trials with IL-17 inhibitors, including BIMZELX. Avoid use of BIMZELX in patients with active IBD. Monitor patients for signs and symptoms of IBD and discontinue treatment if new onset or worsening of signs and symptoms occurs. (5.5) • Immunizations: Avoid the use of live vaccines in patients treated with BIMZELX. (5.6) ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions are: • Psoriasis and Hidradenitis Suppurativa (incidence ≥ 1%): upper respiratory tract infections, oral candidiasis, headache, injection site reactions, tinea infections, gastroenteritis, Herpes simplex infections, acne, folliculitis, other candida infections, and fatigue. (6.1) • Psoriatic Arthritis (incidence ≥ 2%): upper respiratory tract infections, oral candidiasis, headache, diarrhea, and urinary tract infection. (6.1) • Non-Radiographic Axial Spondyloarthritis (incidence ≥ 2%): upper respiratory tract infections, oral candidiasis, headache, diarrhea, cough, fatigue, musculoskeletal pain, myalgia, tonsilitis, transaminase increase, and urinary tract infection. (6.1) • Ankylosing Spondylitis (incidence ≥ 2%): upper respiratory tract infections, oral candidiasis, headache, diarrhea, injection site pain, rash and vulvovaginal mycotic infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis 1.2 Psoriatic Arthritis 1.3 Non-Radiographic Axial Spondyloarthritis 1.4 Ankylosing Spondylitis 1.5 Hidradenitis Suppurativa 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation 2.2 Recommended Dosage for Plaque Psoriasis 2.3 Recommended Dosage for Psoriatic Arthritis 2.4 Recommended Dosage for Non-Radiographic Axial Spondyloarthritis 2.5 Recommended Dosage for Ankylosing Spondylitis 2.6 Recommended Dosage for Hidradenitis Suppurativa 2.7 Missed Doses 2.8 Preparation Instructions 2.9 Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Ideation and Behavior 5.2 Infections 5.3 Tuberculosis 5.4 Liver Biochemical Abnormalities 5.5 Inflammatory Bowel Disease 5.6 Immunizations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use Reference ID: 5481440 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Plaque Psoriasis 14.2 Psoriatic Arthritis 14.3 Non-Radiographic Axial Spondyloarthritis 14.4 Ankylosing Spondylitis 14.5 Hidradenitis Suppurativa 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the Full Prescribing Information are not listed. Reference ID: 5481440 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis BIMZELX is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. 1.2 Psoriatic Arthritis BIMZELX is indicated for the treatment of adults with active psoriatic arthritis. 1.3 Non-Radiographic Axial Spondyloarthritis BIMZELX is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation. 1.4 Ankylosing Spondylitis BIMZELX is indicated for the treatment of adults with active ankylosing spondylitis. 1.5 Hidradenitis Suppurativa BIMZELX is indicated for the treatment of adults with moderate to severe hidradenitis suppurativa. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation • Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with BIMZELX [see Warnings and Precautions (5.3)]. • Test liver enzymes, alkaline phosphatase and bilirubin prior to initiating treatment with BIMZELX [see Warnings and Precautions (5.4)]. • Complete all age-appropriate vaccinations as recommended by current immunization guidelines [see Warning and Precautions (5.6)]. 2.2 Recommended Dosage for Plaque Psoriasis The recommended dosage is 320 mg by subcutaneous injection at Weeks 0, 4, 8, 12, and 16, then every 8 weeks thereafter. For patients weighing 120 kg or more, consider a dosage of 320 mg every 4 weeks after Week 16 [see Clinical Pharmacology (12.3)]. 2.3 Recommended Dosage for Psoriatic Arthritis The recommended dosage is 160 mg by subcutaneous injection every 4 weeks. For psoriatic arthritis patients with coexistent moderate to severe plaque psoriasis, use the dosing regimen for adult patients with plaque psoriasis [see Dosage and Administration (2.2)]. 2.4 Recommended Dosage for Non-Radiographic Axial Spondyloarthritis The recommended dosage is 160 mg by subcutaneous injection every 4 weeks. 2.5 Recommended Dosage for Ankylosing Spondylitis The recommended dosage is 160 mg by subcutaneous injection every 4 weeks. 2.6 Recommended Dosage for Hidradenitis Suppurativa The recommended dosage is 320 mg by subcutaneous injection at Weeks 0, 2, 4, 6, 8, 10, 12, 14, and 16, then every 4 weeks thereafter. Reference ID: 5481440 2.7 Missed Doses If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regularly scheduled interval. 2.8 Preparation Instructions • Before injecting, remove the carton with BIMZELX from the refrigerator and allow BIMZELX to reach room temperature (30 to 45 minutes) without removing the prefilled syringes or autoinjectors from the carton to protect from light. • Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. BIMZELX injection is clear to slightly opalescent, and colorless to pale brownish- yellow. Do not use if the solution contains visible particles, is discolored or cloudy. 2.9 Administration Instructions • BIMZELX is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of BIMZELX according to the “Instructions for Use” [see Instructions for Use]. • If two separate 160 mg injections are used to achieve the recommended dose, administer each injection subcutaneously at a different anatomic location (such as thighs, abdomen or back of upper arm). Discard the syringes or autoinjectors after use. Do not reuse. • Do not inject BIMZELX within 2 inches (5 cm) of the navel or into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. Administration of BIMZELX in the upper, outer arm may only be performed by a healthcare professional or caregiver. Rotate the injection site with each injection. 3 DOSAGE FORMS AND STRENGTHS • Injection (1 mL): 160 mg/mL clear to slightly opalescent, and colorless to pale brownish-yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector. • Injection (2 mL): 320 mg/2 mL (160 mg/mL) clear to slightly opalescent, and colorless to pale brownish-yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Ideation and Behavior An increased incidence of new onset or worsening suicidal ideation and behavior was observed in subjects treated with BIMZELX. A causal association between treatment with BIMZELX and increased risk of suicidal ideation and behavior has not been definitively established. Suicidal ideation and behavior were prospectively monitored using the Columbia Suicide Severity Rating Scale (C-SSRS) in clinical trials. The C-SSRS is an interview-based instrument used to monitor for the presence and severity of suicidal ideation (ranging from “none” to “active suicidal ideation with specific plan and intent”) and behaviors (rating the injury and potential lethality of self-injury, if present). Plaque Psoriasis During the two 16-week, placebo-controlled periods of Trials Ps-1 and Ps-2, higher rates of suicidal ideation as assessed by C-SSRS were reported in BIMZELX-treated subjects than in subjects receiving Reference ID: 5481440 placebo. Pooled analysis of C-SSRS data indicated that 12/670 (1.8%) BIMZELX-treated subjects and 1/169 (0.6%) subjects receiving placebo reported passive suicidal ideation with an estimated relative risk of 3.0 (95% confidence interval: 0.39, 22.74). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new onset suicidal ideation on the C-SSRS than subjects receiving placebo (1.3% vs 0.6%). During the open-label extension trial, one completed suicide was reported in a BIMZELX-treated subject [see Adverse Reactions (6.1)]. Psoriatic Arthritis Pooled analysis of C-SSRS data from the two 16-week, placebo-controlled periods of Trials PsA-1 and PsA-2 indicated that 2/698 (0.3%) BIMZELX-treated subjects and 3/413 (0.7%) subjects receiving placebo reported passive suicidal ideation with an estimated relative risk of 0.35 (95% confidence interval: 0.05, 2.29) [see Adverse Reactions (6.1)]. Non-Radiographic Axial Spondyloarthritis Analysis of C-SSRS data from a 16-week, placebo-controlled period of Trial nr-axSpA-1 indicated that no subjects, being treated either with BIMZELX or placebo, reported suicidal ideation [see Adverse Reactions (6.1)]. Ankylosing Spondylitis Analysis of C-SSRS data from a 16-week, placebo-controlled period of Trial AS-1 indicated that no subjects, being treated either with BIMZELX or placebo, reported suicidal ideation [see Adverse Reactions (6.1)]. Hidradenitis Suppurativa During the two 16-week, placebo-controlled periods of Trials HS-1 and HS-2, higher rates of suicidal ideation as assessed by C-SSRS were reported in BIMZELX-treated subjects than in subjects receiving placebo. Based on a pooled analysis of the first 16 weeks of the placebo controlled clinical trials, 16/861 subjects in the BIMZELX group (1.9 %) reported suicidal ideation on the C-SSRS compared to 1/146 subjects in the placebo group (0.7%) with an estimated relative risk of 2.70 (95% confidence interval: 0.36, 20.12). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new-onset suicidal ideation on the C-SSRS than subjects treated with placebo (0.9% vs. 0%). [see Adverse Reactions 6.1]. Consider the potential risks and benefits before prescribing BIMZELX to patients with a history of severe depression or suicidal ideation or behavior. Advise patients, their caregivers, and families to monitor for the emergence or worsening of depression, suicidal ideation, or other mood changes. If such changes occur, instruct patients to promptly seek medical attention or call the National Suicide and Crisis Lifeline at 988 [see Patient Counseling Information (17)]. Refer BIMZELX-treated patients with new or worsening symptoms of depression or suicidal ideation and/or behavior to a mental health professional, as appropriate. Re-evaluate the risks and benefits of continuing treatment with BIMZELX if such events occur. 5.2 Infections BIMZELX may increase the risk of infections, including serious infections. Do not initiate treatment with BIMZELX in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing BIMZELX. Instruct patients to seek medical advice if signs or symptoms of clinically Reference ID: 5481440 important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and discontinue BIMZELX until the infection resolves. 5.3 Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with BIMZELX. Avoid the use of BIMZELX in patients with active TB infection. Initiate treatment of latent TB prior to administering BIMZELX. Consider anti-TB therapy prior to initiation of BIMZELX in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients treated with BIMZELX for signs and symptoms of active TB during and after treatment. 5.4 Liver Biochemical Abnormalities Treatment with BIMZELX was associated with increased incidence of liver enzyme elevations compared to treatment with placebo in randomized clinical trials. Liver serum transaminase elevations > 3 times the upper limit of normal were reported in subjects treated with BIMZELX [see Adverse Reactions (6.1)]. Elevated liver serum transaminases resolved after discontinuation of BIMZELX. Test liver enzymes, alkaline phosphatase, and bilirubin at baseline, periodically during treatment with BIMZELX and according to routine patient management. If treatment-related increases in liver enzymes occur and drug-induced liver injury is suspected, interrupt BIMZELX until a diagnosis of liver injury is excluded. Permanently discontinue BIMZELX in patients with causally associated combined elevations of transaminases and bilirubin. Patients with acute liver disease or cirrhosis may be at increased risk for severe hepatic injury; avoid use of BIMZELX in these patients. 5.5 Inflammatory Bowel Disease Cases of inflammatory bowel disease (IBD) have been reported in patients treated with IL-17 inhibitors, including BIMZELX [see Adverse Reactions (6.1)]. Avoid use of BIMZELX in patients with active IBD. During BIMZELX treatment, monitor patients for signs and symptoms of IBD and discontinue treatment if new onset or worsening of signs and symptoms occurs. 5.6 Immunizations Prior to initiating therapy with BIMZELX, complete all age-appropriate vaccinations according to current immunization guidelines. Avoid the use of live vaccines in patients treated with BIMZELX. Limited data are available regarding coadministration of BIMZELX with non-live vaccines [see Clinical Pharmacology (12.2)]. 6 ADVERSE REACTIONS The following adverse reactions have been observed with BIMZELX and are discussed in greater detail in other sections of the labeling: • Suicidal Ideation and Behavior [see Warnings and Precautions (5.1)] • Infections [see Warnings and Precautions (5.2)] • Liver Biochemical Abnormalities [see Warnings and Precautions (5.4)] • Inflammatory Bowel Disease [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis Clinical Trials In clinical trials, a total of 1,789 subjects with plaque psoriasis were treated with BIMZELX. Of these, 1,073 subjects were exposed to BIMZELX for at least one year. Reference ID: 5481440 The safety of BIMZELX was evaluated in two placebo-controlled trials (Ps-1 and Ps-2), an active- controlled trial (Ps-3), and an open-label extension trial. Data from Trials Ps-1 and Ps-2 in 839 subjects (mean age 45 years, 72% male, 84% White) were pooled to evaluate the safety of BIMZELX in comparison to placebo up to 16 weeks after treatment initiation. A total of 670 subjects were treated during this initial period with BIMZELX 320 mg at Weeks 0, 4, 8, 12, and 16. Table 1 summarizes the adverse reactions that occurred at a rate of 1% or greater and at a higher rate in the BIMZELX group than the placebo group. Table 1: Adverse Reactions Occurring in ≥1% of Subjects with Plaque Psoriasis in the BIMZELX Group and More Frequently than in the Placebo Group in Trials Ps-1 and Ps-2 BIMZELX N=670 n (%) Placebo N=169 n (%) URIa 102 (15) 24 (14) Oral Candidiasisb 61 (9) 0 (0) Headache 22 (3) 0 (0) Injection Site Reactionsc 19 (3) 2 (1) Tinea Infectionsd 18 (3) 1 (1) Gastroenteritise 12 (2) 0 (0) Herpes Simplex Infectionsf 9 (1) 0 (0) Acne 8 (1) 0 (0) Folliculitis 8 (1) 0 (0) Other Candida Infectionsg 7 (1) 1 (1) Fatigue 7 (1) 0 (0) a Upper Respiratory Infections include nasopharyngitis, upper respiratory tract infection, pharyngitis, rhinitis, viral upper respiratory tract infection, tonsillitis, sinusitis, pharyngitis streptococcal, pharyngitis bacterial, peritonsillar abscess, viral rhinitis, and influenza b Oral Candidiasis includes oral candidiasis, oropharyngeal candidiasis, oral fungal infection, fungal pharyngitis, and oropharyngitis fungal c Injection Site Reactions include injection site reaction, injection site erythema, injection site pain, injection site edema, injection site bruising, and injection site swelling d Tinea Infections include tinea pedis, fungal skin infection, tinea versicolor, tinea cruris, tinea infection, body tinea, and onychomycosis e Gastroenteritis includes Enterovirus infection, gastroenteritis, gastroenteritis bacterial, and gastroenteritis viral f Herpes Simplex Infections include herpes simplex and oral herpes g Other Candida Infections include vulvovaginal candidiasis, vulvovaginal mycotic infection, skin candida, and genital candidiasis. Adverse reactions that occurred in < 1% but > 0.1% of subjects in the BIMZELX group and at a higher rate than in the placebo group through Week 16 were neutropenia, eczema, otitis externa, otitis media, and pyrexia. The safety of BIMZELX was evaluated in another active-controlled trial (Ps-4) in 743 adult subjects who received BIMZELX 320 mg every 4 weeks or every 8 weeks through Week 48. Specific Adverse Reactions Suicidal Ideation and Behavior: The study populations of Trial Ps-1, Trial Ps-2, Trial Ps-3 and Trial Ps-4 excluded subjects with active suicidal ideation, suicidal ideation within the month prior to screening, a Reference ID: 5481440 history of suicide attempt within the past 5 years prior to screening, or moderately severe to severe major depression (i.e., score of ≥15 on the screening Patient Health Questionnaire-9 (PHQ-9)). Analysis of pooled C-SSRS data from the first 16 weeks of placebo-controlled clinical trials indicated that 12/670 (1.8%) BIMZELX-treated subjects and 1/169 (0.6%) subjects receiving placebo reported passive suicidal ideation with an estimated relative risk of 3.0 (95% confidence interval: 0.39, 22.74). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new onset suicidal ideation on the C-SSRS than subjects receiving placebo (1.3% vs 0.6%). During the course of the clinical trials for plaque psoriasis, there was 1 completed suicide in the open label extension trial after 718 days of treatment (1/2,480; 0.01/100 patient-years). The completed suicide was reported in a subject without a past reported psychiatric history. There were also 3 suicide attempts (3/2,480; 0.04/100 patient-years); 2 of these subjects had a history of prior suicide attempts. Infections: During the placebo-controlled period of Trials Ps-1 and Ps-2, infections were reported in 36% of subjects (141.7 per 100 patient-years) treated with BIMZELX compared with 23% of subjects (84.6 per 100 patient-years) receiving placebo. Serious infections occurred in 0.3% of subjects (1.0 per 100 patient- years) treated with BIMZELX and 0% subjects receiving placebo. The most common infections were upper respiratory tract infections and Candida infections, including oral candidiasis (oral candidiasis, oropharyngeal candidiasis, oral fungal infection, fungal pharyngitis, and oropharyngitis fungal) occurring in 9% (30.6 per 100 patient-years) of subjects treated with BIMZELX and other Candida infections (vulvovaginal candidiasis, vulvovaginal mycotic infection, skin candida, and genital candidiasis) in 1% (3.4 per 100 patient-years) of subjects treated with BIMZELX compared to 0% and 1%, respectively, of subjects receiving placebo. During the combined initial, maintenance, and open-label extension treatment periods of trials Ps-1, Ps-2, Ps-3, and the open-label extension trial, infections were reported in 63% of subjects treated with BIMZELX (120.4 per 100 patient-years). Serious infections were reported in 1.5% of subjects treated with BIMZELX (1.6 per 100 patient-years). Inflammatory Bowel Disease: In clinical trials in subjects with plaque psoriasis, subjects with active inflammatory bowel disease were excluded. In these trials, which included 2,480 subjects exposed to BIMZELX accounting for 5,830 patient-years, adjudicated cases of new onset of inflammatory bowel disease (including ulcerative colitis (UC), Crohn’s disease (CD) and IBD-undetermined) occurred in seven subjects (0.12 per 100 patient-years); the majority of these cases were serious and resulted in discontinuation of therapy. Liver Biochemical Abnormalities: During the placebo-controlled period of Trials Ps-1 and Ps-2, liver serum transaminase elevations (> 3 times the upper limit of normal [ULN]) occurred in 1.0% of subjects treated with BIMZELX versus 0.6% of subjects receiving placebo. The time to onset of these adverse reactions varied between 28 and 198 days after starting BIMZELX treatment. Elevated liver serum transaminases resolved during continued treatment or after discontinuation of BIMZELX. Safety through Week 56 During the maintenance period (Week 16 through Week 52 of Trial Ps-1 and Week 56 of Trial Ps-2), adverse reactions were consistent with those observed during the initial 16 weeks of treatment with BIMZELX. During the maintenance treatment periods of Trial Ps-2 and Trial Ps-3, the rates of adverse reactions were similar between subjects treated with BIMZELX 320 mg every four week and every eight weeks, after the initial 16 weeks of treatment. Reference ID: 5481440 Safety through Week 128 During the open-label extension trial, including data from Week 56 through Week 128, new adverse reactions of suicide attempt and a completed suicide occurred [described above in Suicidal Ideation and Behavior]. Additional Safety Data In an active-controlled clinical trial (Trial Ps-4), 691 subjects with plaque psoriasis were treated with BIMZELX for up to 144 weeks. Adverse reactions were consistent with those observed during the initial 16 weeks of treatment and with the overall safety profile of BIMZELX. Psoriatic Arthritis Clinical Trials The safety of BIMZELX was evaluated in two placebo-controlled trials (PsA-1 and PsA-2). Data from Trials PsA-1 and PsA-2 in 1,111 subjects (mean age 49 years, 47% male, 96% White) were pooled to evaluate the safety of BIMZELX in comparison to placebo up to 16 weeks after treatment initiation. A total of 698 subjects were treated during this initial period with BIMZELX 160 mg at Weeks 0, 4, 8, 12, and 16. Table 2 summarizes the adverse reactions that occurred at a rate of 2% or greater and at a higher rate in the BIMZELX group than the placebo group. Table 2: Adverse Reactions Occurring in ≥2% of Subjects with Psoriatic Arthritis in the BIMZELX Group and More Frequently than in the Placebo Group in Trials PsA-1 and PsA-2 BIMZELX N=698 n (%) Placebo N=413 n (%) URIa 99 (14) 41 (10) Headache 25 (4) 7 (2) Diarrhea 19 (3) 8 (2) Urinary Tract Infection 14 (2) 7 (2) Oral Candidiasis 16 (2) 0 aUpper Respiratory Tract Infections (URI) includes: nasopharyngitis, upper respiratory tract infection, pharyngitis, sinusitis, and rhinitis. Adverse reactions that occurred in < 2% but > 1% of subjects in the BIMZELX group and at a higher rate than in the placebo group through Week 16 included neutropenia (placebo: n=0; BIMZELX: n=8 (1.1%)), stomatitis (placebo: n=0; BIMZELX: n=8 (1.1%)), bronchitis (placebo: n=1 (0.2%); BIMZELX: n=11 (1.6%)), and oropharyngeal pain (placebo: n=0; BIMZELX: n=9 (1.3%)). Specific Adverse Reactions Suicidal Ideation and Behavior: The neuropsychiatric inclusion/exclusion criteria in PsA trials were the same as in PSO. Based on a pooled analysis of the first 16 weeks of the placebo controlled clinical trials, 2 of the 698 subjects in the BIMZELX group (0.3%) reported passive suicidal ideation on the C-SSRS compared to 3 of 413 subjects in the placebo group (0.7%). During the entire clinical trial program for PsA (2,664 patient-years), there were 2 cases of suicidal ideation (2/1413; 0.08/100 patient-years) and 1 suicide attempt (1/1413; 0.04/100 patient-years); all reported in BIMZELX-treated subjects with pre-existing psychiatric conditions. Reference ID: 5481440 Infections: During the placebo-controlled period of Trials PsA-1 and PsA-2, infections were reported in 27% of subjects (100.7 per 100 patient-years) treated with BIMZELX compared with 18% of subjects (62.8 per 100 patient-years) treated with placebo. Serious infections occurred in 0.4% of subjects (1.4 per 100 patient-years) treated with BIMZELX and 0% treated with placebo. The most common infections were upper respiratory tract infections, nasopharyngitis, urinary tract infection and Candida infections, including oral candidiasis (oral candidiasis, oral fungal infection, and tongue fungal infection), occurring in 3.2% (10.2 per 100 patient-years) of subjects treated with BIMZELX and other Candida infections (skin candida, vulvovaginal candidiasis, and vulvovaginal mycotic infection) in 0.6% (1.8 per 100 patient-years) of subjects treated with BIMZELX compared to 0% and 1%, respectively, of subjects treated with placebo. During the combined placebo-controlled, maintenance and open-label extension treatment periods of Trials PsA-1 and PsA-2, infections were reported in 58% of subjects treated with BIMZELX (58.5 per 100 patients-years). Serious infections were reported in 2% of subjects treated with BIMZELX (1.3 per 100 patient-years). Inflammatory Bowel Disease: In clinical trials in subjects with psoriatic arthritis, subjects with active inflammatory bowel disease were excluded. In these trials, which included 1,413 subjects exposed to BIMZELX accounting for 2,664 patient-years, adjudicated cases of new onset of inflammatory bowel disease (including ulcerative colitis (UC) and IBD) occurred in 2 subjects (0.08 per 100 patient-years); one of these cases was serious and none resulted in discontinuation of therapy. Liver Biochemical Abnormalities: During the placebo-controlled period of Trials PsA-1 and PsA-2, liver serum transaminase elevations (> 3 times the upper limit of normal [ULN]) occurred in 1.3% of subjects treated with BIMZELX versus 0% of subjects receiving placebo. Elevated liver serum transaminases resolved during continued treatment or after discontinuation of BIMZELX. Safety through Week 52 During the maintenance period (Week 16 through Week 52 of Trial PsA-1), adverse reactions were consistent with those observed during the initial 16 weeks of treatment and with the overall safety profile of BIMZELX. Non-Radiographic Axial Spondyloarthritis Clinical Trials BIMZELX was evaluated in a placebo-controlled trial (Trial nr-axSpA-1) in subjects with non- radiographic axial spondyloarthritis (128 subjects on BIMZELX and 126 subjects on placebo). The safety profile observed in subjects with non-radiographic axial spondyloarthritis treated with BIMZELX was overall similar to the safety profile seen in subjects with psoriatic arthritis, except for cough, musculoskeletal pain, myalgia, tonsilitis, transaminase increase (placebo: n=0; BIMZELX: n=3 (2.3%) for each), and fatigue (placebo: n=1 (0.8%); BIMZELX: n=3 (2.3%)). Specific Adverse Reactions Suicidal Ideation and Behavior: The neuropsychiatric inclusion/exclusion criteria were the same in non- radiographic axial spondyloarthritis trials as in PSO. During the first 16 weeks of the placebo controlled clinical trial (Trial nr-axSpA-1), no subjects in the BIMZELX or placebo group reported suicidal ideation on the C-SSRS. During the entire clinical trial program for nr-axSpA (398 patient-years), there were no cases of suicidal ideations. One suicide attempt (1/244; 0.25/100 patient-years) was reported in a BIMZELX-treated patient with pre-existing psychiatric conditions and recent life stressors. Reference ID: 5481440 Infections: During the placebo-controlled period of Trial nr-axSpA-1, infections were reported in 36% of subjects (144.8 per 100 patient-years) treated with BIMZELX compared with 25% of subjects (94.4 per 100 patient-years) receiving placebo. There were no reports of serious infections reported during the placebo-controlled period of the trial. During the combined 52 week treatment period of Trial nr-axSpA-1, and subsequent open-label treatment, infections were reported in 68% of subjects treated with BIMZELX (78.0 per 100 patient-years). Serious infections were reported in 1.6% of subjects treated with BIMZELX (1.0 per 100 patient-years). Inflammatory Bowel Disease: In the clinical trial in subjects with non-radiographic axial spondyloarthritis, subjects with active inflammatory bowel disease were excluded. In placebo-controlled, maintenance, and open label treatment periods of this trial, which included 244 subjects exposed to BIMZELX accounting for 397 patient-years, adjudicated cases of new onset of inflammatory bowel disease occurred in 1 subject (Ulcerative Colitis; 0.26 per 100 patient-years); this case of ulcerative colitis was nonserious and did not result in discontinuation of therapy. Liver Biochemical Abnormalities: During the placebo-controlled period of Trials nr-axSpA-1, liver serum transaminase elevations (> 3 times the upper limit of normal [ULN]) occurred in 1.6% of subjects treated with BIMZELX versus 0.8% of subjects receiving placebo. Elevated liver serum transaminases resolved during continued treatment or after discontinuation of BIMZELX. Safety through Week 52 During the maintenance period (Week 16 through Week 52 of Trial nr-axSpA-1), adverse reactions were consistent with those observed during the initial 16 weeks of treatment and with the overall safety profile of BIMZELX. Ankylosing Spondylitis Clinical Trials BIMZELX was evaluated in a placebo-controlled trial (Trial AS-1) in subjects with ankylosing spondylitis (221 subjects on BIMZELX and 111 subjects on placebo). The safety profile observed in subjects with ankylosing spondylitis treated with BIMZELX was overall similar to the safety profile seen in subjects with psoriatic arthritis, except for injection site pain, rash (placebo: n=1 (0.9%); BIMZELX: n=6 (2.7%), for each) and vulvovaginal mycotic infection (placebo: n=0; BIMZELX: n=5 (2.3%)). Specific Adverse Reactions Suicidal Ideation and Behavior: The neuropsychiatric inclusion/exclusion criteria were the same in AS trials as in PSO. During the first 16 weeks of the placebo controlled clinical Trial AS-1, no subjects in the BIMZELX or placebo group reported suicidal ideation on the C-SSRS. During the entire clinical trial program for AS (1,844 patient-years), there was 1 case of suicidal ideation (1/684; 0.05/100 patient-years) reported in a subject with pre-existing psychiatric conditions. Infections: During the placebo-controlled period of Trial AS-1, infections were reported in 28% of subjects (110.3 per 100 patient-years) treated with BIMZELX compared with 23% of subjects (83.7 per 100 patient-years) receiving placebo. Serious infections occurred in 1 (0.5%) subject (1.5 per 100 patient- years) treated with BIMZELX and 1 (0.9%) subject (2.9 per 100 patient-years) receiving placebo. Reference ID: 5481440 During the combined 52 week treatment period of Trial AS-1, and subsequent open-label treatment, infections were reported in 62% of subjects treated with BIMZELX (58.8 per 100 patient-years). Serious infections were reported in 2.7% of subjects treated with BIMZELX (1.5 per 100 patient-years). Inflammatory Bowel Disease: In clinical trials in subjects with AS, subjects with active inflammatory bowel disease were excluded. In these phase 2/3 trials, which included 593 subjects exposed to BIMZELX accounting for 1,599 patient-years, adjudicated cases of new onset of inflammatory bowel disease (including ulcerative colitis (UC), Crohn’s disease (CD) and IBD-undetermined) occurred in 6 subjects (0.38 per 100 patient-years); 4 cases were serious, and 3 cases resulted in discontinuation of therapy. Liver Biochemical Abnormalities: During the placebo-controlled period of Trial AS-1, liver serum transaminase elevations (> 3 times the upper limit of normal [ULN]) occurred in 1.4% of subjects treated with BIMZELX versus 1.8% of subjects receiving placebo. Elevated liver serum transaminases resolved during continued treatment or after discontinuation of BIMZELX. Safety through Week 52 During the maintenance period (Week 16 through Week 52 of Trial AS-1), adverse reactions were consistent with those observed during the initial 16 weeks of treatment and with the overall safety profile of BIMZELX. Hidradenitis Suppurativa Clinical Trials BIMZELX was evaluated in two placebo-controlled trials (Trial HS-1 and Trial HS-2) in 1,007 adult subjects with moderate to severe hidradenitis suppurativa (861 BIMZELX-treated subjects and 146 subjects receiving placebo) [see Clinical Studies (14.5)]. The safety profile observed in subjects with hidradenitis suppurativa treated with BIMZELX was overall similar to the safety profile seen in subjects with PSO treated with BIMZELX. Upon completion of both trials, a total of 657 subjects enrolled in a long-term extension treatment period for up to an additional 188 weeks. Specific Adverse Reactions Suicidal Ideation and Behavior: The neuropsychiatric inclusion/exclusion criteria were the same in HS trials as in PSO. Analysis of pooled C-SSRS data from the first 16 weeks of the placebo-controlled clinical trials indicated that 16/861 (1.9%) BIMZELX-treated subjects and 1/146 (0.7%) subjects receiving placebo reported suicidal ideation with an estimated relative risk of 2.70 (95% confidence interval: 0.36, 20.12). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new-onset suicidal ideation on the C-SSRS than subjects treated with placebo (0.9% vs. 0%). There were 2 reported cases of suicidal ideation that were adjudicated as suicide attempts (2/1,041; 0.15/100 patient-years). Both subjects had a history of neuropsychiatric disorders. Infections: During the placebo-controlled period of Trials HS-1 and HS-2, infections were reported in 33% of subjects (132.2 per 100 patient-years) treated with BIMZELX compared with 21% of subjects (76.4 per 100 patient-years) receiving placebo. Serious infections occurred in 0.1% of subjects (0.4 per 100 patient- years) treated with BIMZELX and 0% of subjects receiving placebo.  Reference ID: 5481440 The most commonly reported infections were comparable to those reported in subjects with PSO. Oral candidiasis occurred in 7.8% of subjects (26.7 per 100 patient years) treated with BIMZELX 320 mg Q2W, 3.9% of subjects (12.9 per 100 patient-years) treated with BIMZELX 320 mg Q4W, and 0 subjects receiving placebo. Other candida infections occurred in 3.6% of subjects (12.2 per 100 patient-years) treated with BIMZELX 320 mg Q2W, 6.7% of subjects (22.6 per 100 patient-years) treated with BIMZELX 320 mg Q4W, and 0 subjects receiving placebo. Tinea infections occurred in 3.1% of subjects (10.4 per 100 patient-years) treated with BIMZELX 320 mg Q2W, 2.5% of subjects (8.1 per 100 patient- years) treated with BIMZELX 320 mg Q4W, and 0.7% (2.3 per 100 patient-years) receiving placebo. During the combined placebo-controlled, maintenance treatment periods and open-label extension treatment periods of Trials HS-1 and HS-2, infections were reported in 68% of subjects treated with BIMZELX (104.7 per 100 patient-years). Serious infections were reported in 2.1% of subjects treated with BIMZELX (1.7 per 100 patient-years). Inflammatory Bowel Disease: In clinical trials in subjects with hidradenitis suppurativa, subjects with active inflammatory bowel disease were excluded. During the combined placebo-controlled, maintenance, and open-label extension treatment periods of Trials HS-1 and HS-2, which included 995 subjects exposed to BIMZELX accounting for 1,272 patient-years, adjudicated cases of new onset of inflammatory bowel disease (including ulcerative colitis (UC), Crohn’s disease (CD) and undetermined) occurred in 5 subjects (0.39 per 100 patient-years); 3 of these cases were serious, all of which resulted in discontinuation of therapy. Additionally, flares of pre-existing IBD occurred in 2 subjects, which resulted in discontinuation of BIMZELX in both. Liver Biochemical Abnormalities: During the placebo-controlled period of Trials HS-1 and HS-2, liver serum transaminase elevations (> 3 times the upper limit of normal [ULN]) occurred in 1.2% of subjects treated with BIMZELX versus 0% of subjects receiving placebo. Elevated liver serum transaminases resolved during continued treatment or after discontinuation of BIMZELX. Safety through Week 48 During the maintenance period (Week 16 through Week 48 of Trials HS-1 and HS-2), adverse reactions were consistent with those observed during the initial 16 weeks of treatment and with the overall safety profile of BIMZELX. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of BIMZELX. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: conjunctivitis, esophageal candidiasis 7 DRUG INTERACTIONS CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL- 6, IL-10, TNFα, IFN) during chronic inflammation. Treatment with BIMZELX may modulate serum levels of some cytokines. Therefore, upon initiation or discontinuation of BIMZELX in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate. Reference ID: 5481440 Population pharmacokinetic (PK) data analyses indicated that the clearance of BIMZELX was not impacted by concomitant administration of cDMARDs including methotrexate, or by prior exposure to biologics. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BIMZELX during pregnancy. For more information, healthcare providers or patients can contact the Organization of Teratology Information Specialists (OTIS) AutoImmune Diseases Study at 1-877-311- 8972 or visit http://mothertobaby.org/pregnancy-studies/. Risk Summary Available data from case reports on BIMZELX use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, BIMZELX may be transmitted from the mother to the developing fetus (see Clinical Considerations). In an enhanced pre- and postnatal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of bimekizumab-bkzx during the period of organogenesis through parturition at doses up to 38 times the maximum recommended human dose (MRHD) (see Data). All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions: Because bimekizumab-bkzx may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to BIMZELX in utero. There are no data regarding infant serum levels of bimekizumab-bkzx at birth and the duration of persistence of bimekizumab-bkzx in infant serum after birth. Although a specific timeframe to delay live virus immunizations in infants exposed in utero is unknown, a minimum of 4 months after birth may be considered because of the half-life of the product. Data Animal Data: An enhanced pre- and postnatal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered subcutaneous doses of bimekizumab-bkzx of 20 or 50 mg/kg/week from gestation day 20 to parturition and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery. No maternal toxicity was noted in this study. There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology or neurobehavioral development. The no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was identified as 50 mg/kg/week (38 times the MRHD, based on mg/kg comparison of 1.33 mg/kg/week administered as a 320 mg dose to a 60 kg individual once every 4 weeks). 8.2 Lactation Risk Summary There are no data on the presence of bimekizumab-bkzx in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Endogenous IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in Reference ID: 5481440 the breastfed infant to bimekizumab-bkzx are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BIMZELX and any potential adverse effects on the breastfed infant from BIMZELX or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of BIMZELX in pediatric patients have not been established. 8.5 Geriatric Use Of the 1,789 subjects with plaque psoriasis that were exposed to BIMZELX, a total of 153 subjects were 65 years of age or older, and 18 subjects were 75 years of age or older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, clinical trials in PSO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects. Of the 1,197 subjects with PsA that were exposed to BIMZELX, a total of 148 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, clinical trials in PsA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects. Of the 244 subjects with nr-axSpA that were exposed to BIMZELX, a total of 6 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, the clinical trial in nr-axSpA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects. Of the 330 subjects with AS that were exposed to BIMZELX, a total of 11 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, the clinical trial in AS did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects. Of the 995 subjects with hidradenitis suppurativa that were exposed to BIMZELX, a total of 18 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, clinical trials in HS did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects. 11 DESCRIPTION Bimekizumab-bkzx, an interleukin-17 A and F antagonist, is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody. Bimekizumab-bkzx is produced by recombinant DNA technology in Chinese Hamster Ovary cells, and has an approximate molecular weight of 150 kDa. BIMZELX (bimekizumab-bkzx) injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to pale brownish-yellow solution for subcutaneous use. Each BIMZELX 1 mL (160 mg/mL) prefilled syringe or prefilled autoinjector delivers 1 mL containing 160 mg bimekizumab-bkzx, glacial acetic acid (1.23 mg), glycine (16.5 mg), polysorbate 80 (0.4 mg), sodium acetate (2.83 mg), and Water for Injection, USP at pH 5.1. Each BIMZELX 2 mL (160 mg/mL) prefilled syringe or prefilled autoinjector delivers 2 mL containing 320 mg bimekizumab-bkzx, glacial acetic acid (2.46 mg), glycine (33.0 mg), polysorbate 80 (0.8 mg), sodium acetate (5.65 mg), and Water for Injection, USP at pH 5.1. Reference ID: 5481440 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bimekizumab-bkzx is a humanized immunoglobulin IgG1/ κ monoclonal antibody with two identical antigen binding regions that selectively bind to human interleukin 17A (IL-17A), interleukin 17F (IL- 17F), and interleukin 17-AF cytokines, and inhibits their interaction with the IL-17 receptor complex. IL- 17A and IL-17F are naturally occurring cytokines that are involved in normal inflammatory and immune responses. Bimekizumab-bkzx inhibits the release of proinflammatory cytokines and chemokines. 12.2 Pharmacodynamics Elevated levels of IL-17A and IL-17F are found in lesional psoriatic skin, and lesional skin in HS. Bimekizumab-bkzx exposure-response relationships to serum biomarkers, including IL-17A and IL-17F, and the time course of such pharmacodynamic responses are unknown. Immune Response to Inactivated or Non-Live Vaccines Healthy individuals who received a single 320 mg dose of BIMZELX two weeks prior to vaccination with an inactivated seasonal influenza vaccine had similar antibody responses compared to individuals who did not receive BIMZELX prior to vaccination. The effectiveness of inactivated seasonal influenza vaccines and other inactivated and non-live vaccines has not been evaluated in patients treated with BIMZELX. 12.3 Pharmacokinetics Bimekizumab-bkzx pharmacokinetics are comparable in adult patients with moderate to severe plaque psoriasis, psoriatic arthritis, non-radiographic axial spondyloarthritis, and ankylosing spondylitis. The median peak plasma concentration of bimekizumab-bkzx was 25 (range: 12-50) μg/mL and was reached in 3-4 days. Bimekizumab-bkzx exhibited dose-proportional pharmacokinetics in patients with plaque psoriasis over a dose range of 64 mg to 480 mg (0.2 to 1.5 times the approved recommended dosage) following subcutaneous administration. The median steady-state trough concentration of bimekizumab-bkzx was approximately 40% lower in HS subjects than that of PSO subjects. Absorption The absolute bioavailability of bimekizumab-bkzx was 70% in healthy subjects. Distribution The median volume of distribution at steady state was 11.2 L in subjects with moderate to severe plaque psoriasis. The volume of distribution in subjects with moderate to severe hidradenitis suppurativa was estimated to be approximately 18% higher than in subjects with moderate to severe plaque psoriasis. Elimination The median (coefficient of variation %) clearance (CL/F) of bimekizumab-bkzx was 0.337 L/day (32.7%). The mean terminal elimination half-life was 23 days, with clearance independent of dose. The apparent clearance in subjects with moderate to severe hidradenitis suppurativa was estimated to be approximately 31% higher than in subjects with moderate to severe plaque psoriasis. Metabolism: Bimekizumab-bkzx is expected to be degraded into small peptides by catabolic pathways. Specific Populations No significant differences in the pharmacokinetics of bimekizumab-bkzx were observed based on age (≥18 years). Reference ID: 5481440 Body Weight: The average plasma concentration in adult subjects weighing ≥120 kg was predicted to be at least 30% lower than those weighing < 120 kg (median of 87 kg) [see Dosage and Administration (2.2)]. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of BIMZELX or of other bimekizumab products. Across the pivotal trials in all indications, there was no identified clinically significant effect of anti- bimekizumab-bkzx antibodies, including neutralizing anti-drug antibodies, on safety or effectiveness of BIMZELX. Plaque Psoriasis During the 52–56-week treatment period in Trial Ps-1, Trial Ps-2, and Trial Ps-3 [see Clinical Studies (14.1)], 116/257 (45%) of BIMZELX-treated subjects (at the recommended dosage) developed anti- bimekizumab-bkzx antibodies (also referred to as ADA). Of the BIMZELX-treated subjects who developed ADA in these trials, approximately 16% had neutralizing antibodies. Psoriatic Arthritis During the 52-week treatment period in Trial PsA-1 [see Clinical Studies (14.2)], 201/431 (47%) of subjects treated with BIMZELX had ADA, and 18% had neutralizing ADA. Non-Radiographic Axial Spondyloarthritis During the 52-week treatment period in Trial nr-axSpA-1 [see Clinical Studies (14.3)], 68/119 (57%) of BIMZELX-treated subjects had anti-bimekizumab-bkzx ADA, and approximately 25% had neutralizing ADA. Ankylosing Spondylitis During the 52-week treatment period in Trial AS-1 [see Clinical Studies (14.4)], 86/194 (44%) of BIMZELX-treated subjects had anti-bimekizumab-bkzx ADA, and approximately 20% had neutralizing ADA. Hidradenitis Suppurativa During the 48-week treatment period in Trials HS-1 and HS-2 [see Clinical Studies (14.5)], 171/291 (59%) of BIMZELX-treated subjects had anti-bimekizumab-bkzx ADA, and of those who developed ADA, approximately 63% had neutralizing ADA. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and mutagenicity studies have not been conducted with bimekizumab-bkzx. No effects on fertility parameters such as effects on reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature cynomolgus monkeys that were subcutaneously administered 200 mg/kg/week bimekizumab-bkzx (150 times the MRHD, based on mg/kg comparison) for 26 weeks. The monkeys were not mated to evaluate fertility. 14 CLINICAL STUDIES 14.1 Plaque Psoriasis Reference ID: 5481440 Three multicenter, randomized, double-blind trials [Trial Ps-1 (NCT03370133), Trial Ps-2 (NCT03410992), and Trial Ps-3 (NCT03412747)] enrolled a total of 1,480 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, an Investigator’s Global Assessment (IGA) score of ≥3 (“moderate”) in the overall assessment of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12. In Trial Ps-1, 567 subjects were randomized to receive either BIMZELX 320 mg by subcutaneous injection every 4 weeks, ustekinumab (for subjects weighing ≤100kg, 45 mg initially and 4 weeks later, then every 12 weeks; for subjects weighing >100kg, 90 mg initially and 4 weeks later, then every 12 weeks), or placebo through Week 52. At Week 16, subjects originally randomized to placebo received BIMZELX 320 mg every 4 weeks through Week 52. In Trial Ps-2, 435 subjects were randomized to either BIMZELX 320 mg by subcutaneous injection every 4 weeks or placebo. At Week 16, subjects who achieved a PASI 90 response continued into a 40-week randomized withdrawal period. Subjects originally randomized to BIMZELX 320 mg every 4 weeks were re-randomized to either BIMZELX 320 mg every 4 weeks or BIMZELX 320 mg every 8 weeks or placebo. Subjects originally randomized to placebo continued to receive placebo if they were PASI 90 responders. Subjects who did not achieve a PASI 90 response at week 16 entered an open-label escape arm and received BIMZELX 320 mg every 4 weeks for 12 weeks. Subjects who relapsed, defined as having a less than PASI 75 response compared to baseline, during the randomized withdrawal period also entered the 12-week escape arm. In Trial Ps-3, 478 subjects were randomized to receive either BIMZELX 320 mg by subcutaneous injection every 4 weeks through week 56, BIMZELX 320 mg every 4 weeks through week 16 followed by BIMZELX every 8 weeks through week 56, or adalimumab (80 mg as an initial dose followed by 40 mg every other week starting 1 week after initial dose through Week 24) followed by BIMZELX 320 mg every 4 weeks through Week 56. In Trial Ps-1, Trial Ps-2, and Trial Ps-3, 71% of the subjects were male and 84% of the subjects were White, with a mean age of 45 years and a mean weight of 89 kg. At baseline, subjects had a median baseline PASI score of 18, median baseline for BSA of 20%, and baseline IGA score of 4 (“severe”) in 33% of subjects. A total of 93% subjects had psoriasis of the scalp (Scalp IGA score of ≥1) and a total of 26% of subjects had a history of psoriatic arthritis. Additionally, 38% had received prior biologic therapy. Clinical Response at Week 16 (Trial Ps-1 and Trial Ps-2) Trial Ps-1 and Trial Ps-2 responses at Week 16 compared to placebo for the two co-primary endpoints: • The proportion of subjects who achieved an IGA score of 0 (“clear”) or 1 (“almost clear”) with at least a 2-grade improvement from baseline • The proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90) Secondary endpoints included the proportion of subjects who achieved PASI 100, IGA 0, and Scalp IGA response (defined as Scalp IGA score of 0 [clear] or 1 [almost clear] with at least 2-grade of improvement from baseline) at Week 16, and PASI 75 at Week 4. In addition, secondary endpoints included assessment of psoriasis symptoms (itching, pain, and scaling) measured by the Patient Symptom Diary (PSD) at Week 16. The proportion of subjects who achieved IGA 0 or 1, PASI 90, IGA 0, and PASI 100 response at Week 16 are presented in Table 3. Reference ID: 5481440 Table 3: Efficacy Results at Week 16 in BIMZELX or Placebo-Treated Adults with Plaque Psoriasis in Trial Ps-1 and Trial Ps-2 Trial Ps-1 Trial Ps-2 BIMZELX 320 mg every 4 weeks (N=321) n (%) Placebo (N=83) n (%) BIMZELX 320 mg every 4 weeks (N=349) n (%) Placebo (N=86) n (%) IGA 0 or 1 (“clear” or “almost clear”) a 270 (84%) 4 (5%) 323 (93%) 1 (1%) Difference (95% CI) 79% (73%, 85%) 91% (88%, 95%) PASI 90a 273 (85%) 4 (5%) 317 (91%) 1 (1%) Difference (95% CI) 80% (74%, 86%) 90% (86%, 93%) IGA 0 (“clear”) 188 (59%) 0 (0%) 243 (70%) 1 (1%) Difference (95% CI) 59% (53%, 64%) 69% (64%, 74%) PASI 100 188 (59%) 0 (0%) 238 (68%) 1 (1%) Difference (95% CI) 59% (53%, 64%) 67% (62%, 73%) a Co-primary endpoints Examination of age, gender, race, baseline IGA score and previous treatment with systemic or biologic agents did not identify differences in response to BIMZELX among these subgroups at Week 16. A greater proportion of subjects randomized to BIMZELX achieved PASI 75 at Week 4 in both trials compared to placebo. In Trial Ps-1, 77% of subjects treated with BIMZELX achieved PASI 75 compared to 2% treated with placebo. In Trial Ps-2, 76% of subjects treated with BIMZELX achieved PASI 75 compared to 1% treated with placebo. Among subjects with Scalp IGA score of at least 2 at baseline, a greater proportion of subjects randomized to BIMZELX achieved Scalp IGA response at Week 16 in both trials compared to placebo. In Trial Ps-1, 84% (240/285) of subjects treated with BIMZELX achieved Scalp IGA response compared to 15% (11/72) of placebo treated subjects. In Trial Ps-2, 92% (286/310) of subjects treated with BIMZELX achieved Scalp IGA response compared to 7% (5/74) of placebo treated subjects. Maintenance and Durability of Response In Trial Ps-2, subjects randomized to BIMZELX every 4 weeks at Week 0 and who were PASI 90 responders at Week 16 were re-randomized to either continue treatment with BIMZELX every 4 weeks, switched to BIMZELX every 8 weeks, or be withdrawn from therapy (i.e., received placebo). Figure 1 and Figure 2 present the percentage of subjects maintaining IGA score of 0 (“Clear”) or 1 (“Almost Clear”) and PASI 90, respectively, through Week 56 after re-randomization at Week 16. Figure 1: Percentage of Subjects Maintaining IGA 0 or 1 through Week 56 after Re-Randomization at Week 16 Reference ID: 5481440 For IGA 0 or 1 responders at Week 16 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to loss of IGA 0 or 1 response was approximately 24 weeks. Among these subjects with IGA score of 2 at retreatment, 58% (14/24) achieved IGA score of 0 within 12 weeks of restarting treatment with BIMZELX 320 mg every 4 weeks. Among these subjects with IGA score ≥ 3 at retreatment, 87% (34/39) regained IGA 0 or 1 response with at least 2-grade improvement from retreatment within 12 weeks of restarting treatment with BIMZELX 320 mg every 4 weeks. Figure 2: Percentage of Subjects Maintaining PASI 90 through Week 56 after Re-Randomization at Week 16 For PASI 90 responders at Week 16 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to loss of PASI 90 response was approximately 24 weeks. Patient Reported Outcomes Greater improvements in itch, pain, and scaling at Week 16 with BIMZELX compared to placebo were observed in both trials as measured by the Patient Symptom Diary (PSD). Reference ID: 5481440 14.2 Psoriatic Arthritis The safety and efficacy of BIMZELX were assessed in 1,112 subjects in two multicenter, randomized, double-blind, placebo-controlled studies [Trial PsA-1 (NCT 03895203) and Trial PsA-2 (NCT 03896581)] in subjects 18 years and older with active psoriatic arthritis (PsA). Subjects in these studies had a diagnosis of PsA of at least 6 months based on Classification Criteria for Psoriatic Arthritis (CASPAR), a median duration of 4.6 years at baseline, and active disease with ≥3 tender joint count and ≥3 swollen joint count. Subjects with each subtype of PsA were enrolled in these studies, including polyarticular symmetric arthritis (63.5%), oligoarticular asymmetric arthritis (25.9%), distal interphalangeal joint predominant (4.4%), spondylitis predominant (4.2%), and arthritis mutilans (1.5%). At baseline, 56% of subjects had ≥3% Body Surface Area (BSA) with active plaque psoriasis. At baseline across both studies, 32% and 12% of subjects had enthesitis and dactylitis, respectively, 58% of subjects had psoriatic nail disease, and 53% of subjects were receiving concomitant methotrexate. The PsA-1 study evaluated 852 biologic-naïve subjects, who were treated with either BIMZELX 160 mg every 4 weeks up to Week 52, adalimumab 40 mg every 2 weeks up to Week 52 (active reference arm), or placebo. Subjects receiving placebo were switched to BIMZELX every 4 weeks at Week 16 to Week 52. In this study, 78% of subjects had received prior treatment with ≥ 1 conventional DMARDs (cDMARDs), and 22 % of subjects had no prior treatment with cDMARDs. At baseline, 58% of subjects were receiving concomitant methotrexate (MTX), 11% were receiving concomitant cDMARDs other than MTX, and 31% were receiving no cDMARDs. The PsA-2 study evaluated 400 anti-TNFα experienced subjects (inadequate response or intolerance to treatment), who were treated with BIMZELX 160 mg every 4 weeks or placebo up to Week 16. In this study, 43% of subjects were receiving concomitant MTX, 8% were receiving concomitant cDMARDs other than MTX, and 50% were receiving no cDMARDs. For both studies, the primary endpoint was the proportion of subjects who achieved an America College of Rheumatology (ACR) 50 response at Week 16. Clinical Response In both studies, treatment with BIMZELX resulted in significant improvement in disease activity, as measured by ACR, compared to placebo at Week 16 (see Table 4). Responses in Trial PsA-2 (anti-TNF experienced) were similar to Trial PsA-1. Table 4: Clinical Responses at Week 16 in Trial PsA-1 and Trial PsA-2 Trial PsA-1 – bDMARD naïve Trial PsA-2 – anti-TNFα experienced Endpoint BIMZELX 160 mg Q4W N=431 n (%) Placebo N=281 n (%) Difference from Placebo* (95% CI) BIMZELX 160 mg Q4W N=267 n (%) Placebo N=133 n (%) Difference from Placebo** (95% CI) ACR 20 Response Week 16 268 (62.2) 67 (23.8) 38.3 (31.6, 45.1) 179 (67.0) 21 (15.8) 51.3 (42.9, 59.6) ACR 50 Response Week 16 189 (43.9)* 28 (10.0) 33.9 (28.0, 39.7) 116 (43.4)* 9 (6.8) 36.7 (29.4, 44.0) ACR 70 Response Week 16 105 (24.4) 12 (4.3) 20.1 (15.4, 24.8) 71 (26.6) 1 (0.8) 25.8 (15.6, 35.7)*** CI= confidence interval Reference ID: 5481440 * Multiplicity-controlled p<0.001 95% CI based on normal approximation Exact 95% CI used The percentage of subjects achieving ACR50 responses in Trial PsA-1 by visit through Week 16 is shown in Figure 3. Similar responses were seen in Trial PsA-2 up to Week 16. Figure 3: Percent of Subjects Achieving ACR 50 Responses in Trial PsA-1 through Week 16 The results of the components of the ACR response criteria are shown in Table 5. Table 5: Mean change from Baseline in ACR Component Scores at Week 16 in Trial PsA-1 and Trial PsA-2 Trial PsA-1 – bDMARD naïve Trial PsA-2 – anti-TNFα experienced Placebo (N=281) BIMZELX 160 mg Q4W (N=431) Placebo (N=133) BIMZELX 160 mg Q4W (N=267) Number of Swollen Joints Baseline 9.5 9.0 10.3 9.7 Mean change at Week 16 -3.0 -6.6 -2.0 -7.0 Number of Tender Joints Baseline 17.1 16.8 19.3 18.4 Mean change at Week 16 -3.2 -10.0 -2.4 -10.9 Patient’s Assessment of Pain Baseline 56.8 53.7 61.7 58.3 Mean change at Week 16 -6.2 -23.6 -4.5 -27.7 Reference ID: 5481440 Patient’s Global Assessment Baseline 58.6 54.4 63.0 60.5 Mean change at Week 16 -7.7 -26.3 -5.5 -31.8 Physician Global Assessment Baseline 57.3 57.2 57.7 59.3 Mean change at Week 16 -12.5 -37.4 -6.8 -49.4 Health Assessment Questionnaire- Disability Index (HAQ-DI) Baseline 0.9 0.8 1.0 1.0 Mean Change at Week 16 -0.1 -0.3 -0.1 -0.4* High Sensitivity C-reactive Protein (hsCRP) mg/L Baseline 11.4 8.7 11.6 12.4 Mean Change at Week 16 -2.4 -4.2 3.6 -7.0 Multiple Imputation (MI) is used for all endpoints presented in Table 5. p<0.001 reference-based imputation versus placebo adjusted for multiplicity. Treatment with BIMZELX resulted in improvement in dactylitis and enthesitis in subjects with pre- existing dactylitis or enthesitis, compared to placebo. In subjects with coexistent plaque psoriasis receiving BIMZELX, the skin lesions of psoriasis improved with treatment, relative to placebo, as measured by the Psoriasis Area Severity Index (PASI 90) at Week 16. Radiographic Response In Trial PsA-1, inhibition of progression of structural damage was assessed radiographically and expressed as the change from baseline in the Van der Heijde modified total Sharp Score (vdHmTSS) and its components, the Erosion Score (ES) and the Joint Space Narrowing score (JSN), at Week 16 (see Table 6). BIMZELX significantly inhibited the rate of progression of joint damage at Week 16 in the overall population compared to placebo. The change from Baseline in erosion subscores contributed more to the change from Baseline in vdHmTSS total score than the change from Baseline in joint narrowing subscore. The percentage of subjects with no radiographic joint damage progression (defined as a change from baseline in mTSS of ≤0.0) from randomization to Week 16 was 77% for BIMZELX and 69% for placebo in the overall population. Similar responses were achieved in the population with elevated hsCRP and/or at least 1 bone erosion (75% for BIMZELX and 67% for placebo). Table 6: Change in vdHmTSS in PsA-1 at Week 16 Placebo BIMZELX 160 mg Q4W Difference from Placebo (95% CI)a Overall population (N=269) (N=420) Baseline mean (SE) 12.34 (1.37) 12.47 (1.46) Mean change from baseline at Week 16 (SE) 0.32 (0.09) 0.04 (0.04) -0.26 (-0.29, -0.23) p≤0.001 versus placebo. p-values are based on reference-based imputation using difference in LS Mean using an ANCOVA model with treatment, bone erosion at Baseline and region as fixed effects and Baseline score as a covariate. a) Unadjusted differences are shown Reference ID: 5481440 Physical Function In both studies, subjects treated with BIMZELX showed statistically significant improvement from baseline in physical function compared with placebo as assessed by HAQ-DI at Week 16 (see Table 5). In both studies, a greater proportion of subjects achieved a reduction of at least 0.35 in HAQ-DI score from baseline in the BIMZELX group compared with placebo at Week 16. Other Health Related Outcomes Fatigue was assessed by Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT- Fatigue). Additionally, in both studies at Week 16, subjects treated with BIMZELX showed improvements in FACIT-Fatigue scores. 14.3 Non-Radiographic Axial Spondyloarthritis The efficacy and safety were assessed in 254 patients in one randomized, double-blind, placebo-controlled study [Trial nr-axSpA-1 (NCT03928704)] in adult subjects 18 years of age and older with active non- radiographic axial spondyloarthritis. Subjects had to have objective signs of inflammation with elevated C-reactive protein (CRP) level and/or evidence of sacroiliitis on Magnet Resonance Imaging (MRI). Subjects met ASAS classification criteria for axial spondyloarthritis and have active disease as defined by BASDAI greater than or equal to 4, spinal pain of greater than or equal to 4 (0-10 numeric rating scale (NRS)), and no definitive radiographic evidence of structural damage in the sacroiliac joints. At baseline, 73% of subjects had enthesitis. Subjects also had a history of inadequate response to 2 different non- steroidal anti-inflammatory drugs (NSAIDs), or intolerance or contraindication to NSAIDs. Approximately 24% of subjects were on concomitant cDMARDs. Overall, 11% of subjects had received previous treatment (failed or were intolerant to) with anti-TNF alpha agents. Subjects were randomized to receive BIMZELX 160 mg or placebo every 4 weeks up to the completion of Week 16 assessments. Starting at Week 16, all subjects received BIMZELX every 4 weeks up to Week 52. The primary endpoint was at least 40% improvement in Assessment of Spondyloarthritis International Society (ASAS 40) at Week 16. Clinical Response In Trial nr-axSpA-1, treatment with BIMZELX resulted in significant improvements in the measure of disease activity compared to placebo at Week 16 (Table 7). Table 7: Clinical Response in Trial nr-axSpA-1 at Week 16 BIMZELX 160 mg Q4W (N=128) n (%) Placebo (N=126) n (%) Difference from placebo (95% CI)* ASAS 40 response 61 (47.7%)* 27 (21.4%) 26.2 (15.0, 37.5) ASAS 20 response 88 (68.8%)* 48 (38.1%) 30.7 (19.0, 42.3) NRI is used CI= confidence interval * Multiplicity-controlled p<0.001 *95% CI based on normal approximation Similar responses were seen regardless of prior anti-TNF alpha therapy. Treatment with BIMZELX resulted in improvement in enthesitis in subjects with pre-existing enthesitis. The results of the main components of the ASAS 40 response criteria and other measures of disease activity are shown in Table 8. Reference ID: 5481440 Table 8: Components of the ASAS 40 Response Criteria and Other Measures of Disease Activity in nr-axSpA Subjects at Baseline and Week 16 in Trial nr-axSpA-1 BIMZELX 160 mg Q4W (N= 128) Placebo (N=126) ASAS Components - Patient Global Assessment (0-10) Baseline Mean Change from Baseline 7.1 -3.2 6.9 -1.4 - Total Spinal Pain (0-10) Baseline Mean Change from Baseline 7.3 -3.4 7.1 -1.7 - BASFI (0-10) Baseline Mean Change from Baseline 5.5 -2.5 5.3 -1.0 - Inflammation (0-10)a Baseline Mean Change from Baseline 7.0 -3.6 6.9 -1.9 Other Measures of Disease Activity BASDAI Score Baseline Mean Change from Baseline 6.9 -3.1* 6.7 -1.5 BASMI Baseline Mean Change from Baseline 2.9 -0.4 3.0 -0.1 hsCRP (mg/L) Baseline Mean Change from Baseline 11.1 -6.7 10.2 0.0 a Inflammation is the mean of patient-reported stiffness self-assessments (questions 5 and 6) in BASDAI BASFI = Bath Ankylosing Spondylitis Functional Index BASMI = Bath Ankylosing Spondylitis Metrology Index BASDAI = Bath Ankylosing Spondylitis Disease Activity Index MI is used for all endpoints presented in Table 8 Multiplicity-controlled p<0.001 The percentage of subjects achieving ASAS 40 responses in Trial nr-axSpA-1 by visit through Week 16 is shown in Figure 4. Figure 4: Percent of Subjects Achieving ASAS 40 Responses in Trial nr-axSpA-1 Week 16 Reference ID: 5481440 Health Related Quality of Life BIMZELX treated subjects showed significantly greater improvement compared to subjects receiving placebo at Week 16 in health-related quality of life as measured by the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score. 14.4 Ankylosing Spondylitis The efficacy and safety were assessed in 332 patients in one randomized, double-blind, placebo-controlled study [Trial AS-1 (NCT03928743)] in adult subjects 18 years of age and older with active ankylosing spondylitis. Subjects had to have documented radiologic evidence (x-ray) fulfilling the Modified New York criteria for AS. Subjects had active disease as defined by BASDAI ≥4 and spinal pain ≥4 on a 0 to 10 numeric rating scale (NRS) (from BASDAI Item 2). Subjects also had a history of inadequate response to 2 different non-steroidal anti-inflammatory drugs (NSAIDs), or intolerance or contraindication to NSAIDs. Approximately 20% of subjects were on concomitant cDMARDs. Overall, 16% of subjects had received previous treatment (failed or were intolerant to) with anti-TNF alpha agents. Subjects were randomized 2:1 to receive BIMZELX 160 mg or placebo every 4 weeks up to the completion of Week 16 assessments. Starting at Week 16, all subjects received BIMZELX every 4 weeks up to Week 52. The primary endpoint was at least 40% improvement in Assessment of Spondyloarthritis International Society (ASAS 40) at Week 16. Clinical Response In Trial AS-1, treatment with BIMZELX resulted in significant improvements in the measure of disease activity compared to placebo at Week 16 (Table 9). Table 9: Clinical Response in Trial AS-1 at Week 16 BIMZELX 160 mg Q4W (N=221) Placebo (N=111) Difference from placebo (95% CI)* Reference ID: 5481440 n (%) n (%) ASAS 40 response 99 (44.8%)* 25 (22.5%) 22.3 (12.1, 32.4) ASAS 20 response 146 (66.1%)* 48 (43.2%) 22.8 (11.7, 34.0) NRI is used CI= confidence interval * Multiplicity-controlled p<0.001 *95% CI based on normal approximation Similar responses were seen regardless of prior anti-TNF alpha therapy. Treatment with BIMZELX resulted in improvement in enthesitis in subjects with pre-existing enthesitis. The results of the main components of the ASAS 40 response criteria and other measures of disease activity are shown in Table 10. Table 10: Components of the ASAS 40 Response Criteria and Other Measures of Disease Activity in Ankylosing Spondylitis Subjects at Baseline and Week 16 in Trial AS-1 BIMZELX 160 mg Q4W (N= 221) Placebo (N=111) ASAS Components - Patient Global Assessment (0-10) Baseline Mean Change from Baseline 6.6 -2.7 6.7 -1.6 - Total Spinal Pain (0-10) Baseline Mean Change from Baseline 7.1 -3.3 7.2 -1.9 - BASFI (0-10) Baseline Mean Change from Baseline 5.3 -2.2* 5.2 -1.1 - Inflammation (0-10)a Baseline Mean Change from Baseline 6.7 -3.2 6.8 -2.1 Other Measures of Disease Activity BASDAI Score Baseline Mean Change from Baseline 6.4 -2.9* 6.5 -1.9 BASMI Baseline Mean Change from Baseline 3.9 -0.5** 3.8 -0.2 hsCRP (mg/L) Baseline Mean Change from Baseline 14.7 -8.6 13.6 -2.2 a Inflammation is the mean of patient-reported stiffness self-assessments (questions 5 and 6) in BASDAI.; BASFI = Bath Ankylosing Spondylitis Functional Index BASMI = Bath Ankylosing Spondylitis Metrology Index BASDAI = Bath Ankylosing Spondylitis Disease Activity Index MI is used for all endpoints presented in Table 10 * Multiplicity-controlled p<0.001 **Multiplicity-controlled p<0.006 The percentage of subjects achieving ASAS 40 responses in Trial AS-1 by visit through Week 16 is shown in Figure 5. Reference ID: 5481440 Figure 5: Percent of Subjects Achieving ASAS 40 Responses in Trial AS-1 Through Week 16 Health Related Quality of Life BIMZELX treated subjects showed significantly greater improvement compared to subjects receiving placebo at Week 16 in health-related quality of life as measured by the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score. 14.5 Hidradenitis Suppurativa The safety and efficacy of BIMZELX were assessed in two Phase 3 multicenter, randomized, double- blind, placebo-controlled trials [Trial HS-1 (NCT04242446) and Trial HS-2 (NCT04242498)] in 1,014 adult subjects with moderate to severe HS of at least 6 months with Hurley Stage II or Hurley Stage III disease, and with ≥5 inflammatory lesions [i.e., number of abscesses plus number of inflammatory nodules (AN count)], and a history of inadequate response to a course of systemic antibiotics for the treatment of HS. Subjects received BIMZELX 320 mg every 2 weeks (Q2W) for 48 weeks, or BIMZELX 320 mg every 4 weeks (Q4W) up to Week 48, or BIMZELX 320 mg Q2W to Week 16, followed by 320 mg Q4W up to Week 48, or placebo. At Week 16, subjects receiving placebo were switched to BIMZELX 320 mg Q2W to Week 48. Concomitant oral doxycycline, minocycline, or an equivalent systemic tetracycline for HS was allowed if the subject was on a stable dose regimen for 28 days prior to baseline. In these trials, at baseline the mean age of all subjects was 37 years, 57% of subjects were female, 80% were White, 11% were Black or African American, and 4% were Asian; for ethnicity, 7% identified as Hispanic or Latino. Of the subjects enrolled in trials conducted in the United States, 33% were Black or African American. The mean BMI was 33, and 46% were current smokers. Subjects had a median disease duration of 5 years. Overall, 9% of subjects were receiving concomitant antibiotic therapy for HS, and 19% of subjects had received previous treatment with biologics. The proportion of Hurley Stage II and Stage III subjects were 56% and 44%, respectively. Additionally, the mean number of draining tunnels was 3.6 and mean AN count was 16.3. Reference ID: 5481440 The primary efficacy endpoint in both trials was the Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) at Week 16, defined by at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess or draining tunnel count relative to baseline. Secondary endpoints included the proportion of subjects who achieved HiSCR75 and HS-specific skin pain response as assessed by a 0 to 10 numeric rating scale (NRS). Clinical Response at Week 16 (Trials HS-1 and HS-2) In both trials, a higher proportion of BIMZELX-treated subjects achieved HiSCR50 and HiSCR75 compared to placebo (see Table 11). Table 11: Efficacy Results in Adults with HS in Trials HS-1 and HS-2 at Week 16 a Trial HS-1 Trial HS-2 BIMZELX 320mg Q2W (N=289) Placebo (N=72) BIMZELX 320 mg Q2W (N=291) Placebo (N=74) HiSCR50 48% 29% 52% 32% Difference (95% CI) 18% (6%, 30%) 20% (8%, 32%) HiSCR75 33% 18% 36% 16% Difference (95% CI) 15% (4%, 27%) 20% (10%, 31%) a Subjects who initiated systemic antibiotics (new antibiotic or change in the dose/type of current antibiotic) for any reason or who discontinued due to adverse event or lack of efficacy are treated as non-responders at all subsequent visits. Other missing data were imputed via multiple imputation. Examination of age, gender, race, disease duration, weight, prior biologic therapy, systemic antibiotic use at baseline, Hurley stage, and smoking status did not identify meaningful differences in response to BIMZELX among these subgroups at Week 16. Figure 6 presents the proportion of subjects achieving HiSCR50 response in Trials HS-1 and HS-2 by visit through Week 16. Figure 6: HiSCR50 Response through Week 16 in Adults with HS in Trials HS-1 and HS-2 Reference ID: 5481440 Subjects who initiated systemic antibiotics (new antibiotic or change in the dose/type of current antibiotic) for any reason through Week 16 or who discontinued due to adverse event or lack of efficacy are treated as non-responders at all subsequent visits. Other missing data were imputed via multiple imputation. BIMZELX was associated with an improvement in patient-reported worst skin pain (lesion pain) based on the achievement of a reduction of at least 3 points (as measured on a 0 to 10 NRS) compared to placebo at Week 16. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied BIMZELX (bimekizumab-bkzx) injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to pale brownish-yellow solution. Each prefilled autoinjector or prefilled syringe contains 1 mL or 2 mL of a 160 mg/mL solution. The autoinjectors and prefilled syringes are not made with natural rubber latex. BIMZELX is supplied as: BIMZELX autoinjector: • NDC 50474-781-85: Carton of two 160 mg/mL single-dose autoinjectors. Each prefilled autoinjector is fixed with a 27 gauge ½ inch needle. • NDC 50474-781-84: Carton of one 160 mg/mL single-dose autoinjector. The prefilled autoinjector is fixed with a 27 gauge ½ inch needle. • NDC 50474-782-84: Carton of one 320 mg/2 mL (160 mg/mL) single-dose autoinjector fixed with a 27 gauge ½ inch needle. BIMZELX prefilled syringe: • NDC 50474-780-79: Carton of two 160 mg/mL single-dose prefilled syringes. Each prefilled syringe is fixed with a 27 gauge ½ inch needle with needle guard. • NDC 50474-780-78: Carton of one 160 mg/mL single dose prefilled syringe. The prefilled syringe is fixed with a 27 gauge ½ inch needle with a needle guard. • NDC 50474-783-78: Carton of one 320 mg/2 mL (160 mg/mL) single-dose prefilled syringe with a 27 gauge ½ inch needle. Storage and Handling Store cartons with BIMZELX refrigerated between 2°C to 8°C (36°F to 46°F). Keep the product in the original carton to protect it from light until the time of use. Do not freeze. Do not shake. Do not use beyond expiration date. BIMZELX does not contain a preservative; discard any unused portion. When necessary, BIMZELX prefilled syringes or autoinjectors may be stored at room temperature up to 25°C (77°F) in the original carton for a single period of up to 30 days. Once BIMZELX prefilled syringes or autoinjectors have been stored at room temperature, do not place back in refrigerator. Write the date removed from the refrigerator in the space provided on the carton and discard if not used within a 30-day period. 17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Administration Instructions Instruct patients or caregivers to perform the first self-injection under the supervision and guidance of a qualified healthcare professional for proper training in subcutaneous injection technique [see Dosage and Administration (2.9), Instructions for Use]. Reference ID: 5481440 If two separate 160 mg injections are used to achieve the recommended dose, instruct patients or caregivers to administer each injection subcutaneously at a different anatomic location [see Dosage and Administration (2.9)]. Instruct patients or caregivers in the technique of needle and syringe disposal [see Instructions for Use]. Advise patients if they forget to take their dose of BIMZELX to inject their dose as soon as they remember. Instruct patients to then take their next dose at the appropriate scheduled time [see Dosage and Administration (2.7)]. Suicidal Ideation and Behavior Instruct patients and their caregivers to monitor for the emergence of suicidal ideation and behavior and promptly seek medical attention if the patient experiences suicidal ideation or behavior; or new onset or worsening depression, anxiety, or other mood changes. Instruct patients to call the National Suicide and Crisis Lifeline at 988 if they experience suicidal ideation or behavior [see Warnings and Precautions (5.1)]. Infections Inform patients that BIMZELX may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection [see Warnings and Precautions (5.2)]. Liver Biochemical Abnormalities Inform patients that BIMZELX may increase the risk of elevated liver enzymes. Acute liver disease or cirrhosis may increase this risk. Advise patients that laboratory evaluation is needed prior to and periodically during treatment. Advise patients to hold the next dose of BIMZELX and call their healthcare provider right away, if signs or symptoms of liver dysfunction occur [see Warnings and Precautions (5.4)]. Inflammatory Bowel Disease Instruct patients to seek medical advice if they develop signs and symptoms of Crohn’s disease or ulcerative colitis [see Warnings and Precautions (5.5)]. Immunizations Advise patients to avoid vaccination with live vaccines during BIMZELX treatment. Instruct patients to inform their healthcare practitioner that they are taking BIMZELX prior to a potential vaccination [see Warnings and Precautions (5.6)]. Pregnancy Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in patients exposed to BIMZELX during pregnancy [see Use in Specific Populations (8.1)]. Manufactured by: UCB, Inc. 1950 Lake Park Drive Smyrna, GA 30080 US License No. 1736 Reference ID: 5481440 MEDICATION GUIDE BIMZELX® (bim zel’ex) (bimekizumab-bkzx) injection, for subcutaneous use What is the most important information I should know about BIMZELX? BIMZELX is a medicine that affects your immune system. BIMZELX may increase your risk of having serious side effects, including: • Suicidal thoughts and behavior. New or worsening suicidal thoughts and behavior have happened in some people treated with BIMZELX. Get medical help right away or call the National Suicide and Crisis Lifeline at 988 if you, your caregiver or your family member notice in you any of the following symptoms: o new or worsening depression or anxiety o thoughts of suicide, dying, or hurting yourself o changes in behavior or mood o acting on dangerous impulses o attempt to commit suicide • Infections. BIMZELX is a medicine that may lower the ability of your immune system to fight infections and may increase your risk of infections, including serious infections. o Your healthcare provider should check you for infections and tuberculosis (TB) before starting treatment with BIMZELX. o If your healthcare provider feels you are at risk for TB, you may be treated with medicine for TB before you begin treatment with BIMZELX and during your treatment with BIMZELX. o Your healthcare provider should watch you closely for signs and symptoms of TB during and after treatment with BIMZELX. Do not take BIMZELX if you have an active TB infection. Before starting BIMZELX, tell your healthcare provider if you: • are being treated for an infection • have an infection that does not go away or keeps coming back • have TB or have been in close contact with someone with TB • think you have an infection or have symptoms of an infection such as: o fever, sweats, or chills o weight loss o muscle aches o warm, red, or painful skin or sores on your body different from your psoriasis o cough o diarrhea or stomach pain o shortness of breath o burning when you urinate or urinating more often than normal o blood in your phlegm After starting BIMZELX, call your healthcare provider right away if you have any of the signs of infection listed above. Do not use BIMZELX if you have any signs of infection unless you are instructed to by your healthcare provider. See “What are the possible side effects of BIMZELX?” for more information about side effects. What is BIMZELX? BIMZELX is a prescription medicine used to treat: • adults with moderate to severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or treatment using ultraviolet light alone or with pills (phototherapy). • adults with active psoriatic arthritis. • adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation. • adults with active ankylosing spondylitis. • adults with moderate to severe hidradenitis suppurativa. It is not known if BIMZELX is safe and effective in children. Before using BIMZELX, tell your healthcare provider about all of your medical conditions, including if you: • have any of the conditions or symptoms listed in the section “What is the most important information I should know about BIMZELX?” • have a history of depression, or suicidal thoughts or behavior • have liver problems Reference ID: 5481440 • have inflammatory bowel disease (Crohn’s disease or ulcerative colitis) • have recently received or are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with BIMZELX. Tell all your healthcare providers that you are being treated with BIMZELX before receiving a vaccine. • are pregnant or plan to become pregnant. It is not known if BIMZELX can harm your unborn baby. o If you become pregnant while taking BIMZELX, you are encouraged to enroll in the Pregnancy Registry. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your healthcare provider or call 1-877-311-8972 to enroll in this registry or visit http://mothertobaby.org/pregnancy- studies/. • are breastfeeding or plan to breastfeed. It is not known if BIMZELX passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with BIMZELX. Tell your healthcare provider about all the medicines you take, including prescription and over the counter medicines, vitamins and herbal supplements. How should I use BIMZELX? See the detailed “Instructions for Use” that comes with your BIMZELX for information on how to prepare and inject a dose of BIMZELX, and how to properly throw away (dispose of) used BIMZELX autoinjectors and prefilled syringes. • Use BIMZELX exactly as prescribed by your healthcare provider. • If you miss your BIMZELX dose, inject a dose as soon as you remember. Then, take your next dose at your regular scheduled time. Call your healthcare provider if you are not sure what to do. What are the possible side effects of BIMZELX? BIMZELX may cause serious side effects, including: • See “What is important information I should know about BIMZELX?” • Elevated liver enzyme levels. Your healthcare provider will do blood tests to check your liver enzyme levels before starting treatment and during treatment with BIMZELX. Your healthcare provider may temporarily stop or permanently stop your treatment with BIMZELX if you develop liver problems. Call your healthcare provider right away if you develop any signs or symptoms of liver problems, including: o pain on the right side of your stomach-area o feeling very tired o loss of appetite o nausea and vomiting o itching o dark urine o light-colored stool o yellowing of your skin or the whites of your eyes • Inflammatory bowel disease. New cases of inflammatory bowel disease or “flare-ups” have happened with BIMZELX. If you have inflammatory bowel disease (Crohn’s disease or ulcerative colitis), tell your healthcare provider if you have worsening disease symptoms during treatment with BIMZELX or develop new symptoms of stomach pain or diarrhea. Your healthcare provider will stop treatment with BIMZELX if you develop new or worsening signs of Crohn’s disease or ulcerative colitis. The most common side effects of BIMZELX in people treated for Psoriasis and Hidradenitis Suppurativa include: • upper respiratory tract infections • headache • herpes simplex infections (cold sores in or around the mouth) • small red bumps on your skin • feeling tired • fungal infections (oral thrush or infections in the mouth, throat, skin, nails, feet or genitals) • pain, redness or swelling at injection site • stomach flu (gastroenteritis) • acne The most common side effects of BIMZELX in people treated for psoriatic arthritis include: • upper respiratory tract infections • headache • urinary tract infection • oral thrush or infections in the mouth • diarrhea The most common side effects of BIMZELX in people treated for non-radiographic axial spondyloarthritis include: • upper respiratory tract infections • oral thrush or infections in the mouth Reference ID: 5481440 • headache • cough • joint pain • tonsilitis • urinary tract infection • diarrhea • feeling tired • muscle aches • liver enzyme increase The most common side effects of BIMZELX in people treated for ankylosing spondylitis include: • upper respiratory tract infections • headache • pain at injection site • vaginal yeast infections • oral thrush or infections in the mouth • diarrhea • rash These are not all of the possible side effects of BIMZELX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store BIMZELX? • Store BIMZELX in the refrigerator between 36°F to 46°F (2°C to 8°C). • BIMZELX may be stored at room temperature up to 77°F (25°C) for up to 30 days in the original carton. Do not place BIMZELX prefilled syringes or autoinjectors back in the refrigerator after they have been stored at room temperature. • Write the date removed from the refrigerator in the space provided on the carton and throw away BIMZELX if it has been kept at room temperature and not been used within 30 days. • Keep BIMZELX in the original carton until ready for use to protect from light. • Do not freeze BIMZELX. • Do not shake BIMZELX. • Do not use BIMZELX past the expiration date printed on the carton. Keep BIMZELX and all medicines out of the reach of children. General information about the safe and effective use of BIMZELX. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BIMZELX for a condition for which it was not prescribed. Do not give BIMZELX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BIMZELX that is written for health professionals. What are the ingredients in BIMZELX? Active ingredient: bimekizumab-bkzx Inactive ingredients: glacial acetic acid, glycine, polysorbate 80, sodium acetate and Water for Injection, USP. Manufactured by: UCB, Inc. 1950 Lake Park Drive Smyrna, GA 30080 US License No. 1736 For more information, go to www.BIMZELX.com or call 1-844-599-2273 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: November 2024 Reference ID: 5481440	custom-source	2025-02-12T15:46:49.430678	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761151s010lbl.pdf', 'application_number': 761151, 'submission_type': 'SUPPL ', 'submission_number': 10}
80,251	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EPINEPHRINE INJECTION safely and effectively. See full prescribing information for EPINEPHRINE INJECTION. EPINEPHRINE injection, for intramuscular or subcutaneous use Initial U.S. Approval: 1939 ----------------------------INDICATIONS AND USAGE--------------------------- Epinephrine injection is a non-selective alpha and beta-adrenergic receptor agonist, indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis. (1) -----------------------DOSAGE AND ADMINISTRATION----------------------- • Patients greater than or equal to 30 kg (66 lbs): 0.3 mg (2) • Patients 15 to 30 kg (33 lbs-66 lbs): 0.15 mg (2) Inject intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Each device is a single-dose injection. (2) ----------------------DOSAGE FORMS AND STRENGTHS--------------------- • Injection: 0.3 mg (0.3 mg/0.3 mL) single-dose pre-filled auto-injector (3) • Injection: 0.15 mg (0.15 mg/0.15 mL) single-dose pre-filled auto- injector (3) -------------------------------CONTRAINDICATIONS------------------------------ None. (4) ------------------------WARNINGS AND PRECAUTIONS----------------------- • In conjunction with use, seek immediate medical or hospital care. (5.1) • Do not inject intravenously, into buttock, or into digits, hands, or feet. (5.2) • To minimize the risk of injection related injury, hold the child’s leg firmly in place and limit movement prior to and during injection when administering to young children. (5.2) • Rare cases of serious skin and soft tissue infections have been reported following epinephrine injection. Advise patients to seek medical care if they develop signs or symptoms of infection. (5.3) • The presence of a sulfite in this product should not deter use. (5.4) • Administer with caution in patients with heart disease; may aggravate angina pectoris or produce ventricular arrhythmias. (5.5) -------------------------------ADVERSE REACTIONS------------------------------ Adverse reactions to epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ • Cardiac glycosides or diuretics: observe for development of cardiac arrhythmias. (7) • Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines: potentiate effects of epinephrine. (7) • Beta-adrenergic blocking drugs: antagonize cardiostimulating and bronchodilating effects of epinephrine. (7) • Alpha-adrenergic blocking drugs: antagonize vasoconstricting and hypertensive effects of epinephrine. (7) • Ergot alkaloids: may reverse the pressor effects of epinephrine. (7) ------------------------USE IN SPECIFIC POPULATIONS----------------------- • Elderly patients may be at greater risk of developing adverse reactions. (5.5, 8.5) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 02/2021 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage According to Patient Body Weight 2.2 Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Emergency Treatment 5.2 Injection-Related Complications 5.3 Serious Infections at the Injection Site 5.4 Allergic Reactions Associated with Sulfite 5.5 Disease Interactions 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482285 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Epinephrine injection is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which includes bees, wasps, hornets, yellow jackets and fire ants), and biting insects (e.g., triatoma, mosquitoes), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media), and other allergens, as well as idiopathic anaphylaxis or exercise- induced anaphylaxis. Epinephrine injection is intended for immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Anaphylactic reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria, or angioedema. Epinephrine injection is intended for immediate administration as emergency supportive therapy only and is not a replacement or substitute for immediate medical care. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage According to Patient Body Weight • Patients greater than or equal to 30 kg (approximately 66 pounds or more): 0.3 mg • Patients 15 kg to 30 kg (33 pounds to 66 pounds): 0.15 mg 2.2 Administration Instructions • Inject the single-dose epinephrine injection intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Do not inject intravenously, and do not inject into buttocks, into digits, hands or feet [see Warnings and Precautions (5.2)]. • Instruct caregivers of young children who are prescribed an epinephrine injection and who may be uncooperative and kick or move during an injection to hold the leg firmly in place and limit movement prior to and during an injection [see Warnings and Precautions (5.2)]. • Each epinephrine injection is a single-dose of epinephrine injection for single use. Since the doses of epinephrine delivered from epinephrine injection are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. • With severe persistent anaphylaxis, repeat injections with an additional epinephrine injection may be necessary. More than two sequential doses of epinephrine should only be administered under direct medical supervision [see Warnings and Precautions (5.1)]. • The epinephrine solution in the viewing window of epinephrine injection should be inspected visually for particulate matter and discoloration. 3 DOSAGE FORMS AND STRENGTHS Reference ID: 5482285 • Injection: 0.3 mg (0.3 mg/0.3 mL) of clear and colorless solution in single-dose pre-filled auto-injector • Injection: 0.15 mg (0.15 mg/0.15 mL) of clear and colorless solution in single-dose pre-filled auto-injector 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Emergency Treatment Epinephrine injection is intended for immediate administration as emergency supportive therapy and is not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision [see Indications and Usage (1), Dosage and Administration (2) and Patient Counseling Information (17)]. 5.2 Injection-Related Complications Epinephrine injection should only be injected into the anterolateral aspect of the thigh [see Dosage and Administration (2) and Patient Counseling Information (17)]. Do not inject intravenously Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to a sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Do not inject into buttock Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Additionally, injection into the buttock has been associated with the development of Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower the risk. Do not inject into digits, hands or feet Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. Treatment of such inadvertent administration should consist of vasodilation, in addition to further appropriate treatment of anaphylaxis [see Adverse Reactions (6)]. Hold leg firmly during injection Lacerations, bent needles, and embedded needles have been reported when epinephrine has been injected into the thigh of young children who are uncooperative and kick or move during an injection. To minimize the risk of injection related injury when administering, hold the child’s leg firmly in place and limit movement prior to and during injection. 5.3 Serious Infections at the Injection Site Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Clostridium spores can be present on the skin and introduced into the deep tissue with subcutaneous or intramuscular injection. While cleansing with alcohol may reduce presence of bacteria on the Reference ID: 5482285 skin, alcohol cleansing does not kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject epinephrine injection into the buttock [see Warnings and Precautions (5.2)]. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site. 5.4 Allergic Reactions Associated with Sulfite The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive. Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium bisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. 5.5 Disease Interactions Some patients may be at greater risk for developing adverse reactions after epinephrine administration. Despite these concerns, it should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Therefore, patients with these conditions, and/or any other person who might be in a position to administer epinephrine injection to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used. Patients with Heart Disease Epinephrine should be administered with caution to patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias [see Drug Interactions (7) and Adverse Reactions (6)]. Other Patients and Diseases Epinephrine should be administered with caution to patients with hyperthyroidism, diabetes, elderly individuals, and pregnant women. Patients with Parkinson’s disease may notice a temporary worsening of symptoms. 6 ADVERSE REACTIONS Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below. Common adverse reactions to systemically administered epinephrine include anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism [see Warnings and Precautions (5.5)]. Cardiovascular Reactions • Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [see Warnings and Precautions (5.5) and Drug Interactions (7)]. Reference ID: 5482285 • Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see Warnings and Precautions (5.5)]. • Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.5)]. • Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine. Reactions from Accidental Injection and/or Improper Technique • Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.2)]. • Adverse reactions experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. • Lacerations, bent needles, and embedded needles have been reported when epinephrine injection has been injected into the thigh of young children who are uncooperative and kick or move during an injection [see Warnings and Precautions (5.2)]. • Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.2)]. Skin and Soft Tissue Infections • Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection in the thigh [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS Cardiac Glycosides, Diuretics, and Anti-arrhythmics Patients who receive epinephrine while concomitantly taking cardiac glycosides, diuretics, or anti-arrhythmics should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.5)]. Antidepressants, Monoamine Oxidase Inhibitors, Levothyroxine, and Antihistamines The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine. Beta-Adrenergic Blockers The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol. Alpha-Adrenergic Blockers The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentolamine. Ergot Alkaloids Ergot alkaloids may also reverse the pressor effects of epinephrine. 8 USE IN SPECIFIC POPULATIONS Reference ID: 5482285 8.1 Pregnancy Risk Summary There are no available human data on the use of epinephrine injection in pregnant women to inform a drug- associated risk of adverse developmental outcomes. In animal reproduction studies, epinephrine administered by the subcutaneous route to rabbits, mice, and hamsters during the period of organogenesis was teratogenic at doses 7 times and higher than the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis (see Data). Epinephrine is the first-line medication of choice for the treatment of anaphylaxis during pregnancy in humans. Epinephrine should be used for treatment of anaphylaxis during pregnancy in the same manner as it is used in non-pregnant patients. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk: During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately 3 cases per 100,000 deliveries. Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. Data Animal Data In an embryofetal development study with rabbits dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including gastroschisis and embryonic lethality) at doses approximately 40 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days). In an embryofetal development study with mice dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including embryonic lethality) at doses approximately 8 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 4 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). In an embryofetal development study with hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine was shown to be teratogenic at doses approximately 7 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day). 8.2 Lactation Risk Summary Reference ID: 5482285 There are no data on the presence of epinephrine in human milk, or the effects of epinephrine on the breastfed infant or on milk production. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in breastfeeding and no-breastfeeding patients. 8.4 Pediatric Use Epinephrine injection may be administered to pediatric patients at a dosage appropriate to body weight [see Dosage and Administration (2.1)]. Clinical experience with the use of epinephrine suggests that the adverse reactions seen in children are similar in nature and extent to those both expected and reported in adults. Since the dose of epinephrine delivered from epinephrine injection is fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. 8.5 Geriatric Use Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Therefore, epinephrine injection should be administered with caution in elderly individuals, who may be at greater risk for developing adverse reactions after epinephrine administration [see Warnings and Precautions (5.5) and Overdosage (10)]. 10 OVERDOSAGE Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting vasodilators or alpha-adrenergic blocking drugs and/or respiratory support. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia, and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug such as propranolol. Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis, and kidney failure. Suitable corrective measures must be taken in such situations. 11 DESCRIPTION Epinephrine injection, USP 0.3 mg and 0.15 mg is an auto-injector and a combination product containing drug and device components. Each epinephrine injection, USP 0.3 mg delivers a single dose of 0.3 mg epinephrine from epinephrine injection, USP (0.3 mL) in a sterile solution. Each epinephrine injection, USP 0.15 mg delivers a single dose of 0.15 mg epinephrine from epinephrine injection, USP (0.15 mL) in a sterile solution. Epinephrine injection, USP 0.3 mg and epinephrine injection, USP 0.15 mg each contain 1.1 mL of epinephrine solution. 0.3 mL and 0.15 mL epinephrine solution are dispensed for epinephrine injection, USP 0.3 mg and Reference ID: 5482285 epinephrine injection, USP 0.15 mg, respectively, when activated. The solution remaining after activation is not available for future use and should be discarded. Each 0.3 mL in epinephrine injection, USP 0.3 mg contains 0.3 mg epinephrine, 2.6 mg sodium chloride, not more than 1.5 mg chlorobutanol, 0.45 mg sodium bisulfite, hydrochloric acid and sodium hydroxide to adjust pH, and water for injection. The pH range is 2.2-5.0. Each 0.15 mL in epinephrine injection, USP 0.15 mg contains 0.15 mg epinephrine, 1.3 mg sodium chloride, not more than 0.75 mg chlorobutanol, 0.225 mg sodium bisulfite, hydrochloric acid and sodium hydroxide to adjust pH, and water for injection. The pH range is 2.2-5.0. Epinephrine is a sympathomimetic catecholamine. Chemically, epinephrine is (-)-3,4-Dihydroxy-α- [(methylamino)methyl]benzyl alcohol with the following structure: Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. Replace epinephrine injection, USP if the epinephrine solution appears discolored (pinkish or brown color), cloudy, or contains particles. Thoroughly review the patient instructions and operation of epinephrine injection, USP with patients and caregivers prior to use [see Patient Counseling Information (17)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Epinephrine acts on both alpha- and beta-adrenergic receptors. 12.2 Pharmacodynamics Through its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing, and dyspnea that may occur during anaphylaxis. Epinephrine also alleviates pruritus, urticaria, and angioedema, and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus and urinary bladder. When given intramuscularly or subcutaneously, epinephrine has a rapid onset and short duration of action. Reference ID: 5482285 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of epinephrine have not been conducted. Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro. Epinephrine was positive in the Salmonella bacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivo micronucleus assay. Epinephrine is an oxidative mutagen based on the E. coli WP2 Mutoxitest bacterial reverse mutation assay. This should not prevent the use of epinephrine where indicated under the conditions noted under [see Indications and Usage (1)]. The potential for epinephrine to impair reproductive performance has not been evaluated, but epinephrine has been shown to decrease implantation in female rabbits dosed subcutaneously with 1.2 mg/kg/day (40-fold the highest human intramuscular or subcutaneous daily dose) during gestation days 3 to 9. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied • Carton containing two epinephrine injection, USP 0.3 mg single-dose pre-filled auto-injectors: NDC 0115- 1694-49. • Carton containing one epinephrine injection, USP 0.3 mg single-dose pre-filled auto-injector: NDC 0115- 1694-30. • Carton containing two epinephrine injection, USP 0.15 mg single-dose pre-filled auto-injectors: NDC 0115- 1695-49. • Carton containing one epinephrine injection, USP 0.15 mg single-dose pre-filled auto-injector: NDC 0115- 1695-30. Storage and Handling Protect from light. Epinephrine is light sensitive and should be stored in the carrying-case provided to protect it from light. Store at room temperature (20°C to 25°C (68°F to 77°F)); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate. Before using, check to make sure the solution in the auto-injector is clear and colorless. Replace the auto-injector if the solution is discolored (pinkish or brown color), cloudy, or contains particles. Properly dispose of all used, unwanted, or expired epinephrine injection, USP. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information and Instructions for Use) A healthcare provider should review the patient instructions and operation of epinephrine injection, in detail, with the patient or caregiver. Epinephrine is essential for the treatment of anaphylaxis. Carefully instruct patients who are at risk of or with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens, as well as idiopathic and exercise-induced anaphylaxis, about the circumstances under which epinephrine should be used. Reference ID: 5482285 Administration Instruct patients and/or caregivers in the appropriate use of epinephrine injection. Epinephrine injection should be injected into the middle of the outer thigh (through clothing if necessary). Instruct caregivers to hold the leg of young children firmly in place and limit movement prior to and during injection. Lacerations, bent needles, and embedded needles have been reported when epinephrine injection has been injected into the thigh of young children who are uncooperative and kick during an injection [see Warnings and Precautions (5.2)]. Advise patients to seek immediate medical care in conjunction with administration of epinephrine injection. Complete patient information, including dosage, directions for proper administration and precautions can be found inside each epinephrine injection carton. A printed label on the surface of epinephrine injection shows instructions for use and a diagram depicting the injection process. Training Instruct patients and/or caregivers to use the Trainer to familiarize themselves with the use of epinephrine injection in an allergic emergency. The Trainer may be used multiple times. Adverse Reactions Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These signs and symptoms usually subside rapidly, especially with rest, quiet, and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms [see Warnings and Precautions (5.5)]. Accidental Injection Advise patients to seek immediate medical care in the case of accidental injection. Since epinephrine is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an accidental injection to these areas [see Warnings and Precautions (5.2)]. Serious Infections at the Injection Site Rare cases of skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site [see Warnings and Precautions (5.3)]. Pregnancy and Breastfeeding Inform patients that epinephrine injection has not been studied in pregnant women or breastfeeding mothers so the effects of epinephrine injection on pregnant women or breastfed infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant. Reference ID: 5482285 Instruct patients to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations (8.1, 8.2)]. Storage and Handling Instruct patients to inspect the epinephrine solution visually through the viewing window periodically. Replace epinephrine injection if the epinephrine solution appears discolored (pinkish or brown), cloudy, or contains particles. Epinephrine is light sensitive, store in the outer case provided to protect it from light. Instruct patients that epinephrine injection must be properly disposed of once the blue caps have been removed or after use [see How Supplied/Storage and Handling (16)]. Complete patient information, including dosage, directions for proper administration and precautions are provided inside each epinephrine injection carton. Manufactured by: Hospira, Inc. McPherson, KS 67460 Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 © 2021 Amneal Pharmaceuticals LLC. All rights reserved. For inquiries call 1-877-835-5472 1871-04 Rev. 02-2021-04 Reference ID: 5482285 PATIENT INFORMATION EPINEPHRINE injection (ep-in-eph-rine), for intramuscular or subcutaneous use For allergic emergencies (anaphylaxis) Read this Patient Information leaflet carefully before you use epinephrine injection and each time you get a refill. There may be new information. You, your parent, caregiver, or others who may be in a position to administer epinephrine injection should know how to use it before you have an allergic emergency. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about epinephrine injection? 1. Epinephrine injection contains epinephrine, a medicine used to treat allergic emergencies (anaphylaxis). Anaphylaxis can be life-threatening, can happen within minutes, and can be caused by stinging and biting insects, allergy injections, foods, medicines, exercise, or other unknown causes. Symptoms of anaphylaxis may include:  trouble breathing  wheezing  hoarseness (changes in the way your voice sounds)  hives (raised reddened rash that may itch)  severe itching  swelling of your face, lips, mouth, or tongue  skin rash, redness, or swelling  fast heartbeat  weak pulse  feeling very anxious  confusion  stomach pain  losing control of urine or bowel movements (incontinence)  diarrhea or stomach cramps  dizziness, fainting, or “passing out” (unconsciousness) 2. Always carry your epinephrine injection with you because you may not know when anaphylaxis may happen. Talk to your healthcare provider if you need additional units to keep at work, school, or other locations. Tell your family members, caregivers, and others where you keep your epinephrine injection and how to use it before you need it. You may be unable to speak in an allergic emergency. 3. When you have an allergic emergency (anaphylaxis)  Use epinephrine injection right away.  Get emergency medical help right away. You may need further medical attention. You may need to use a second epinephrine injection if symptoms continue or recur. Only a healthcare provider should give additional doses of epinephrine if you need more than 2 injections for a single anaphylaxis episode. What is epinephrine injection?  Epinephrine injection is a disposable, prefilled automatic injection device (auto-injector) used to treat life-threatening, allergic emergencies including anaphylaxis in people who are at risk for or have a history of serious allergic emergencies. Each device contains a single dose of epinephrine.  Epinephrine injection is for immediate self (or caregiver) administration and does not take the place of emergency medical care. You should get emergency medical help right away after using epinephrine injection.  Epinephrine injection is for people who have been prescribed this medicine by their healthcare provider.  The epinephrine injection 0.3 mg auto-injector is for patients who weigh 66 pounds or more (30 kilograms or more).  The epinephrine injection 0.15 mg auto-injector is for patients who weigh about 33 to 66 pounds (15 to 30 kilograms).  It is not known if epinephrine injection is safe and effective in children who weigh less than 33 pounds (15 kilograms). Before using epinephrine injection, tell your healthcare provider about all your medical conditions, especially if you:  have heart problems or high blood pressure  have diabetes  have thyroid problems  have asthma  have a history of depression  have Parkinson’s disease  are pregnant or plan to become pregnant. It is not known if epinephrine will harm your unborn baby.  are breastfeeding or plan to breastfeed. It is not known if epinephrine passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Tell your healthcare provider of all known allergies. Especially tell your healthcare provider if you take certain asthma medicines. Epinephrine injection and other medicines may affect each other, causing side effects. Epinephrine injection may affect the way other medicines work, and other medicines may affect how epinephrine injection works. Reference ID: 5482285 Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Use your epinephrine injection for treatment of anaphylaxis as prescribed by your healthcare provider, regardless of your medical conditions or the medicine you take. How should I use epinephrine injection?  Each epinephrine injection contains only 1 dose of medicine.  Epinephrine injection should only be injected into the middle of the outer thigh (upper leg). It can be injected through clothing if needed.  Read the Instructions for Use at the end of this Patient Information Leaflet for information about the right way to use epinephrine injection.  Your healthcare provider will show you how to safely use epinephrine injection.  Use epinephrine injection exactly as your healthcare provider tells you to use it. You may need to use a second epinephrine injection if symptoms continue or recur. Only a healthcare provider should give additional doses of epinephrine if you need more than 2 injections for a single anaphylaxis episode.  Caution: Never put your thumb, fingers, or hand over the red tip. Never press or push the red tip with your thumb, fingers, or hand. The needle comes out of the red tip. Accidental injection into finger, hands, or feet may cause a loss of blood flow to those areas. If this happens, go immediately to the nearest emergency room. Tell the healthcare provider where on your body you received the accidental injection.  Your epinephrine injection comes packaged in a carton containing 1 or 2 epinephrine injections.  You may request a separate Trainer, that comes packaged with instructions. Additional video instructions on the use of epinephrine injection are available from www.epinephrineautoinject.com. The epinephrine injection Trainer has a beige color. The beige epinephrine injection Trainer contains no medicine and no needle. Practice with your epinephrine injection Trainer before an allergic emergency happens to make sure you are able to safely use the real epinephrine injection in an emergency. Always carry your real epinephrine injection, USP auto-injector with you in case of an allergic emergency.  Do not drop the carrying case or epinephrine injection. If the carrying case or epinephrine injection is dropped, check for damage and leakage. Throw away (dispose of) epinephrine injection and the carrying case, and replace if damage or leakage is noticed or suspected. What are the possible side effects of epinephrine injection? Epinephrine injection may cause serious side effects.  Epinephrine injection should only be injected into the middle of your outer thigh (upper leg). Do not inject epinephrine injection into your: o veins o buttocks o fingers, toes, hands or feet If you accidentally inject epinephrine injection into any other part of your body, go to the nearest emergency room right away. Tell the healthcare provider where on your body you received the accidental injection.  Rarely, people who have used epinephrine injection may develop infections at the injection site within a few days of an injection. Some of these infections can be serious. Call your healthcare provider right away if you have any of the following at an injection site: o redness that does not go away o swelling o tenderness o the area feels warm to the touch  Cuts on the skin, bent needles, and needles that remain in the skin after the injection, have happened in young children who do not cooperate and kick or move during an injection. If you inject a young child with epinephrine injection, hold their leg firmly in place before and during the injection to prevent injuries. Ask your healthcare provider to show you how to properly hold the leg of a young child during an injection.  If you have certain medical conditions, or take certain medicines, your condition may get worse or you may have more or longer lasting side effects when you use epinephrine injection. Talk to your healthcare provider about all your medical conditions. Common side effects of epinephrine injection include:  faster, irregular or “pounding” heartbeat  sweating  headache  weakness  shakiness  paleness  feelings of over excitement, nervousness or anxiety  dizziness  nausea and vomiting  breathing problems These side effects may go away with rest. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of epinephrine injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store epinephrine injection?  Store epinephrine injection at room temperature between 68°F to 77°F (20°C to 25°C).  Protect from light. Reference ID: 5482285  Do not expose to extreme heat or cold. For example, do not store in your vehicle’s glove box and do not store in the refrigerator or freezer.  Examine the contents in the viewing window of your epinephrine injection periodically. The solution should be clear. If the solution is discolored (pinkish or brown), cloudy or contains solid particles, replace the unit.  Always keep your epinephrine injection in the carrying case to protect it from damage. The carrying case is not waterproof.  The two blue end caps help to prevent accidental injection. Do not remove the blue end caps until you are ready to use epinephrine injection.  Your epinephrine injection has an expiration date. Replace it before the expiration date.  Throw away (dispose of) expired, unwanted, or unused epinephrine injections in an FDA-cleared sharps disposal container. Do not throw away epinephrine injection in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o Made of heavy-duty plastic, o Can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o Upright and stable during use, o Leak-resistant, and o Properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. Visit the FDA’s website (https://www.fda.gov/drugs/safe-disposal- medicines/disposal- unused-medicines-what-you-should-know) for more information about how to throw away (dispose of) unused, unwanted or expired medicines. Keep epinephrine injection and all medicines out of the reach of children. General information about the safe and effective use of epinephrine injection: Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use epinephrine injection for a condition for which it was not prescribed. Do not give epinephrine injection to other people. This Patient Information leaflet summarizes the most important information about epinephrine injection. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about epinephrine injection that is written for health professionals. What are the ingredients in epinephrine injection? Active Ingredient: epinephrine Inactive Ingredients: sodium chloride, chlorobutanol, sodium bisulfite, hydrochloric acid and sodium hydroxide, and water. For more information and video instructions on the use of epinephrine injection, go to www.epinephrineautoinject.com or call 1-877-835-5472. Important Information  The epinephrine injection, 0.3 mg auto-injector has a yellow colored label.  The epinephrine injection, 0.15 mg auto-injector has an orange colored label.  The epinephrine injection Trainer has a beige color, and contains no medicine and no needle.  Your epinephrine injection is designed to work through clothing.  The two blue end caps on epinephrine injection help to prevent accidental injection of the device. Do not remove the two blue end caps until you are ready to use it.  Only inject into the middle of the outer thigh (upper leg). Never inject into any other part of the body.  Never put your thumb, fingers, or your hand over the red tip. The needle comes out of the red tip.  If an accidental injection happens, get medical help right away.  Do not place patient information or any other foreign objects in carrier with the auto-injector, as this may prevent you from removing epinephrine injection for use. This Patient Information has been approved by the U.S. Food and Drug Administration Rev. 02-2021-04 Reference ID: 5482285 Instructions for Use EPINEPHRINE injection (ep-in-eph-rine) for intramuscular or subcutaneous use For allergic emergencies (anaphylaxis) Read this Instructions for Use carefully before you use epinephrine injection and each time you get a refill. There may be new information. Before you need to use your epinephrine injection, make sure your healthcare provider shows you the right way to use it. Parents, caregivers, and others who may be in a position to administer epinephrine injection should also understand how to use it well. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. If you have any questions, ask your healthcare provider. Your epinephrine injection Step 1. Prepare epinephrine injection, for injection  Remove epinephrine injection from its protective carrying case. See Figure A. Reference ID: 5482285 Figure A  Pull off blue end caps. You will now see a red tip. Grasp epinephrine injection in your fist with the red tip pointing downward. See Figure B. Note:  The needle comes out of the red tip.  To avoid an accidental injection, never put your thumb, fingers or hand over the red tip. If an accidental injection happens, get medical help right away. Figure B Step 2. Administer epinephrine injection  If you are administering epinephrine injection to a young child, hold the leg firmly in place and limit movement prior to and while administering an injection.  Place the red tip against the middle of the outer thigh (upper leg) at a 90° angle (perpendicular) to the thigh.  Press down hard and hold firmly against the thigh for approximately 10 seconds to deliver the medicine. See Figure C. Reference ID: 5482285 Figure C  Only inject into the middle of the outer thigh. Do not inject into any other part of the body.  Remove epinephrine injection from the thigh.  Massage the area for 10 seconds.  Check the red tip. The injection is complete and you have received the correct dose of the medicine if you see the needle sticking out of the red tip. If you do not see the needle, repeat Step 2. Step 3. Get emergency medical help right away. You may need further medical attention. You may need to use a second epinephrine injection if symptoms continue or recur. Step 4. After use Disposal Carefully cover the needle with the carrying case.  Lay the labeled half of the carrying case cover down on a flat surface. Use one hand to carefully slide the end of epinephrine injection, needle first, into the labeled carrying case cover. See Figure D. Figure D  After the needle is inside the labeled cover, push the unlabeled half of the carrying case cover firmly over the non-needle end of epinephrine injection. See Figure E. Figure E  Take your used epinephrine injection with you when you go to see a healthcare provider. Reference ID: 5482285  Tell the healthcare provider that you have received an injection of epinephrine. Show the healthcare provider where you received the injection.  Give your used epinephrine injection to the healthcare provider for inspection and proper disposal.  Ask for a refill, if needed. Note:  Epinephrine injection is a single-use injectable device that delivers a fixed dose of epinephrine. Epinephrine injection cannot be reused. Do not attempt to reuse epinephrine injection after the device has been activated. It is normal for most of the medicine to remain in the auto-injector after the dose is injected. The correct dose has been administered if you see the needle sticking out of the red tip.  A separate epinephrine injection Trainer is available. The epinephrine injection Trainer has a beige color. The beige epinephrine injection Trainer contains no medicine and no needle. Practice with your epinephrine injection Trainer, but always carry your real epinephrine injection in case of an allergic emergency.  If you will be administering epinephrine injection to a young child, ask your healthcare provider to show you how to properly hold the leg in place while administering a dose.  Do not try to take epinephrine injection apart. For more information and video instructions on the use of epinephrine injection, go to www.epinephrineautoinject.com or call 1-877-835-5472. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. © 2021 Amneal Pharmaceuticals LLC. All rights reserved. Manufactured by: Hospira, Inc. McPherson, KS 67460 Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 1872-05 Revised 11-2024-05 Reference ID: 5482285 Rev 04 11-2024 NDC 0115- 1695 -49 Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 © 2024 Amneal Pharmaceuticals LLC. All rights reserved. PANTONE® Proc. Cyan PANTONE® Proc. Magenta PANTONE® Proc. Yellow PANTONE® Proc. Black PANTONE® PMS 151 C 1875-04 1875-04 Remove from protective carrying case. 2 3 4 1 Twist and Pull Close Case. First slide needle into labeled half of carying case. 5 • Protect from heat or light • Do not refrigerate • Replace auto-injector if solution is discolored, cloudy, or contains particles • Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Non-Varnish Area for Lot No and Exp Date and Serialization LOT: TEST EXP: YYYY-MMM-DD SN: 0000000000 GTIN: 00000000000000 FPO Page 1 of 2 Reference ID: 5482285 1877-04 Rev 04 11-2024 NDC 0115- 1694 -49 Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 © 2024 Amneal Pharmaceuticals LLC. All rights reserved. PANTONE® Proc. Cyan PANTONE® Proc. Magenta PANTONE® Proc. Yellow PANTONE® Proc. Black PANTONE® PMS 7548 C 1877-04 Remove from protective carrying case. 2 3 4 1 Twist and Pull Close Case. First slide needle into labeled half of carying case. 5 Non-Varnish Area for Lot No and Exp Date and Serialization LOT: TEST EXP: YYYY-MMM-DD SN: 0000000000 GTIN: 00000000000000 FPO • Protect from heat or light • Do not refrigerate • Replace auto-injector if solution is discolored, cloudy, or contains particles • Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Page 2 of 2 Reference ID: 5482285	custom-source	2025-02-12T15:46:49.621792	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020800s052lbl.pdf', 'application_number': 20800, 'submission_type': 'SUPPL ', 'submission_number': 52}
80,253	1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PAXLOVID safely and effectively. See full prescribing information for PAXLOVID. PAXLOVID™ (nirmatrelvir tablets; ritonavir tablets), co-packaged for oral use Initial U.S. Approval: 2023 WARNING: SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID See full prescribing information for complete boxed warning. • PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events. (4, 5.1, 7) • Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring. (7) • Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug- drug interactions for an individual patient can be appropriately managed. (5.1, 7, 14) --------------------------- INDICATIONS AND USAGE ---------------------------- PAXLOVID which includes nirmatrelvir, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. (1) Limitations of Use PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19. (1) ----------------------- DOSAGE AND ADMINISTRATION ----------------------- PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. (2.1) Nirmatrelvir must be co-administered with ritonavir. (2.1) • Initiate PAXLOVID treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. (2.1) • Administer orally with or without food. (2.1) • Dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together twice daily for 5 days. (2.2) • Dose reduction for moderate renal impairment (eGFR ≥30 to <60 mL/min): 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), with both tablets taken together twice daily for 5 days. (2.3) • PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min). (2.3, 8.6) • PAXLOVID is not recommend in patients with severe hepatic impairment (Child-Pugh Class C). (2.4, 8.7) --------------------- DOSAGE FORMS AND STRENGTHS --------------------- • Tablets: nirmatrelvir 150 mg (3) • Tablets: ritonavir 100 mg (3) ------------------------------ CONTRAINDICATIONS ------------------------------ • History of clinically significant hypersensitivity reactions to the active ingredients (nirmatrelvir or ritonavir) or any other components. (4) • Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. (4, 7.3) • Co-administration with potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------- • The concomitant use of PAXLOVID and certain other drugs may result in potentially significant drug interactions. Consult the Full Prescribing Information prior to and during treatment for potential drug interactions. (5.1, 7) • Hypersensitivity Reactions: Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with PAXLOVID. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care. (5.2) • Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. (5.3) • HIV-1 Drug Resistance: PAXLOVID use may lead to a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection. (5.4) ------------------------------ ADVERSE REACTIONS ------------------------------ Most common adverse reactions (incidence ≥1% and greater incidence than in the placebo group) are dysgeusia and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- Co-administration of PAXLOVID can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PAXLOVID. Consider the potential for drug interactions prior to and during PAXLOVID therapy and review concomitant medications during PAXLOVID therapy. (4, 5.1, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Recommended Dosage 2.3 Dosage in Patients with Renal Impairment 2.4 Use in Patients with Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions 5.2 Hypersensitivity Reactions 5.3 Hepatotoxicity 5.4 Risk of HIV-1 Resistance Development 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Potential for PAXLOVID to Affect Other Drugs 7.2 Potential for Other Drugs to Affect PAXLOVID 7.3 Established and Other Potentially Significant Drug Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY Reference ID: 5480648 2 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Efficacy in Subjects at High Risk of Progression to Severe COVID-19 (EPIC-HR) 14.2 Trial in Unvaccinated Subjects Without a Risk Factor for Progression to Severe COVID-19 or Subjects Fully Vaccinated Against COVID-19 With at Least One Factor for Progression to Severe COVID-19 (EPIC-SR) 14.3 Post-Exposure Prophylaxis Trial 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5480648 3 FULL PRESCRIBING INFORMATION WARNING: SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID • PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)]. • Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring [see Drug Interactions (7)]. • Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed [see Warnings and Precautions (5.1), Drug Interactions (7), and Clinical Studies (14)]. 1 INDICATIONS AND USAGE PAXLOVID is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. Limitations of Use PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19 [see Clinical Studies (14.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. There are two different dose packs available: • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg [see Dosage and Administration (2.2)]. • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment [see Dosage and Administration (2.3)]. Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID [see Dosage and Administration (2.2, 2.3)]. Completion of the full 5-day treatment course and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2. The 5-day treatment course of PAXLOVID should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are Reference ID: 5480648 4 mild. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, the patient should complete the full 5-day treatment course per the healthcare provider’s discretion. If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose. PAXLOVID (both nirmatrelvir and ritonavir tablets) can be taken with or without food [see Clinical Pharmacology (12.3)]. The tablets should be swallowed whole and not chewed, broken, or crushed. 2.2 Recommended Dosage The recommended dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together orally twice daily for 5 days. 2.3 Dosage in Patients with Renal Impairment No dosage adjustment is recommended in patients with mild renal impairment (eGFR ≥60 to <90 mL/min). In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the dosage of PAXLOVID is 150 mg nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) with both tablets taken together twice daily for 5 days [see How Supplied/Storage and Handling (16)]. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions [see Patient Counseling Information (17)]. PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min) until more data are available; the appropriate dosage for patients with severe renal impairment has not been determined [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.4 Use in Patients with Hepatic Impairment No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment; therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7)]. 3 DOSAGE FORMS AND STRENGTHS PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets [see How Supplied/Storage and Handling (16)]. • Nirmatrelvir is supplied as oval, pink immediate-release, film-coated tablets debossed with “PFE” on one side and “3CL” on the other side. Each tablet contains 150 mg of nirmatrelvir. • Ritonavir is supplied as white or white to off-white film-coated tablets uniquely identified by the color, shape, and debossing. Each tablet contains 100 mg of ritonavir. Reference ID: 5480648 5 4 CONTRAINDICATIONS PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome] to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product. PAXLOVID is contraindicated with drugs that are primarily metabolized by CYP3A and for which elevated concentrations are associated with serious and/or life-threatening reactions and drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. There are certain other drugs for which concomitant use with PAXLOVID should be avoided and/or dose adjustment, interruption, or therapeutic monitoring is recommended. Drugs listed in this section are a guide and not considered a comprehensive list of all drugs that may be contraindicated with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor like PAXLOVID [see Drug Interactions (7.3)]:  Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.3)]: • Alpha 1-adrenoreceptor antagonist: alfuzosin • Antianginal: ranolazine • Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine • Anti-gout: colchicine (in patients with renal and/or hepatic impairment [see Table 1, Drug Interactions (7.3)]) • Antipsychotics: lurasidone, pimozide • Benign prostatic hyperplasia agents: silodosin • Cardiovascular agents: eplerenone, ivabradine • Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine • HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use [see Table 1, Drug Interactions (7.3)]) • Immunosuppressants: voclosporin • Microsomal triglyceride transfer protein inhibitor: lomitapide • Migraine medications: eletriptan, ubrogepant • Mineralocorticoid receptor antagonists: finerenone • Opioid antagonists: naloxegol • PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH) • Sedative/hypnotics: triazolam, oral midazolam • Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin • Vasopressin receptor antagonists: tolvaptan  Drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer [see Drug Interactions (7.3)]: • Anticancer drugs: apalutamide • Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin • Antimycobacterials: rifampin, rifapentine Reference ID: 5480648 6 • Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor • Herbal products: St. John’s Wort (hypericum perforatum) 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of PAXLOVID, which contains ritonavir, a strong CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to: • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. • Loss of therapeutic effect of PAXLOVID and possible development of viral resistance. Severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse reactions were calcineurin inhibitors (e.g., tacrolimus, cyclosporine), followed by calcium channel blockers. Prior to prescribing PAXLOVID, review all medications taken by the patient to assess potential drug-drug interactions and determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring (e.g., calcineurin inhibitors) [see Contraindications (4) and Drug Interactions (7)]. See Table 1 for clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 1 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed [see Drug Interactions (7) and Clinical Studies (14)]. 5.2 Hypersensitivity Reactions Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with PAXLOVID [see Adverse Reactions (6.1)]. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care. 5.3 Hepatotoxicity Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering PAXLOVID to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. 5.4 Risk of HIV-1 Resistance Development Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection [see Contraindications (4) and Drug Interactions (7)]. Reference ID: 5480648 7 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity reactions [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PAXLOVID is based on two Phase 2/3 randomized, placebo-controlled trials in symptomatic adult subjects 18 years of age and older with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Subjects in both studies received PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo every 12 hours for 5 days for the treatment of mild-to-moderate COVID-19 within 5 days of symptom onset [see Clinical Studies (14)]: • Trial C4671005 (EPIC-HR) enrolled subjects who were at high risk for progression to severe disease. • Trial C4671002 (EPIC-SR) enrolled subjects who were at standard risk for progression to severe disease (previously unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease). Adverse reactions were those reported while subjects were on study medication and through 28 days after the last dose of study treatment. In Trial C4671005 (EPIC-HR), 1,038 subjects received PAXLOVID and 1,053 subjects received placebo. The most common adverse reactions (≥1% incidence in the PAXLOVID group and occurring at a greater frequency than in the placebo group) were dysgeusia (5% and <1%, respectively) and diarrhea (3% and 2%, respectively). Among vaccinated or unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease in Trial C4671002 (EPIC-SR), 540 subjects received PAXLOVID and 528 subjects received placebo. The adverse reactions observed were consistent with those observed in EPIC-HR. Emergency Use Authorization Experience in Subjects with COVID-19 The following adverse reactions have been identified during use of PAXLOVID under Emergency Use Authorization. Immune System Disorders: Anaphylaxis, hypersensitivity reactions [see Warnings and Precautions (5.2)] Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome [see Warnings and Precautions (5.2)] Nervous System Disorders: Headache Vascular Disorders: Hypertension Gastrointestinal Disorders: Abdominal pain, nausea, vomiting General Disorders and Administration Site Conditions: Malaise Reference ID: 5480648 8 7 DRUG INTERACTIONS 7.1 Potential for PAXLOVID to Affect Other Drugs PAXLOVID (nirmatrelvir co-packaged with ritonavir) is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of PAXLOVID with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse events. Co-administration of PAXLOVID with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated [see Contraindications (4) and Drug Interactions (7.3) Table 1]. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 1. 7.2 Potential for Other Drugs to Affect PAXLOVID Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect [see Contraindications (4) and Drug Interactions (7.3) Table 1]. 7.3 Established and Other Potentially Significant Drug Interactions Table 1 provides a listing of clinically significant drug interactions, including contraindicated drugs [see Contraindications (4) and Warnings and Precautions (5.1)]. Drugs listed in Table 1 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor such as ritonavir. Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Alpha 1- adrenoreceptor antagonist alfuzosin ↑ alfuzosin Co-administration contraindicated due to potential hypotension [see Contraindications (4)]. Alpha 1- adrenoreceptor antagonist tamsulosin ↑ tamsulosin Avoid concomitant use with PAXLOVID. Antianginal ranolazine ↑ ranolazine Co-administration contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)]. Antiarrhythmics amiodarone, dronedarone, flecainide, propafenone, quinidine ↑ antiarrhythmic Co-administration contraindicated due to potential for cardiac arrhythmias [see Contraindications (4)]. Antiarrhythmics lidocaine (systemic), disopyramide ↑ antiarrhythmic Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics if available. Reference ID: 5480648 9 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Anticancer drugs apalutamide ↓ nirmatrelvir/ritonavir Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)]. Anticancer drugs abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer drugs Avoid co-administration of encorafenib or ivosidenib due to potential risk of serious adverse events such as QT interval prolongation. Avoid use of neratinib, venetoclax or ibrutinib. Co-administration of vincristine and vinblastine may lead to significant hematologic or gastrointestinal side effects. For further information, refer to individual product label for anticancer drug. Anticoagulants warfarin ↑↓ warfarin Closely monitor international normalized ratio (INR) if co-administration with warfarin is necessary. rivaroxaban ↑ rivaroxaban Increased bleeding risk with rivaroxaban. Avoid concomitant use. dabigatrana ↑ dabigatran Increased bleeding risk with dabigatran. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to the dabigatran product label for further information. apixaban ↑ apixaban Combined P-gp and strong CYP3A inhibitors increase blood levels of apixaban and increase the risk of bleeding. Dosing recommendations for co-administration of apixaban with PAXLOVID depend on the apixaban dose. Refer to the apixaban product label for more information. Anticonvulsants carbamazepinea, phenobarbital, primidone, phenytoin ↓ nirmatrelvir/ritonavir Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)]. Anticonvulsants clonazepam ↑ anticonvulsant A dose decrease may be needed for clonazepam when co-administered with PAXLOVID and clinical monitoring is recommended. Reference ID: 5480648 10 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Antidepressants bupropion ↓ bupropion and active metabolite hydroxy- bupropion Monitor for an adequate clinical response to bupropion. trazodone ↑ trazodone Adverse reactions of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. Refer to trazadone product label for further information. Antifungals voriconazole ↓ voriconazole Avoid concomitant use of voriconazole. ketoconazole, isavuconazonium sulfate, itraconazolea ↑ ketoconazole ↑ isavuconazonium sulfate ↑ itraconazole ↑ nirmatrelvir/ritonavir Refer to ketoconazole, isavuconazonium sulfate, and itraconazole product labels for further information. A nirmatrelvir/ritonavir dose reduction is not needed. Anti-gout colchicine ↑ colchicine Co-administration contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4)]. Anti-HIV protease inhibitors atazanavir, darunavir, tipranavir ↑ protease inhibitor For further information, refer to the respective protease inhibitors’ prescribing information. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or protease inhibitor adverse events. Anti-HIV efavirenz, maraviroc, nevirapine, zidovudine, bictegravir/ emtricitabine/ tenofovir ↑ efavirenz ↑ maraviroc ↑ nevirapine ↓ zidovudine ↑ bictegravir ↔ emtricitabine ↑ tenofovir For further information, refer to the respective anti-HIV drugs prescribing information. Anti-infective clarithromycin, erythromycin ↑ clarithromycin ↑ erythromycin Refer to the respective prescribing information for anti-infective dose adjustment. Antimycobacterial rifampin, rifapentine ↓ nirmatrelvir/ritonavir Co-administration contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered [see Contraindications (4)]. Reference ID: 5480648 11 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Antimycobacterial bedaquiline ↑ bedaquiline Refer to the bedaquiline product label for further information. rifabutin ↑ rifabutin Refer to rifabutin product label for further information on rifabutin dose reduction. Antipsychotics lurasidone, pimozide ↑ lurasidone ↑ pimozide Co-administration contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Antipsychotics quetiapine ↑ quetiapine If co-administration is necessary, reduce quetiapine dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations. clozapine ↑ clozapine If co-administration is necessary, consider reducing the clozapine dose and monitor for adverse reactions. Benign prostatic hyperplasia agents silodosin ↑ silodosin Co-administration contraindicated due to potential for postural hypotension [see Contraindications (4)]. Calcium channel blockers amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil ↑ calcium channel blocker Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PAXLOVID. If co-administered, refer to individual product label for calcium channel blocker for further information. Cardiac glycosides digoxin ↑ digoxin Caution should be exercised when co-administering PAXLOVID with digoxin, with appropriate monitoring of serum digoxin levels. Refer to the digoxin product label for further information. Cardiovascular agents eplerenone ↑ eplerenone Co-administration with eplerenone is contraindicated due to potential for hyperkalemia [see Contraindications (4)]. ivabradine ↑ ivabradine Co-administration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances [see Contraindications (4)]. Reference ID: 5480648 12 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Cardiovascular agents aliskiren, ticagrelor, vorapaxar clopidogrel ↑ aliskiren ↑ ticagrelor ↑ vorapaxar ↓ clopidogrel active metabolite Avoid concomitant use with PAXLOVID. cilostazol ↑ cilostazol Dosage adjustment of cilostazol is recommended. Refer to the cilostazol product label for more information. Corticosteroids primarily metabolized by CYP3A betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone ↑ corticosteroid Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. However, the risk of Cushing’s syndrome and adrenal suppression associated with short-term use of a strong CYP3A inhibitor is low. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone should be considered. Cystic fibrosis transmembrane conductance regulator potentiators lumacaftor/ivacaftor ↓ nirmatrelvir/ritonavir Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)]. Cystic fibrosis transmembrane conductance regulator potentiators ivacaftor elexacaftor/tezacaftor/ ivacaftor tezacaftor/ivacaftor ↑ ivacaftor ↑ elexacaftor/tezacaftor/ ivacaftor ↑ tezacaftor/ivacaftor Reduce dosage when co-administered with PAXLOVID. Refer to individual product labels for more information. Dipeptidyl peptidase 4 (DPP4) inhibitors saxagliptin ↑ saxagliptin Dosage adjustment of saxagliptin is recommended. Refer to the saxagliptin product label for more information. Endothelin receptor antagonists bosentan ↑ bosentan ↓ nirmatrelvir/ritonavir Discontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID. Refer to the bosentan product label for further information. Ergot derivatives dihydroergotamine, ergotamine, methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Co-administration contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4)]. Reference ID: 5480648 13 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Hepatitis C direct acting antivirals elbasvir/grazoprevir glecaprevir/pibrentasvir ↑ antiviral Increased grazoprevir concentrations can result in alanine transaminase (ALT) elevations. Avoid concomitant use of glecaprevir/pibrentasvir with PAXLOVID. ombitasvir/paritaprevir/ ritonavir and dasabuvir Refer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information. sofosbuvir/velpatasvir/ voxilaprevir Refer to the sofosbuvir/velpatasvir/voxilaprevir product label for further information. Patients on ritonavir-containing HCV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or HCV drug adverse events with concomitant use. Herbal products St. John’s Wort (hypericum perforatum) ↓ nirmatrelvir/ritonavir Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)]. HMG-CoA reductase inhibitors lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)]. If treatment with PAXLOVID is considered medically necessary, discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID, during the 5 days of PAXLOVID treatment, and for 5 days after completing PAXLOVID. HMG-CoA reductase inhibitors atorvastatin ↑ atorvastatin Consider temporary discontinuation of atorvastatin during treatment with PAXLOVID. Atorvastatin does not need to be withheld prior to or after completing PAXLOVID. Hormonal contraceptive ethinyl estradiol ↓ ethinyl estradiol An additional, non-hormonal method of contraception should be considered during the 5 days of PAXLOVID treatment and until one menstrual cycle after stopping PAXLOVID. Immunosuppressants voclosporin ↑ voclosporin Co-administration contraindicated due to potential for acute and/or chronic nephrotoxicity [see Contraindications (4)]. Reference ID: 5480648 14 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Immunosuppressants calcineurin inhibitors: cyclosporine, tacrolimus ↑ cyclosporine ↑ tacrolimus Avoid concomitant use of calcineurin inhibitors with PAXLOVID when close monitoring of immunosuppressant concentrations is not feasible. If co-administered, dose adjustment of the immunosuppressant and close and regular monitoring for immunosuppressant concentrations and adverse reactions are recommended during and after treatment with PAXLOVID. Obtain expert consultation to appropriately manage the complexity of this coadministration [see Warnings and Precautions (5.1)]. mTOR inhibitors: everolimus, sirolimus ↑ everolimus ↑ sirolimus Avoid concomitant use of everolimus and sirolimus and PAXLOVID. Refer to the individual immunosuppressant product label and latest guidelines for further information. Janus kinase (JAK) inhibitors tofacitinib ↑ tofacitinib Dosage adjustment of tofacitinib is recommended. Refer to the tofacitinib product label for more information. upadacitinib ↑ upadacitinib Dosing recommendations for co-administration of upadacitinib with PAXLOVID depends on the upadacitinib indication. Refer to the upadacitinib product label for more information. Long-acting beta-adrenoceptor agonist salmeterol ↑ salmeterol Avoid concomitant use with PAXLOVID. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Microsomal triglyceride transfer protein (MTTP) inhibitor lomitapide ↑ lomitapide Co-administration contraindicated due to potential for hepatotoxicity and gastrointestinal adverse reactions [see Contraindications (4)]. Migraine medications eletriptan ↑ eletriptan Co-administration of eletriptan within at least 72 hours of PAXLOVID is contraindicated due to potential for serious adverse reactions including cardiovascular and cerebrovascular events [see Contraindications (4)]. ubrogepant ↑ ubrogepant Co-administration of ubrogepant with PAXLOVID is contraindicated due to potential for serious adverse reactions [see Contraindications (4)]. Reference ID: 5480648 15 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Migraine medications rimegepant ↑ rimegepant Avoid concomitant use with PAXLOVID. Mineralocorticoid receptor antagonists finerenone ↑ finerenone Co-administration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia [see Contraindications (4)]. Muscarinic receptor antagonists darifenacin ↑ darifenacin The darifenacin daily-dose should not exceed 7.5 mg when co-administered with PAXLOVID. Refer to the darifenacin product label for more information. Narcotic analgesics fentanyl, hydrocodone, oxycodone, meperidine ↑ fentanyl ↑ hydrocodone ↑ oxycodone ↑ meperidine Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl, hydrocodone, oxycodone, or meperidine is concomitantly administered with PAXLOVID. If concomitant use with PAXLOVID is necessary, consider a dosage reduction of the narcotic analgesic and monitor patients closely at frequent intervals. Refer to the individual product label for more information. methadone ↓ methadone Monitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Neuropsychiatric agents suvorexant ↑ suvorexant Avoid concomitant use of suvorexant with PAXLOVID. aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin ↑ aripiprazole ↑ brexpiprazole ↑ cariprazine ↑ iloperidone ↑ lumateperone ↑ pimavanserin Dosage adjustment of aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, and pimavanserin is recommended. Refer to individual product label for more information. Opioid antagonists naloxegol ↑ naloxegol Co-administration contraindicated due to the potential for opioid withdrawal symptoms [see Contraindications (4)]. Pulmonary hypertension agents (PDE5 inhibitors) sildenafil (Revatio®) ↑ sildenafil Co-administration of sildenafil with PAXLOVID is contraindicated for use in pulmonary hypertension due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope [see Contraindications (4)]. Reference ID: 5480648 16 Table 1: Established and Other Potentially Significant Drug Interactions Drug Class Drugs within Class Effect on Concentration Clinical Comments Pulmonary hypertension agents (PDE5 inhibitors) tadalafil (Adcirca®) ↑ tadalafil Avoid concomitant use of tadalafil with PAXLOVID for pulmonary hypertension. Pulmonary hypertension agents (sGC stimulators) riociguat ↑ riociguat Dosage adjustment is recommended for riociguat when used for pulmonary hypertension. Refer to the riociguat product label for more information. Erectile dysfunction agents (PDE5 inhibitors) avanafil ↑ avanafil Do not use PAXLOVID with avanafil because a safe and effective avanafil dosage regimen has not been established. sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Dosage adjustment is recommended for use of sildenafil, tadalafil or vardenafil with PAXLOVID when used for erectile dysfunction. Refer to individual product label for more information. Sedative/hypnotics triazolam, oral midazolama ↑ triazolam ↑ midazolam Co-administration contraindicated due to potential for extreme sedation and respiratory depression [see Contraindications (4)]. Sedative/hypnotics buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotic A dose decrease may be needed for these drugs when co-administered with PAXLOVID and monitoring for adverse events. midazolam (administered parenterally) ↑ midazolam Co-administration of midazolam (parenteral) should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Refer to the midazolam product label for further information. Serotonin receptor 1A agonist/ serotonin receptor 2A antagonist flibanserin ↑ flibanserin Co-administration contraindicated due to potential for hypotension, syncope, and CNS depression [see Contraindications (4)]. Vasopressin receptor antagonists tolvaptan ↑ tolvaptan Co-administration contraindicated due to potential for dehydration, hypovolemia and hyperkalemia [see Contraindications (4)]. a. See Pharmacokinetics, Clinical Drug Interaction Studies (12.3). Reference ID: 5480648 17 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on the use of nirmatrelvir during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug associated risk of miscarriage (see Data). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations). In an embryo-fetal development study with nirmatrelvir, reduced fetal body weights following oral administration of nirmatrelvir to pregnant rabbits were observed at systemic exposures (AUC) approximately 11 times higher than clinical exposure at the approved human dose of PAXLOVID. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures (AUC) greater than or equal to 3 times higher than clinical exposure at the approved human dose of PAXLOVID (see Data). In embryo-fetal developmental studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at systemic exposures (AUC) 5 (rat) or 8 (rabbits) times higher than clinical exposure at the approved human dose of PAXLOVID (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. Data Human Data Ritonavir Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,500 live births exposed in the first-trimester and over 3,500 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of birth defects in live births was 2.4% [95% confidence interval (CI): 1.9%, 2.9%] following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%, 3.5%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair. Reference ID: 5480648 18 Animal Data Nirmatrelvir Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and GD 7 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC24) in rats was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. At 1,000 mg/kg/day, the systemic exposure (AUC24) in rabbits was approximately 11 times higher than clinical exposures at the approved human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed up to the highest dose tested, 1,000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC24) approximately 3 times higher than clinical exposures at the approved human dose of PAXLOVID. A pre- and postnatal developmental (PPND) study in pregnant rats administered oral nirmatrelvir doses of up to 1,000 mg/kg/day from GD 6 through Lactation Day (LD) 20 showed no adverse findings. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir-treated versus control animals, a decrease in the body weight of offspring was observed on Postnatal Day (PND) 17 (8% decrease) and PND 21 (up to 7% decrease) in the absence of maternal toxicity. No significant differences in offspring body weight were observed from PND 28 to PND 56. The maternal systemic exposure (AUC24) at 1,000 mg/kg/day was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. No body weight changes in the offspring were noted at 300 mg/kg/day, where maternal systemic exposure (AUC24) was approximately 6 times higher than clinical exposures at the approved human dose of PAXLOVID. Ritonavir Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 in rats and GD 6 through 19 in rabbits). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) 5 (rats) or 8 (rabbits) times higher than exposure at the approved human dose of PAXLOVID. Increased incidences of early resorptions, ossification delays, and developmental variations, as well as decreased fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures (AUC) approximately 10 times higher than exposure at the approved human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses, at systemic exposures greater than 8 times higher than exposure at the approved human dose of PAXLOVID. In a PPND study in rats, administration of 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through PND 20 resulted in no developmental toxicity, at ritonavir systemic exposures greater than 10 times the exposure at the approved human dose of PAXLOVID. 8.2 Lactation Risk Summary Nirmatrelvir and ritonavir are present in human breast milk in small amounts (less than 2%). In a clinical lactation study in 8 lactating women, nirmatrelvir and ritonavir were estimated to be present in human milk at a mean weight-normalized infant daily dose of 0.16 mg/kg/day (1.8% of maternal weight-adjusted daily dose) and 0.006 mg/kg/day (0.2% of maternal weight-adjusted daily dose), respectively (see Data). There are no available data on the effects of nirmatrelvir or ritonavir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from Reference ID: 5480648 19 PAXLOVID or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. Data In a clinical pharmacokinetics study, 8 healthy lactating women who were at least 12 weeks postpartum were administered 3 oral doses every 12 hours (steady state dosing) of 300 mg/100 mg nirmatrelvir/ritonavir. The mean daily amount of nirmatrelvir and ritonavir recovered in breast milk was 0.752 mg and 0.027 mg, respectively, representing 0.13% and 0.014% of the corresponding administered daily maternal doses (unadjusted for weight). The estimated daily infant dose (assuming average milk consumption of 150 mL/kg/day), was 0.16 mg/kg/day and 0.006 mg/kg/day, 1.8% and 0.2% of the maternal dose, respectively, for nirmatrelvir and ritonavir. 8.3 Females and Males of Reproductive Potential Contraception Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3)]. 8.4 Pediatric Use The optimal dose of PAXLOVID has not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of PAXLOVID include subjects 65 years of age and older and their data contributes to the overall assessment of safety and efficacy [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Of the total number of subjects in the integrated dataset consisting of EPIC-HR and EPIC-SR who were randomized to and received PAXLOVID (N=1,578), 165 (10%) were 65 years of age and older and 39 (2%) were 75 years of age and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in safety between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Renal impairment increases nirmatrelvir exposure, which may increase the risk of PAXLOVID adverse reactions. No dosage adjustment is recommended in patients with mild renal impairment (eGFR ≥60 to <90 mL/min). Reduce the PAXLOVID dosage in patients with moderate renal impairment (eGFR ≥30 to <60 mL/min). PAXLOVID is not recommended for use in patients with severe renal impairment (eGFR <30 mL/min) or patients with end stage renal disease (eGFR <15 mL/min) receiving dialysis until more data are available. The appropriate dosage for patients with severe renal impairment has not been determined [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions [see Patient Counseling Information (17)]. 8.7 Hepatic Impairment No dosage adjustment of PAXLOVID is recommended for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding Reference ID: 5480648 20 the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment, therefore, PAXLOVID is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Treatment of overdose with PAXLOVID should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with PAXLOVID. 11 DESCRIPTION PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a SARS-CoV-2 main protease (Mpro) inhibitor, and ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor. Nirmatrelvir The chemical name of active ingredient of nirmatrelvir is (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin- 3-yl)ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide]. It has a molecular formula of C23H32F3N5O4 and a molecular weight of 499.54. Nirmatrelvir has the following structural formula: Nirmatrelvir is available as immediate-release, film-coated tablets. Each tablet contains 150 mg nirmatrelvir with the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. The following are the ingredients in the film coating: hydroxy propyl methylcellulose, iron oxide red, polyethylene glycol, and titanium dioxide. Ritonavir Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1 methylethyl)-4- thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R,8R,10R,11R)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula: N H O (S) 1 3 (S) NH O (S) 2 N (S) 5 (R) 1 O 2 (S) HN O F F F N Reference ID: 5480648 21 Ritonavir is available as film-coated tablets. Each tablet contains 100 mg ritonavir with the following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating may include the following ingredients: colloidal anhydrous silica, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4)]. Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir. 12.2 Pharmacodynamics Cardiac Electrophysiology At 3 times the steady state peak plasma concentration (Cmax) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics The pharmacokinetics of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19. Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range from 250 mg to 750 mg (0.83 to 2.5 times the approved recommended dose) and multiple dose range from 75 mg to 500 mg (0.25 to 1.67 times the approved recommended dose), when administered in combination with 100 mg ritonavir. Nirmatrelvir steady state was achieved on Day 2 following administration of the approved recommended dosage and the mean accumulation ratio was approximately 2-fold. The pharmacokinetic properties of nirmatrelvir/ritonavir are displayed in Table 2. Reference ID: 5480648 22 Table 2: Pharmacokinetic Properties of Nirmatrelvir and Ritonavir in Healthy Subjects Nirmatrelvir (When Given With Ritonavir) Ritonavir Absorption Tmax (hr), median 3.00a 3.98a Food effect Test/reference (fed/fasted) ratios of adjusted geometric means (90% CI) AUCinf and Cmax for nirmatrelvir were 119.67 (108.75, 131.68) and 161.01 (139.05, 186.44), respectively.b Distribution % bound to human plasma proteins 69% 98-99% Blood-to-plasma ratio 0.60 0.14d Vz/F (L), mean 104.7c 112.4c Elimination Major route of elimination Renal eliminationd Hepatic metabolism Half-life (T½) (hr), mean 6.05a 6.15a Oral clearance (CL/F) (L/hr), mean 8.99c 13.92c Metabolism Metabolic pathways Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal. Major CYP3A, Minor CYP2D6 Excretion % drug-related material in feces 35.3%e 86.4%f % of dose excreted as total (unchanged drug) in feces 27.5%e 33.8%f % drug-related material in urine 49.6%e 11.3%f % of dose excreted as total (unchanged drug) in urine 55.0%e 3.5%f Abbreviations: CL/F=apparent clearance; hr=hour; L/hr=liters per hour; T½=terminal elimination half-life; Tmax=the time to reach Cmax; Vz/F=apparent volume of distribution. a. Represents data after a single dose of 300 mg nirmatrelvir (2 x 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects. b. Following a single oral dose of nirmatrelvir 300 mg boosted ritonavir 100 mg at -12 hours, 0 hours and 12 hours, administered under fed (high fat and high calorie meal) or fasted conditions. c. 300 mg nirmatrelvir (oral suspension formulation) co-administered with 100 mg ritonavir (tablet formulation) twice daily for 3 days. d. Red blood cell to plasma ratio. e. Determined by 19F-NMR analysis following 300 mg nirmatrelvir oral suspension administered at 0 hr enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours. f. Determined by 14C analysis following 600 mg 14C-ritonavir oral solution (6 times the approved ritonavir dose). The predicted Day 5 nirmatrelvir exposure parameters in adult subjects with mild-to-moderate COVID-19 who were treated with PAXLOVID in EPIC-HR are presented in Table 3. Reference ID: 5480648 23 Table 3: Predicted Day 5 Nirmatrelvir Exposure Parameters Following Administration of Nirmatrelvir/Ritonavir 300 mg/100 mg Twice Daily in Subjects with Mild-to-Moderate COVID-19 Pharmacokinetic Parameter (units)a Nirmatrelvirb Cmax (µg/mL) 3.43 (2.59, 4.52) AUCtau (µghr/mL)c 30.4 (22.9, 39.8) Cmin (µg/mL) 1.57 (1.16, 2.10) Abbreviations:Cmax=predicted maximal concentration; Cmin=predicted minimal concentration (Ctrough). a. Data presented as geometric mean (10th and 90th percentile). b. Based on 1,016 subjects with their post hoc PK parameters. c. AUCtau=predicted area under the plasma concentration-time profile from time 0 to 12 hours for twice-daily dosing. Effect of Food No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed following administration of a high fat meal (800-1000 calories; 50% fat) to healthy subjects. Specific Populations There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity. Pediatric Patients The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established. Patients with Renal Impairment The pharmacokinetics of nirmatrelvir in patients with renal impairment following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg are presented in Table 4. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively. Table 4: Impact of Renal Impairment on Nirmatrelvir/Ritonavir Pharmacokinetics Normal Renal Function (n=8) Mild Renal Impairment (n=8) Moderate Renal Impairment (n=8) Severe Renal Impairment (n=8) Cmax (µg/mL) 1.60 (31) 2.08 (29) 2.21 (17) 2.37 (38) AUCinf (µghr/mL) 14.46 (20) 17.91 (30) 27.11 (27) 44.04 (33) Tmax (hr) 2.0 (1.0 - 4.0) 2.0 (1.0 – 3.0) 2.50 (1.0 – 6.0) 3.0 (1.0 - 6.1) T½ (hr) 7.73 ± 1.82 6.60 ± 1.53 9.95 ± 3.42 13.37 ± 3.32 Abbreviations: AUCinf=area under the plasma concentration-time profile from time zero extrapolated to infinite time; Cmax=the observed maximum concentration; CV=coefficient of variation; SD=standard deviation; T½=terminal elimination half-life; Tmax=the time to reach Cmax. Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for T½. Patients with Hepatic Impairment The pharmacokinetics of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of nirmatrelvir or ritonavir has not been studied. Reference ID: 5480648 24 Clinical Drug Interaction Studies Table 5 describes the effect of other drugs on the Cmax and AUC of nirmatrelvir. Table 5: The Effect of Other Drugs on the Pharmacokinetic Parameters of Nirmatrelvir Co-administered Drug Dose (Schedule) N Percent Ratio (in combination with co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI); No Effect=100 Co-administered Drug Nirmatrelvir/ Ritonavir Cmax AUCa Carbamazepineb 300 mg twice daily (16 doses) 300 mg/100 mg once daily (2 doses) 10 56.82 (47.04, 68.62) 44.50 (33.77, 58.65) Itraconazole 200 mg once daily (8 doses) 300 mg/100 mg twice daily (5 doses) 11 118.57 (112.50, 124.97) 138.82 (129.25, 149.11) Abbreviations: AUC=area under the plasma concentration-time curve; AUCinf=area under the plasma concentration-time profile from time zero extrapolated to infinite time; AUCtau=area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval. CI=confidence interval; Cmax=observed maximum plasma concentrations. a. For carbamazepine, AUC=AUCinf; for itraconazole, AUC=AUCtau. b. Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7). Table 6 describes the effect of nirmatrelvir/ritonavir on the Cmax and AUCinf of other drugs. Table 6: Effect of Nirmatrelvir/Ritonavir on Pharmacokinetics of Other Drugs Co-administered Drug Dose (Schedule) N Percent Ratio of Test/Reference of Geometric Means (90% CI); No Effect=100 Co-administered Drug Nirmatrelvir/ Ritonavir Cmax AUCinf Midazolama 2 mg (1 dose) 300 mg/100 mg twice daily (9 doses) 10 368.33 (318.91, 425.41) 1430.02 (1204.54, 1697.71) Dabigatrana 75 mg (1 dose) 300 mg/100 mg twice daily (4 doses) 24 233.06 (172.14, 315.54) 194.47 (155.29, 243.55) Rosuvastatina 10 mg (1 dose) 300 mg/100 mg twice daily (3 doses) 12 212.44 (174.31, 258.90) 131.18 (115.89, 148.48) Abbreviations: AUCinf=area under the plasma concentration-time curve from time zero extrapolated to infinite time; CI=confidence interval; Cmax=observed maximum plasma concentrations; CYP3A4=cytochrome P450 3A4; OATP1B1=organic anion transporter polypeptide 1B1; P-gp=p-glycoprotein. a. For midazolam, Test=nirmatrelvir/ritonavir plus midazolam, Reference=Midazolam. Midazolam is an index substrate for CYP3A4. For dabigatran, Test=nirmatrelvir/ritonavir plus dabigatran, Reference=Dabigatran. Dabigatran is an index substrate for P-gp. For rosuvastatin, Test=nirmatrelvir/ritonavir plus rosuvastatin, Reference=Rosuvastatin. Rosuvastatin is an index substrate for OATP1B1. In Vitro Studies Cytochrome P450 (CYP) Enzymes: • Nirmatrelvir is a reversible and time-dependent inhibitor of CYP3A, but not an inhibitor CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Nirmatrelvir is an inducer of CYP2B6, 2C8, 2C9, and 3A4, but there is minimal risk for pharmacokinetic interactions arising from induction of these CYP enzymes at the proposed therapeutic dose. Reference ID: 5480648 25 • Ritonavir is a substrate of CYP2D6 and CYP3A. Ritonavir is an inducer of CYP1A2, CYP2C9, CYP2C19, CYP2B6, and CYP3A. Transporter Systems: Nirmatrelvir is an inhibitor of P-gp and OATP1B1. Nirmatrelvir is a substrate for P-gp, but not BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATP1B1, OATP1B3, OATP2B1, or OATP4C1. 12.4 Microbiology Mechanism of Action Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography. Antiviral Activity Cell Culture Antiviral Activity Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells with EC50 and EC90 values of 62 nM (31 ng/mL) and 181 nM (90 ng/mL), respectively, after 3 days of drug exposure. The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ.1, BQ.1.11, and XBB.1.5 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 83 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold-changes ≤1.5 relative to the USA-WA1/2020 isolate. In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC50 value fold-change of 3.7 relative to USA-WA1/2020. The other variants had EC50 value fold-changes ≤1.1 relative to USA-WA1/2020. Clinical Antiviral Activity In clinical trial EPIC-HR, which enrolled subjects who were primarily infected with the SARS-CoV-2 Delta variant, PAXLOVID treatment was associated with a 0.83 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5 (mITT1 analysis set, all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment); similar results were observed in the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days). In the EPIC-SR trial, which included subjects who were infected with SARS-CoV-2 Delta (79%) or Omicron (19%) variants, PAXLOVID treatment was associated with a 1.05 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5, with similar declines observed in subjects infected with Delta or Omicron variants. The degree of reduction in viral RNA levels relative to placebo following 5 days of PAXLOVID treatment was similar between unvaccinated high-risk subjects in EPIC-HR and vaccinated high-risk subjects in EPIC-SR. Reference ID: 5480648 26 Antiviral Resistance In Cell Culture and Biochemical Assays SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 7 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in nirmatrelvir-selected SARS-CoV-2 in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown. Table 7: SARS-CoV-2 Mpro Amino Acid Substitutions Selected by Nirmatrelvir in Cell Culture Single Substitutions (EC50 value fold change) T21I (1.1-4.6), L50F (1.5-4.2), P108S (ND), T135I (ND), F140L (4.1), S144A (2.2-5.3), C160F (ND), E166A (3.3), E166V (25-288), L167F (ND), T169I (ND), H172Y (ND), A173V (0.9-1.7), V186A (ND), R188G (ND), A191V (ND), A193P (ND), P252L (5.9), S301P (ND), and T304I (1.4-5.5). ≥2 Substitutions (EC50 value fold change) T21I+S144A (9.4), T21I+E166V (83), T21I+A173V (3.1), T21I+T304I (3.0-7.9), L50F+E166V (34-175), L50F+T304I (5.9), T135I+T304I (3.8), F140L+A173V (10.1), H172Y+P252L (ND), A173V+T304I (20.2), T21I+L50F+A193P+S301P (28.8), T21I+S144A+T304I (27.8), T21I+C160F+A173V+V186A+T304I (28.5), T21I+A173V+T304I (15), and L50F+F140L+L167F+T304I (54.7). Abbreviation: ND=no data. In a biochemical assay using recombinant SARS-CoV-2 Mpro containing amino acid substitutions, the following SARS-CoV-2 Mpro substitutions led to ≥3-fold reduced nirmatrelvir activity (fold-change based on Ki values): Y54A (25), F140A (21), F140L (7.6), F140S (260), G143S (3.6), S144A (46), S144E (480), S144T (170), H164N (6.7), E166A (35), E166G (6.2), E166V (7,700), H172Y (250), A173S (4.1), A173V (16), R188G (38), Q192L (29), Q192P (7.8), and V297A (3.0). In addition, the following combinations of Mpro substitutions led to ≥3-fold reduced nirmatrelvir activity: T21I+S144A (20), T21I+E166V (11,000), T21I+A173V (15), L50F+E166V (4,500), T135I+T304I (5.1), F140L+A173V (95), H172Y+P252L (180), A173V+T304I (28), T21I+S144A+T304I (51), T21I+A173V+T304I (55), L50F+E166A+L167F (210), T21I+L50F+A193P+S301P (7.3), L50F+F140L+L167F+T304I (190), and T21I+C160F+A173V+V186A+T304I (28). The following substitutions and substitution combinations emerged in cell culture but conferred <3-fold reduced nirmatrelvir activity in biochemical assays: T21I (1.6), L50F (0.2), P108S (2.9), T135I (2.2), C160F (0.6), L167F (0.9), T169I (1.4), V186A (0.8), A191V (0.8), A193P (0.9), P252L (0.9), S301P (0.2), T304I (1.0), T21I+T304I (1.8), and L50F+T304I (1.3). The clinical significance of these substitutions is unknown. In Clinical Trials Treatment-emergent substitutions were evaluated among subjects in clinical trials EPIC-HR/SR with sequence data available at both baseline and a post-baseline visit (n=907 PAXLOVID-treated subjects, n=946 placebo-treated subjects). SARS-CoV-2 Mpro amino acid changes were classified as PAXLOVID treatment-emergent substitutions if they occurred at the same amino acid position in 3 or more PAXLOVID-treated subjects and were ≥2.5-fold more common in PAXLOVID-treated subjects than placebo-treated subjects. The following PAXLOVID treatment-emergent Mpro substitutions were observed: T98I/R/del(n=4), E166V (n=3), and W207L/R/del (n=4). Within the Mpro cleavage sites, the following PAXLOVID treatment-emergent substitutions were observed: A5328S/V(n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific Mpro substitutions. Reference ID: 5480648 27 None of the treatment-emergent substitutions listed above in Mpro or Mpro cleavage sites occurred in PAXLOVID-treated subjects who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown. Viral RNA Rebound and Treatment-Emergent Substitutions EPIC-HR and EPIC-SR were not designed to evaluate COVID-19 rebound; exploratory analyses were conducted to assess the relationship between PAXLOVID use and rebound in viral RNA shedding levels. Post-treatment increases in SARS-CoV-2 RNA shedding levels in nasopharyngeal samples were observed on Day 10 and/or Day 14 in a subset of PAXLOVID and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment viral RNA rebound varied according to analysis parameters, but was generally similar among PAXLOVID and placebo recipients. A similar or smaller percentage of placebo recipients compared to PAXLOVID recipients had nasopharyngeal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods. In EPIC-HR, of 59 PAXLOVID-treated subjects identified with post-treatment viral RNA rebound and with available viral sequence data, treatment-emergent substitutions in Mpro potentially reducing nirmatrelvir activity were detected in 2 (3%) subjects, including E166V in 1 subject and T304I in 1 subject. Both subjects had viral RNA shedding levels <LLOQ by Day 14. Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID-19 related hospitalization or death from any cause through Day 28 following the single 5-day course of PAXLOVID treatment. The clinical relevance of post-treatment increases in viral RNA following PAXLOVID or placebo treatment is unknown. Cross-Resistance Cross-resistance is not expected between nirmatrelvir and remdesivir or any other anti-SARS-CoV-2 agents with different mechanisms of action (i.e., agents that are not Mpro inhibitors). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Nirmatrelvir Carcinogenicity studies have not been conducted with nirmatrelvir. Nirmatrelvir was negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the in vitro micronucleus assay using human lymphoblastoid TK6 cells, and the in vivo rat micronucleus assays. In a fertility and early embryonic development study, nirmatrelvir was administered orally to male and female rats at doses of 60, 200, or 1,000 mg/kg/day once daily beginning 14 days prior to mating, throughout the mating phase, and continued through GD 6 for females and for a total of 32 doses for males. There were no effects on fertility, reproductive performance, or early embryonic development at doses up to 1,000 mg/kg/day, resulting in systemic exposure (AUC24) approximately 5 times higher than exposure at the approved human dose of PAXLOVID. Reference ID: 5480648 28 Ritonavir Carcinogenicity studies in mice and rats have been conducted on ritonavir. In male mice, at levels of 50, 100, or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 25 times higher than the exposure in humans at the approved human dose of PAXLOVID. No carcinogenic effects were observed in females at up to the highest dose tested, resulting in systemic exposure (AUC24) approximately 25 times higher than the exposure in humans at the approved human dose of PAXLOVID. In rats dosed at levels of 7, 15, or 30 mg/kg/day, there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 5 times higher than the exposure in humans at the approved human dose of PAXLOVID. Ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. Ritonavir produced no effects on fertility in rats at drug exposures approximately 18 (male) and 27 (female) times higher than the exposure in humans at the approved human dose of PAXLOVID. 14 CLINICAL STUDIES 14.1 Efficacy in Subjects at High Risk of Progression to Severe COVID-19 (EPIC-HR) EPIC-HR (NCT04960202) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Subjects with COVID-19 symptom onset of ≤5 days were included in the study. Subjects were randomized (1:1) to receive PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The trial excluded individuals with a history of prior COVID-19 infection or vaccination and excluded individuals taking any medications with clinically significant drug interactions with PAXLOVID. The primary efficacy endpoint was the proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set [all treated subjects with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment], the mITT1 analysis set (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days). A total of 2,113 subjects were randomized to receive either PAXLOVID or placebo. At baseline, mean age was 45 years; 51% were male; 71% were White, 15% were Asian, 9% were American Indian or Alaska Native, 4% were Black or African American, and 1% was missing or unknown; 41% were Hispanic or Latino; 67% of subjects had onset of symptoms ≤3 days before initiation of study treatment; 49% of subjects were serological negative at baseline; the mean (SD) baseline viral RNA in nasopharyngeal samples was 4.71 log10 copies/mL (2.89); 27% of subjects had a baseline viral RNA of ≥10^7 (log10 copies/mL); 6% of subjects either received or were expected to receive COVID-19 therapeutic monoclonal antibody treatment at the time of randomization and were excluded from the mITT and mITT1 analyses. Reference ID: 5480648 29 The baseline demographic and disease characteristics were balanced between the PAXLOVID and placebo groups. The proportions of subjects who discontinued treatment due to an adverse event were 2.0% in the PAXLOVID group and 4.2% in the placebo group. Table 8 provides results of the primary endpoint in mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for PAXLOVID compared to placebo was 86% (95% CI: 72%, 93%). Table 8: COVID-19 Related Hospitalization or Death from Any Cause Through Day 28 in Non-Hospitalized Adults with COVID-19 (mITT1 Analysis Set): EPIC-HR PAXLOVID (N=977) Placebo (N=989) COVID-19 Related Hospitalization or Death from Any Cause Through Day 28 n (%) 9 (0.9%) 64 (6.5%) Reduction Relative to Placeboa (95% CI), % -5.6 (-7.3, -4.0) COVID-19 Related Hospitalization Through Day 28, % 9 (0.9%) 63 (6.4%) All-cause Mortality Through Day 28b, % 0 12 (1.2%) Abbreviations: CI=confidence interval; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT1=modified intent-to-treat 1 (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment). The determination of primary efficacy was based on a planned interim analysis of 754 subjects in mITT population. The estimated risk reduction was -6.5% with a 95% CI of (-9.3%, -3.7%) and 2-sided p-value <0.0001. a. The estimated cumulative proportion of subjects hospitalized or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subjects without hospitalization and death status through Day 28 were censored at the time of study discontinuation. b. For the secondary endpoint of all-cause mortality through Week 24, there were 0 and 15 (1%) events in the PAXLOVID arm and placebo arm, respectively. Consistent results were observed in the mITT and mITT2 analysis populations. Similar trends have been observed across subgroups of subjects (see Figure 1). Reference ID: 5480648 30 Figure 1: Subgroup Analysis of Adults with COVID-19 Dosed within 5 Days of Symptom Onset with COVID-19 Related Hospitalization or Death from Any Cause Through Day 28: EPIC-HR Abbreviations: BMI=body mass index; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT=modified intent-to-treat; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. N=number of subjects in the category of the analysis set. All categories are based on mITT1 population except for COVID-19 mAb treatment which is based on mITT2 population. Seropositivity was defined if results were positive in either Elecsys anti-SARS-CoV-2 S or Elecsys anti-SARS-CoV-2 (N) assay. The difference of the proportions in the 2 treatment groups and its 95% confidence interval based on normal approximation of the data are presented. Among subjects who were SARS-CoV-2 seropositive at baseline, 1/490 (0.2%) PAXLOVID recipients versus 8/479 (1.7%) placebo recipients met the primary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 [reduction relative to placebo -1.47% (-2.70%, -0.25%)]. 14.2 Trial in Unvaccinated Subjects Without a Risk Factor for Progression to Severe COVID-19 or Subjects Fully Vaccinated Against COVID-19 With at Least One Factor for Progression to Severe COVID-19 (EPIC-SR) PAXLOVID is not indicated for the treatment of COVID-19 in patients without a risk factor for progression to severe COVID-19. EPIC-SR (NCT05011513) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age or older with COVID-19 symptom onset of ≤5 days who were at standard risk for progression to severe disease. The trial included previously unvaccinated subjects with no risk factors for progression to severe disease or subjects fully vaccinated against COVID-19 (i.e., completed a primary vaccination series) with at least 1 of the risk factors for progression to severe disease as defined in EPIC-HR. Through the December 19, 2021, data cutoff, a total of 1,075 subjects were randomized (1:1) to receive PAXLOVID or placebo orally every 12 hours for 5 days; of these, 59% were fully vaccinated high-risk subjects. Reference ID: 5480648 31 The primary endpoint in this trial, the difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 among PAXLOVID versus placebo recipients, was not met. In an exploratory analysis of the subgroup of fully vaccinated subjects with at least 1 risk factor for progression to severe disease, a non-statistically significant numerical reduction relative to placebo for the secondary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 was observed. 14.3 Post-Exposure Prophylaxis Trial PAXLOVID is not indicated for the post-exposure prophylaxis of COVID-19. In a double-blind, double-dummy, placebo-controlled trial, the efficacy of PAXLOVID when administered for 5 or 10 days as post-exposure prophylaxis of COVID-19 was evaluated. Eligible subjects were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at baseline and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2. A total of 2,736 subjects were randomized (1:1:1) to receive PAXLOVID orally every 12 hours for 5 days, PAXLOVID orally every 12 hours for 10 days, or placebo. The primary endpoint for this trial was not met. The primary endpoint was the risk reduction between the 5-day and 10-day PAXLOVID regimens versus placebo in the proportion of subjects who developed RT-PCR or RAT-confirmed symptomatic SARS-CoV-2 infection through Day 14 who had a negative SARS-CoV-2 RT-PCR result at baseline. The proportion of subjects who had events through Day 14 was 2.6% for the 5-day PAXLOVID regimen, 2.4% for the 10-day PAXLOVID regimen, and 3.9% for placebo. There was not a statistically significant risk reduction versus placebo for either the 5-day or 10-day PAXLOVID regimen. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. It is supplied in two different Dose Packs. Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card. Dose Pack Content NDC Description 300 mg nirmatrelvir; 100 mg ritonavir Each Carton Contains: 30 tablets divided in 10 blister cards 0069-5001-30 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with the “a” logo and the code NK. Or 0069-5045-30 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Reference ID: 5480648 32 Dose Pack Content NDC Description Ritonavir tablets: White to off-white, capsule-shaped, film-coated tablets debossed with “H” on one side and “R9” on the other side. Or 0069-5321-30 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with “NK” on one side. Each Blister Card Contains: 2 nirmatrelvir tablets (150 mg each) and 1 ritonavir tablet (100 mg) 0069-5001-06 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with the “a” logo and the code NK. Or 0069-5045-06 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White to off-white, capsule-shaped, film-coated tablets debossed with “H” on one side and “R9” on the other side. Or 0069-5321-03 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with “NK” on one side. 150 mg nirmatrelvir; 100 mg ritonavir Each Carton Contains: 20 tablets divided in 10 blister cards 0069-5017-20 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with the “a” logo and the code NK. Or Reference ID: 5480648 33 Dose Pack Content NDC Description 0069-5317-20 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with “NK” on one side. Each Blister Card Contains: 1 nirmatrelvir tablet (150 mg) and 1 ritonavir tablet (100 mg) 0069-5017-04 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with the “a” logo and the code NK. Or 0069-5317-02 Nirmatrelvir tablets: Oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Ritonavir tablets: White film-coated ovaloid tablets debossed with “NK” on one side. Storage and Handling Store at USP controlled room temperature 20○C to 25○C (68○F to 77○F); excursions permitted between 15○C to 30○C (59○F to 86○F). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions Inform patients that PAXLOVID may interact with certain drugs and is contraindicated for use with certain drugs; therefore, advise patients to report to their healthcare provider the use of any prescription, non-prescription medication, or herbal products [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)]. Hypersensitivity Reactions Inform patients that anaphylaxis, serious skin reactions, and other hypersensitivity reactions have been reported, even following a single dose of PAXLOVID. Advise them to immediately discontinue the drug and to inform their healthcare provider at the first sign of a skin rash, hives or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction [see Warnings and Precautions (5.2)]. Reference ID: 5480648 34 Dosage Modification in Patients with Moderate Renal Impairment To ensure appropriate dosing in patients with moderate renal impairment, instruct such patients that they will be taking one 150 mg nirmatrelvir tablet with one 100 mg ritonavir tablet together twice daily for 5 days [see Dosage and Administration (2.3)]. Administration Instructions Inform patients to take PAXLOVID with or without food as instructed. Advise patients to swallow all tablets for PAXLOVID whole and not to chew, break, or crush the tablets. Alert the patient of the importance of completing the full 5-day treatment course and to continuing isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of SARS-CoV-2. If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose [see Dosage and Administration (2)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For Medical Information about PAXLOVID, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-1523-2.2c Reference ID: 5480648 1 PATIENT INFORMATION PAXLOVID (pax-LO-vid) (nirmatrelvir tablets; ritonavir tablets) co-packaged for oral use What is the most important information I should know about PAXLOVID? PAXLOVID can interact with other medicines causing severe or life-threatening side effects or death. It is important to know the medicines that should not be taken with PAXLOVID. Do not take PAXLOVID if: • you are taking any of the following medicines: o alfuzosin o amiodarone o apalutamide o carbamazepine o colchicine o dihydroergotamine o dronedarone o eletriptan o eplerenone o ergotamine o finerenone o flecainide o flibanserin o ivabradine o lomitapide o lovastatin o lumacaftor/ivacaftor o lurasidone o methylergonovine o midazolam (oral) o naloxegol o phenobarbital o phenytoin o pimozide o primidone o propafenone o quinidine o ranolazine o rifampin o rifapentine o St. John’s Wort (hypericum perforatum) o sildenafil (Revatio®) for pulmonary arterial hypertension o silodosin o simvastatin o tolvaptan o triazolam o ubrogepant o voclosporin These are not the only medicines that may cause serious or life-threatening side effects if taken with PAXLOVID. PAXLOVID may increase or decrease the levels of multiple other medicines. It is very important to tell your healthcare provider about all of the medicines you are taking because additional laboratory tests or changes in the dose of your other medicines may be necessary during treatment with PAXLOVID. Your healthcare provider may also tell you about specific symptoms to watch out for that may indicate that you need to stop or decrease the dose of some of your other medicines. • you are allergic to nirmatrelvir, ritonavir, or any of the ingredients in PAXLOVID. See the end of this leaflet for a complete list of ingredients in PAXLOVID. See “What are the possible side effects of PAXLOVID?” for signs and symptoms of allergic reactions. What is PAXLOVID? PAXLOVID is a prescription medicine used to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. PAXLOVID is not approved for use as pre-exposure or post-exposure treatment for prevention of COVID-19. Before taking PAXLOVID, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems. You may need a different dose of PAXLOVID. • have liver problems, including hepatitis. • have Human Immunodeficiency Virus 1 (HIV-1) infection. PAXLOVID may lead to some HIV-1 medicines not working as well in the future. • are pregnant or plan to become pregnant. It is not known if PAXLOVID can harm your unborn baby. Tell your healthcare provider right away if you are or if you become pregnant. • are breastfeeding or plan to breastfeed. PAXLOVID can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PAXLOVID. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. • Your healthcare provider can tell you if it is safe to take PAXLOVID with other medicines. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with PAXLOVID. • Do not start taking a new medicine without telling your healthcare provider. Tell your healthcare provider if you are taking combined birth control (hormonal contraceptive). PAXLOVID may affect how your hormonal contraceptives work. Females who are able to become pregnant should use another effective alternative form of contraception or an additional barrier method of contraception during treatment with PAXLOVID. Talk to your healthcare provider if you have any questions about contraceptive methods that might be right for you. Reference ID: 5480648 2 How should I take PAXLOVID? • Take PAXLOVID exactly as your healthcare provider tells you to take it. • PAXLOVID consists of 2 medicines: nirmatrelvir tablets and ritonavir tablets. The 2 medicines are taken together 2 times each day for 5 days. o Nirmatrelvir is an oval, pink tablet. o Ritonavir is a white or off-white tablet. • PAXLOVID is available in 2 Dose Packs (see Figures A and B below). Your healthcare provider will prescribe the PAXLOVID Dose Pack that is right for you. • If you have kidney disease, your healthcare provider may prescribe a lower dose (see Figure B). Talk to your healthcare provider to make sure you receive the correct Dose Pack. Reference ID: 5480648 3 Figure A If you are prescribed PAXLOVID 300 mg; 100 mg Dose Pack: each dose contains 3 tablets How to take PAXLOVID 300 mg; 100 mg Dose Pack Take the 2 pink nirmatrelvir tablets and 1 white to off-white ritonavir tablet together 2 times a day (in morning and at bedtime). Reference ID: 5480648 4 Figure B If you are prescribed PAXLOVID 150 mg; 100 mg Dose Pack: each dose contains 2 tablets How to take PAXLOVID 150 mg; 100 mg Dose Pack Take the 1 pink nirmatrelvir tablet and 1 white to off-white ritonavir tablet together 2 times a day (in morning and at bedtime). Reference ID: 5480648 5 • Do not remove your PAXLOVID tablets from the blister card before you are ready to take your dose. o Take your first dose of PAXLOVID in the morning or at bedtime, depending on when you pick up your prescription, or as your healthcare provider tells you to. o Take all tablets from your blister card at the same time as one dose. • Swallow the tablets whole. Do not chew, break, or crush the tablets. • Take PAXLOVID with or without food. • Do not stop taking PAXLOVID without talking to your healthcare provider, even if you feel better. • If you miss a dose of PAXLOVID within 8 hours of the time it is usually taken, take it as soon as you remember. If you miss a dose by more than 8 hours, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of PAXLOVID at the same time. • If you take too much PAXLOVID, call your healthcare provider or go to the nearest hospital emergency room right away. • If you are taking a ritonavir- or cobicistat-containing medicine to treat hepatitis C or HIV-1 infection, you should continue to take your medicine as prescribed by your healthcare provider. Talk to your healthcare provider if you do not feel better or if you feel worse after 5 days. What are the possible side effects of PAXLOVID? PAXLOVID may cause serious side effects, including: • Allergic reactions, including severe allergic reactions (anaphylaxis) have happened during treatment with PAXLOVID. Stop taking PAXLOVID and get medical help right away if you get any of the following symptoms of an allergic reaction: o skin rash, hives, blisters or peeling skin o painful sores or ulcers in the mouth, nose, throat or genital area o swelling of the mouth, lips, tongue or face o trouble swallowing or breathing o throat tightness o hoarseness • Liver problems. Tell your healthcare provider right away if you get any of the following signs and symptoms of liver problems during treatment with PAXLOVID: o loss of appetite o yellowing of your skin and the white of eyes o dark-colored urine o pale colored stools o itchy skin o stomach-area (abdominal) pain The most common side effects of PAXLOVID include: altered sense of taste and diarrhea. Other possible side effects include: • headache • vomiting • abdominal pain • nausea • high blood pressure • feeling generally unwell These are not all of the possible side effects of PAXLOVID. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PAXLOVID? • Store PAXLOVID at room temperature between 68°F to 77°F (20°C to 25°C). Keep PAXLOVID and all medicines out of the reach of children. General information about the safe and effective use of PAXLOVID. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PAXLOVID for a condition for which it was not prescribed. Do not give PAXLOVID to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about PAXLOVID that is written for health professionals. Reference ID: 5480648 6 What are the ingredients in PAXLOVID? Active ingredient: nirmatrelvir and ritonavir Nirmatrelvir inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. Film-coating contains: hydroxy propyl methylcellulose, iron oxide red, polyethylene glycol, and titanium dioxide. Ritonavir inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating may contain: colloidal anhydrous silica, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide. LAB-1524-1.2c For more information, go to www.pfizer.com or call 1-800-438-1985. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5480648	custom-source	2025-02-12T15:46:50.063471	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217188s009lbl.pdf', 'application_number': 217188, 'submission_type': 'SUPPL ', 'submission_number': 9}
80,260	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZOSYN safely and effectively. See full prescribing information for ZOSYN. ZOSYN® (piperacillin and tazobactam) injection, for intravenous use Initial U.S. approval: 1993 -------------------------- INDICATIONS AND USAGE----------------------------- ZOSYN is a combination of piperacillin, a penicillin-class antibacterial and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of: • Intra-abdominal infections in adult and pediatric patients 2 months of age and older (1.1) • Nosocomial pneumonia in adult and pediatric patients 2 months of age and older (1.2) • Skin and skin structure infections in adults (1.3) • Female pelvic infections in adults (1.4) • Community-acquired pneumonia in adults (1.5) To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.6) -------------------------- DOSAGE AND ADMINISTRATION ------------------- • If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. (2.1) • Adult Patients With Indications Other Than Nosocomial Pneumonia; The usual daily dosage of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam). (2.2) • Adult Patients with Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam). (2.3) • Adult Patients with Renal Impairment: Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients should be reduced, based on the degree of renal impairment. (2.4) • Pediatric Patients by Indication and Age: See Table below (2.5) Recommended Dosage of ZOSYN for Pediatric Patients 2 months of Age and Older, Weighing up to 40 Kg and With Normal Renal Function Age Appendicitis and /or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 (six) hours Older than 9 months 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 (six) hours • Administer ZOSYN by intravenous infusion over 30 minutes to both adult and pediatric patients (2.2, 2.3, 2.4, 2.5). • ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. (2.7) • See the full prescribing information for the preparation and administration instructions for ZOSYN Injection in GALAXY Containers. -------------------------- DOSAGE FORMS AND STRENGTHS----------------- ZOSYN® Injection: 2.25 g in 50 mL, 3.375 g in 50 mL, and 4.5 g in 100 mL frozen solution in single-dose GALAXY Containers. (3, 16) ---------------------------WARNINGS AND PRECAUTIONS -------------------- • Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving ZOSYN. Discontinue ZOSYN if a reaction occurs. (5.1) • ZOSYN may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Discontinue ZOSYN for progressive rashes. (5.2) • Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of ZOSYN. If HLH is suspected, discontinue ZOSYN immediately. (5.3) • Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. (5.4) • As with other penicillins, ZOSYN may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. (5.5) • Nephrotoxicity in critically ill patients has been observed; the use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN. (5.6) • Clostridioides difficile-associated diarrhea: evaluate patients if diarrhea occurs. (5.8) -------------------------------- ADVERSE REACTIONS ----------------------------- The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache, and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------- DRUG INTERACTIONS ----------------------------- • ZOSYN administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. (7.1) • Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with ZOSYN unless the benefit outweighs the risk. (7.2) • Co-administration of ZOSYN with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving ZOSYN and vancomycin. (7.3) • Monitor coagulation parameters in patients receiving ZOSYN and heparin or oral anticoagulants. (7.4) • ZOSYN may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. (7.5) ---------------------------USE IN SPECIFIC POPULATIONS -------------------- Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) should be reduced based on the degree of renal impairment. (2.4, 8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 -------------------------- CONTRAINDICATIONS ---------------------------------- Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. (4) 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* 6.2 Postmarketing Experience 6.3 Additional Experience with Piperacillin 1 INDICATIONS AND USAGE 7 DRUG INTERACTIONS 1.1 Intra-abdominal Infections 7.1 Aminoglycosides 1.2 Nosocomial Pneumonia 7.2 Probenecid 1.3 Skin and Skin Structure Infections 7.3 Vancomycin 1.4 Female Pelvic Infections 7.4 Anticoagulants 1.5 Community-acquired Pneumonia 7.5 Vecuronium 1.6 Usage 7.6 Methotrexate 2 2.1 DOSAGE AND ADMINISTRATION Important Administration Instructions 7.7 8 Effects on Laboratory Tests USE IN SPECIFIC POPULATIONS 2.2 Dosage in Adult Patients With Indications Other Than Nosocomial 8.1 Pregnancy Pneumonia 8.2 Lactation 2.3 Dosage in Adult Patients With Nosocomial Pneumonia 8.4 Pediatric Use 2.4 Dosage in Adult Patients With Renal Impairment 8.5 Geriatric Use 2.5 Dosage in Pediatric Patients With Appendicitis/Peritonitis or 8.6 Renal Impairment Nosocomial Pneumonia 8.7 Hepatic Impairment 2.6 Directions for Use of ZOSYN Injection 8.8 Patients with Cystic Fibrosis 2.7 Compatibility With Aminoglycosides 10 OVERDOSAGE 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Hypersensitivity Adverse Reactions 12.2 Pharmacodynamics 5.2 Severe Cutaneous Adverse Reactions 12.3 Pharmacokinetics 5.3 Hemophagocytic Lymphohistiocytosis 12.4 Microbiology 5.4 Hematologic Adverse Reactions 13 NONCLINICAL TOXICOLOGY 5.5 Central Nervous System Adverse Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Nephrotoxicity in Critically Ill Patients 15 REFERENCES 5.7 Electrolyte Effects 16 HOW SUPPLIED/STORAGE AND HANDLING 5.8 Clostridioides difficile-Associated Diarrhea 17 PATIENT COUNSELING INFORMATION 5.9 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Sections or subsections omitted from the full prescribing information are not listed. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Intra-abdominal Infections ZOSYN is indicated in adults and pediatric patients (2 months of age and older) for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. 1.2 Nosocomial Pneumonia ZOSYN is indicated in adults and pediatric patients (2 months of age and older) for the treatment of nosocomial pneumonia (moderate to severe) caused by beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin and tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2)]. 1.3 Skin and Skin Structure Infections ZOSYN is indicated in adults for the treatment of uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by beta-lactamase producing isolates of Staphylococcus aureus. 1.4 Female Pelvic Infections ZOSYN is indicated in adults for the treatment of postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of Escherichia coli. 1.5 Community-acquired Pneumonia ZOSYN is indicated in adults for the treatment of community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of Haemophilus influenzae. 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. 2.2 Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of ZOSYN for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of ZOSYN treatment is from 7 to 10 days. 2.3 Dosage in Adult Patients With Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of ZOSYN treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated. 2.4 Dosage in Adult Patients With Renal Impairment In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced based on the degree of renal impairment. The recommended daily dosage of ZOSYN for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Recommended Dosage of ZOSYN in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam)# Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia Greater than 40 mL/min 3.375 every 6 hours 4.5 every 6 hours 20 to 40 mL/min 2.25 every 6 hours 3.375 every 6 hours Less than 20 mL/min* 2.25 every 8 hours 2.25 every 6 hours Hemodialysis** 2.25 every 12 hours 2.25 every 8 hours CAPD 2.25 every 12 hours 2.25 every 8 hours # Administer ZOSYN by intravenous infusion over 30 minutes. * Creatinine clearance for patients not receiving hemodialysis ** 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g ZOSYN (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of ZOSYN is necessary for CAPD patients. 2.5 Dosage in Pediatric Patients With Appendicitis/Peritonitis or Nosocomial Pneumonia The recommended dosage for pediatric patients with appendicitis and/or peritonitis or nosocomial pneumonia aged 2 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table 2 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2: Recommended Dosage of ZOSYN in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function#, ## Age Appendicitis and/or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 (six) hours Older than 9 months of age 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 (eight) hours every 6 (six) hours # Administer ZOSYN by intravenous infusion over 30 minutes ## If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered [see Use in Specific Populations (8.4)]. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose [see Dosage and Administration (2.2, 2.3)]. Dosage of ZOSYN in pediatric patients with renal impairment has not been determined. 2.6 Directions for Use of ZOSYN Injection Important Administration Instructions for ZOSYN Injection in GALAXY Containers Administer ZOSYN Injection in GALAXY Containers using sterile equipment, after thawing to room temperature. ZOSYN containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer’s injection, USP. Do NOT add supplementary medication. Unused portions of ZOSYN Injection should be discarded. Do NOT use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Handle frozen product containers with care. Product containers may be fragile in the frozen state. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thawing of Plastic Container Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]). Do not force thaw by immersion in water baths or by microwave irradiation. Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. The container should be visually inspected. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded. Administration Instructions for ZOSYN Injection in GALAXY Containers to Adult Patients Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution. Administration Instruction for ZOSYN Injection in GALAXY Containers to Pediatric Patients Weighing up to 40 kg If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. Storage of ZOSYN Injection Store in a freezer capable of maintaining a temperature of -20°C (-4°F). For GALAXY Containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F]. Do not refreeze thawed ZOSYN Injection. 2.7 Compatibility With Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)]. In circumstances where co-administration via Y-site is necessary, ZOSYN formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3: Compatibility with Aminoglycosides Aminoglycoside ZOSYN Dose (grams) Aminoglycoside Concentration Range a (mg/mL) Acceptable Diluents 2.25 Amikacin 3.375 1.75 - 7.5 0.9% sodium chloride or 5% dextrose 4.5 2.25 Gentamicin 3.375b 0.7 - 3.32 0.9% sodium chloride or 5% dextrose 4.5 a The concentration ranges in Table 3 are based on administration of the aminoglycoside in divided doses (10- 15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y- site with ZOSYN containing EDTA has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. b ZOSYN 3.375 g per 50 mL GALAXY Containers are NOT compatible with gentamicin for co-administration via a Y-site due to the higher concentrations of piperacillin and tazobactam. Only the concentration and diluents for amikacin or gentamicin with the dosages of ZOSYN listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by ZOSYN. ZOSYN is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of ZOSYN with other aminoglycosides has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 3 DOSAGE FORMS AND STRENGTHS ZOSYN® (piperacillin and tazobactam) Injection is supplied in GALAXY Containers as a frozen, iso-osmotic, sterile, non-pyrogenic solution in single-dose plastic containers: 2.25 g (piperacillin sodium equivalent to 2 g piperacillin and tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL. 3.375 g (piperacillin sodium equivalent to 3 g piperacillin and tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4.5 g (piperacillin sodium equivalent to 4 g piperacillin and tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL. 4 CONTRAINDICATIONS ZOSYN is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Adverse Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with ZOSYN. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with ZOSYN, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, ZOSYN should be discontinued and appropriate therapy instituted. 5.2 Severe Cutaneous Adverse Reactions ZOSYN may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and ZOSYN discontinued if lesions progress. 5.3 Hemophagocytic Lymphohistiocytosis Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with ZOSYN. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue ZOSYN immediately and institute appropriate management. 5.4 Hematologic Adverse Reactions Bleeding manifestations have occurred in some patients receiving beta-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, ZOSYN should be discontinued and appropriate therapy instituted. The leukopenia/neutropenia associated with ZOSYN administration appears to be reversible and most frequently associated with prolonged administration. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., ≥ 21 days [see Adverse Reactions (6.1)]. 5.5 Central Nervous System Adverse Reactions As with other penicillins, ZOSYN may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures [see Adverse Reactions (6.2)]. 5.6 Nephrotoxicity in Critically Ill Patients The use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients [see Adverse Reactions (6.1)]. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN [see Dosage and Administration (2.4)]. Combined use of piperacillin and tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3)]. 5.7 Electrolyte Effects ZOSYN contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics. 5.8 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ZOSYN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.9 Development of Drug-Resistant Bacteria Prescribing ZOSYN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Adverse Reactions [see Warnings and Precautions (5.1)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] • Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.3)] • Hematologic Adverse Reactions [see Warnings and Precautions (5.4)] • Central Nervous System Adverse Reactions [see Warnings and Precautions (5.5)] • Nephrotoxicity in Critically Ill Patients [see Warnings and Precautions (5.6)] • Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Patients During the initial clinical investigations, 2621 patients worldwide were treated with ZOSYN in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, ZOSYN was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%). Table 4: Adverse Reactions from ZOSYN Monotherapy Clinical Trials System Organ Class Adverse Reaction Gastrointestinal disorders Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4: Adverse Reactions from ZOSYN Monotherapy Clinical Trials System Organ Class Adverse Reaction Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%) General disorders and administration site conditions Fever (2.4%) Injection site reaction (≤1%) Rigors (≤1%) Immune system disorders Anaphylaxis (≤1%) Infections and infestations Candidiasis (1.6%) Pseudomembranous colitis (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Musculoskeletal and connective tissue disorders Myalgia (≤1%) Arthralgia (≤1%) Nervous system disorders Headache (7.7%) Psychiatric disorders Insomnia (6.6%) Skin and subcutaneous tissue disorders Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) Purpura (≤1%) 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4: Adverse Reactions from ZOSYN Monotherapy Clinical Trials System Organ Class Adverse Reaction Vascular disorders Phlebitis (1.3%) Thrombophlebitis (≤1%) Hypotension (≤1%) Flushing (≤1%) Respiratory, thoracic and mediastinal disorders Epistaxis (≤1%) Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with ZOSYN in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 6 hours) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin and tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin and tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event. The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside. Table 5: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trialsa System Organ Class Adverse Reaction Blood and lymphatic system disorders Thrombocythemia (1.4%) Anemia (≤1%) Thrombocytopenia (≤1%) Eosinophilia (≤1%) Gastrointestinal disorders Diarrhea (20%) Constipation (8.4%) Nausea (5.8%) Vomiting (2.7%) Dyspepsia (1.9%) Abdominal pain (1.8%) 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 5: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trialsa System Organ Class Adverse Reaction Stomatitis (≤1%) General disorders and administration site conditions Fever (3.2%) Injection site reaction (≤1%) Infections and infestations Oral candidiasis (3.9%) Candidiasis (1.8%) Investigations BUN increased (1.8%) Blood creatinine increased (1.8%) Liver function test abnormal (1.4%) Alkaline phosphatase increased (≤1%) Aspartate aminotransferase increased (≤1%) Alanine aminotransferase increased (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Hypokalemia (≤1%) Nervous system disorders Headache (4.5%) Psychiatric disorders Insomnia (4.5%) Renal and urinary disorders Renal failure (≤1%) Skin and subcutaneous tissue disorders Rash (3.9%) Pruritus (3.2%) Vascular disorders Thrombophlebitis (1.3%) Hypotension (1.3%) a For adverse drug reactions that appeared in both studies the higher frequency is presented. 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other Trials: Nephrotoxicity In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin and tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs1 [see Warnings and Precautions (5.6)]. Adverse Laboratory Changes (Seen During Clinical Trials) Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of ZOSYN was used in combination with an aminoglycoside, changes in laboratory parameters include: Hematologic—decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills) Coagulation—positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time Hepatic—transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin Renal—increases in serum creatinine, blood urea nitrogen Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged. Clinical Trials in Pediatric Patients Clinical studies of ZOSYN in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients, 2 to 12 years of age, with intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with ZOSYN 112.5 mg/kg given IV every 8 hours and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the ZOSYN group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the ZOSYN group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event. In a retrospective, cohort study, 140 pediatric patients 2 months to less than 18 years of age with nosocomial pneumonia were treated with ZOSYN and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ciprofloxacin). The rates of serious adverse reactions were generally similar between the ZOSYN and comparator groups, including patients aged 2 months to 9 months treated with ZOSYN 90 mg/kg IV every 6 hours and patients older than 9 months and less than 18 years of age treated with ZOSYN 112.5 mg/kg IV every 6 hours. 6.2 Postmarketing Experience In addition to the adverse drug reactions identified in clinical trials in Table 4 and Table 5, the following adverse reactions have been identified during post-approval use of ZOSYN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary—hepatitis, jaundice Hematologic—hemolytic anemia, agranulocytosis, pancytopenia Immune—hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), hemophagocytic lymphohistiocytosis (HLH), acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction. Renal—interstitial nephritis Nervous system disorders—seizures Psychiatric disorders—delirium Respiratory—eosinophilic pneumonia Skin and Appendages—erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative, and linear IgA bullous dermatosis. Postmarketing experience with ZOSYN in pediatric patients suggests a similar safety profile to that seen in adults. 6.3 Additional Experience with Piperacillin The following adverse reaction has also been reported for piperacillin for injection: Skeletal—prolonged neuromuscular blockade [see Drug Interactions (7.5)]. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 DRUG INTERACTIONS 7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of ZOSYN and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary. In vitro inactivation: Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. ZOSYN, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. ZOSYN is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.7)]. 7.2 Probenecid Probenecid administered concomitantly with ZOSYN prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with ZOSYN unless the benefit outweighs the risk. 7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone [see Warnings and Precautions (5.6)]. Monitor kidney function in patients concomitantly administered with piperacillin and tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7.4 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [see Warnings and Precautions (5.4)]. 7.5 Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. ZOSYN could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing neuromuscular blockers could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide). 7.6 Methotrexate Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored. 7.7 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin and tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. As with other penicillins, the administration of ZOSYN may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST®). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mice when piperacillin and tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m2) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin and tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m2). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m2). A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin and tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin and tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area). Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin and tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21. 8.2 Lactation Risk Summary Piperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breast- 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOSYN and any potential adverse effects on the breastfed child from ZOSYN or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ZOSYN for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older. Use of ZOSYN in pediatric patients 2 months of age and older with intra-abdominal infections including appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2 to 12 years of age with intra-abdominal infections (including appendicitis and/or peritonitis), in which 273 pediatric patients received piperacillin and tazobactam [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Use of ZOSYN in pediatric patients 2 months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, a simulation study performed with a population pharmacokinetic model, and a retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with ZOSYN and 267 patients treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of ZOSYN Injection supplied in GALAXY Containers, and to avoid unintentional overdose, this product is not recommended for use if a dose of ZOSYN Injection in GALAXY Containers that does not equal 2.25 g, 3.375 g, or 4.5 g is required and an alternative formulation of ZOSYN should be considered [see Dosage and Administration (2.1, 2.5, and 2.6)]. The safety and effectiveness of ZOSYN have not been established in pediatric patients less than 2 months of age [see Clinical Pharmacology (12) and Dosage and Administration (2)]. Dosage of ZOSYN in pediatric patients with renal impairment has not been determined. 8.5 Geriatric Use Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment [see Dosage and Administration (2)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ZOSYN contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced to the degree of renal function impairment [see Dosage and Administration (2)]. 8.7 Hepatic Impairment Dosage adjustment of ZOSYN is not warranted in patients with hepatic cirrhosis [see Clinical Pharmacology (12.3)]. 8.8 Patients with Cystic Fibrosis As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients. 10 OVERDOSAGE There have been postmarketing reports of overdose with piperacillin and tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or seizures if higher than recommended doses are given intravenously (particularly in the presence of renal failure) [see Warnings and Precautions (5.5)]. Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin and tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively [see Clinical Pharmacology (12)]. 11 DESCRIPTION 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ZOSYN (piperacillin and tazobactam) Injection is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the beta-lactamase inhibitor tazobactam sodium for intravenous administration. Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine- carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylate. The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is: Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is: ZOSYN Injection in the GALAXY Container is a frozen iso-osmotic sterile non-pyrogenic premixed solution. The components and dosage formulations are given in the table below: Table 6: ZOSYN In GALAXY Containers Premixed Frozen Solution Component* Function Dosage Formulations 2.25 g/50 mL 3.375 g/50 mL 4.5 g/100 mL Piperacillin active ingredient 2 g 3 g 4 g Tazobactam beta-lactamase inhibitor 250 mg 375 mg 500 mg Dextrose Hydrous osmolality adjusting agent 1 g 350 mg 2 g 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Component* Function Dosage Formulations 2.25 g/50 mL 3.375 g/50 mL 4.5 g/100 mL Sodium Citrate Dihydrate buffering agent 100 mg 150 mg 200 mg Edetate Disodium Dihydrate metal chelator 0.5 mg 0.75 mg 1 mg Water for Injection solvent q.s. 50 mL q.s. 50 mL q.s. 100 mL Piperacillin and tazobactam are present in the formulation as sodium salts. Dextrose hydrous, sodium citrate dihydrate, and edetate disodium dihydrate amounts are approximate. ZOSYN contains a total of 2.84 mEq (65 mg) of sodium (Na+) per gram of piperacillin in the combination product. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ZOSYN is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The pharmacodynamic parameter for piperacillin and tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC. 12.3 Pharmacokinetics The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 7. 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7: Mean (CV%) Piperacillin and Tazobactam PK Parameters Piperacillin Piperacillin and Tazobactam Dosea Cmax (mcg/mL) AUCb (mcg•h/mL) CL (mL/min) V (L) T1/2 (h) CLR (mL/min) 2.25 g 134 131 [14] 257 17.4 0.79 -- 3.375 g 242 242 [10] 207 15.1 0.84 140 4.5 g 298 322 [16] 210 15.4 0.84 -- Tazobactam Piperacillin and Tazobactam Cmax AUCb CL V T1/2 CLR Dosea (mcg/mL) (mcg•h/mL) (mL/min) (L) (h) (mL/min) 2.25 g 15 16.0 [21] 258 17.0 0.77 -- 3.375 g 24 25.0 [8] 251 14.8 0.68 166 4.5 g 34 39.8 [15] 206 14.7 0.82 -- a Piperacillin and tazobactam were given in combination, infused over 30 minutes. b Numbers in []parentheses are coefficients of variation [CV%]. Cmax : maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance V=volume of distribution, T1/2 = elimination half-life Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of ZOSYN. Piperacillin plasma concentrations, following a 30-minute infusion of ZOSYN, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam. Distribution Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 8). Table 8: Piperacillin and Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of ZOSYN Tissue or Fluid Na Sampling periodb (h) Mean PIP Concentration Range (mg/L) Tissue:Plasma Range Tazo Concentration Range (mg/L) Tazo Tissue:Plasma Range Skin 35 0.5 – 4.5 34.8 – 94.2 0.60 – 1.1 4.0 – 7.7 0.49 – 0.93 Fatty Tissue 37 0.5 – 4.5 4.0 – 10.1 0.097 – 0.115 0.7 – 1.5 0.10 – 0.13 Muscle 36 0.5 – 4.5 9.4 – 23.3 0.29 – 0.18 1.4 – 2.7 0.18 – 0.30 Proximal Intestinal Mucosa 7 1.5 – 2.5 31.4 0.55 10.3 1.15 Distal Intestinal Mucosa 7 1.5 – 2.5 31.2 0.59 14.5 2.1 Appendix 22 0.5 – 2.5 26.5 – 64.1 0.43 – 0.53 9.1 – 18.6 0.80 – 1.35 a Each subject provided a single sample. b Time from the start of the infusion Metabolism Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Excretion Following single or multiple ZOSYN doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile. 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Specific Populations Renal Impairment After the administration of single doses of piperacillin and tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for ZOSYN are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of ZOSYN. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal-impairment. Hemodialysis removes 30% to 40% of a piperacillin and tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2)]. Hepatic Impairment The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of ZOSYN due to hepatic cirrhosis. Pediatrics Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults. In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 - 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) L/kg and is independent of age. Geriatrics The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 - 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Race The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses. Drug Interactions The potential for pharmacokinetic drug interactions between ZOSYN and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)]. 12.4 Microbiology Mechanism of Action Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a beta-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen. Antimicrobial Activity ZOSYN has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (methicillin susceptible isolates only) Gram-negative bacteria Acinetobacter baumannii Escherichia coli Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates) Klebsiella pneumoniae Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible) Anaerobic bacteria Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus) 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZOSYN in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria Gram-positive bacteria Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin susceptible isolates only) Streptococcus agalactiae† Streptococcus pneumoniae† (penicillin-susceptible isolates only) Streptococcus pyogenes† Viridans group streptococci† Gram-negative bacteria Citrobacter koseri Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Serratia marcescens Providencia stuartii Providencia rettgeri Salmonella enterica Anaerobic bacteria Clostridium perfringens Bacteroides distasonis Prevotella melaninogenica † These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in animals have not been conducted with piperacillin and tazobactam, piperacillin, or tazobactam. Mutagenesis Piperacillin and tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin and tazobactam did not induce chromosomal aberrations in rats. Fertility Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin and tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m2). 15 REFERENCES 1. Jensen J-US, Hein L, Lundgren B, et al. BMJ Open 2012; 2:e000635. doi:10.1136. 16 HOW SUPPLIED/STORAGE AND HANDLING ZOSYN® (piperacillin and tazobactam) Injection in GALAXY Containers are supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in single-dose plastic containers as follows: • 2.25 g (piperacillin sodium equivalent to 2 g piperacillin and tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL. Each container has 5.58 mEq (128 mg) of sodium. Supplied 24/box—NDC 0338-9632-24 • 3.375 g (piperacillin sodium equivalent to 3 g piperacillin and tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL. Each container has 8.38 mEq (192 mg) of sodium. Supplied 24/box—NDC 0338-9636-24 • 4.5 g (piperacillin sodium equivalent to 4 g piperacillin and tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL. Each container has 11.17 mEq (256 mg) of sodium. Supplied 12/box—NDC 0338-9638-12 ZOSYN® Injection in GALAXY Containers should be stored at or below -20°C (-4°F) [see Dosage and Administration (2.6)]. Handle frozen product containers with care. Product containers may be fragile in the frozen state. 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 PATIENT COUNSELING INFORMATION Serious Hypersensitivity Reactions Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur with use of ZOSYN that require immediate treatment. Ask them about any previous hypersensitivity reactions to ZOSYN, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2)]. Hemophagocytic Lymphohistiocytosis Prior to initiation of treatment with ZOSYN, inform patients that excessive immune activation may occur with ZOSYN and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately [see Warnings and Precautions (5.3)]. Diarrhea Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including ZOSYN, which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.8)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs including ZOSYN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZOSYN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZOSYN or other antibacterial drugs in the future. Pregnancy and Lactation Patients should be counseled that ZOSYN can cross the placenta in humans and is excreted in human milk [see Use in Specific Populations (8.1, 8.2)]. Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in USA 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter, Galaxy and Zosyn are trademarks of Baxter International Inc. or its subsidiaries. Clinitest is a registered trademark of Siemens Healthcare Diagnostics Inc. 07-19-07-565 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration 2° to 8°C (36° to 46°F) or 24 hours at room temperature 20° to 25°C (68° to 77°F). Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA GALAXY Container Each 50 mL contains: Piperacillin Sodium equivalent to 2 g Piperacillin and Tazobactam Sodium equivalent to 0.25 g Tazobactam in Water for Injection. Approximately 1 g Dextrose Hydrous added to adjust osmolality. Approximately 100 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.5 mg Edetate Disodium Dihydrate added as a metal chelator. Dosage and Use: For intravenous use only. As directed by a physician. See package insert. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration 2° to 8°C (36° to 46°F) or 24 hours at room temperature 20° to 25°C (68° to 77°F). Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA GTIN: 20303389632249 07-04-00-1383 2 x 12 x 50 mL Single Dose Containers Contains 2 boxes of 12 of NDC 0338-9632-01 Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. NDC 0338-9632-24 Contains 24 of NDC 0338-9632-01 Code 2G3582 2 x 12 x 50 mL Single Dose Containers Contains 2 boxes of 12 of NDC 0338-9632-01 Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. NDC 0338-9632-24 Contains 24 of NDC 0338-9632-01 Code 2G3582 Sterile Nonpyrogenic GALAXY Container Each 50 mL contains: Piperacillin Sodium equivalent to 2 g Piperacillin and Tazobactam Sodium equivalent to 0.25 g Tazobactam in Water for Injection. Approximately 1 g Dextrose Hydrous added to adjust osmolality. Approximately 100 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.5 mg Edetate Disodium Dihydrate added as a metal chelator. Dosage and Use: For intravenous use only. As directed by a physician. See package insert. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear. Sterile Nonpyrogenic BAR CODE POSITION ONLY (01) 20303389632249 * BAR CODE POSITION ONLY (01) 20303389632249 GTIN: 20303389632249 07-04-00-1383 Rx only Rx only ZOSYN Piperacillin and Tazobactam Injection 2.25 g ZOSYN Piperacillin and Tazobactam Injection 2.25 g This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration 2° to 8°C (36° to 46°F) or 24 hours at room temperature 20° to 25°C (68° to 77°F). Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA GALAXY Container Each 50 mL contains: Piperacillin Sodium equivalent to 3 g Piperacillin and Tazobactam Sodium equivalent to 0.375 g Tazobactam in Water for Injection. Approximately 350 mg Dextrose Hydrous added to adjust osmolality. Approximately 150 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.75 mg Edetate Disodium Dihydrate added as a metal chelator. Dosage and Use: For intravenous use only. As directed by a physician. See package insert. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration 2° to 8°C (36° to 46°F) or 24 hours at room temperature 20° to 25°C (68° to 77°F). Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA GTIN: 20303389636247 07-04-00-1382 2 x 12 x 50 mL Single Dose Containers Contains 2 boxes of 12 of NDC 0338-9636-01 Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. NDC 0338-9636-24 Contains 24 of NDC 0338-9636-01 Code 2G3583 2 x 12 x 50 mL Single Dose Containers Contains 2 boxes of 12 of NDC 0338-9636-01 Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. NDC 0338-9636-24 Contains 24 of NDC 0338-9636-01 Code 2G3583 Sterile Nonpyrogenic Sterile Nonpyrogenic * BAR CODE POSITION ONLY (01) 20303389636247 * BAR CODE POSITION ONLY (01) 20303389636247 GTIN: 20303389636247 07-04-00-1382 GALAXY Container Each 50 mL contains: Piperacillin Sodium equivalent to 3 g Piperacillin and Tazobactam Sodium equivalent to 0.375 g Tazobactam in Water for Injection. Approximately 350 mg Dextrose Hydrous added to adjust osmolality. Approximately 150 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.75 mg Edetate Disodium Dihydrate added as a metal chelator. Dosage and Use: For intravenous use only. As directed by a physician. See package insert. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear. Rx only Rx only ZOSYN Piperacillin and Tazobactam Injection 3.375 g ZOSYN Piperacillin and Tazobactam Injection 3.375 g This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GALAXY Container Each 100 mL contains: Piperacillin Sodium equivalent to 4 g Piperacillin and Tazobactam Sodium equivalent to 0.5 g Tazobactam in Water for Injection. Approximately 2 g Dextrose Hydrous added to adjust osmolality. Approximately 200 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 100 mL also contains approximately 1 mg Edetate Disodium Dihydrate added as a metal chelator. Dosage and Use: For intravenous use only. As directed by a physician. See package insert. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration 2° to 8°C (36° to 46°F) or 24 hours at room temperature 20° to 25°C (68° to 77°F). Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA GTIN: 20303389638128 07-04-00-1381 2 x 6 x 100 mL Single Dose Containers Contains 2 boxes of 6 of NDC 0338-9638-01 Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. NDC 0338-9638-12 Contains 12 of NDC 0338-9638-01 Code 2G3584 2 x 6 x 100 mL Single Dose Containers Contains 2 boxes of 6 of NDC 0338-9638-01 Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. Sterile Nonpyrogenic Sterile Nonpyrogenic * BAR CODE POSITION ONLY (01) 20303389638128 * BAR CODE POSITION ONLY (01) 20303389638128 Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration 2° to 8°C (36° to 46°F) or 24 hours at room temperature 20° to 25°C (68° to 77°F). Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA GTIN: 20303389638128 07-04-00-1381 NDC 0338-9638-12 Contains 12 of NDC 0338-9638-01 Code 2G3584 GALAXY Container Each 100 mL contains: Piperacillin Sodium equivalent to 4 g Piperacillin and Tazobactam Sodium equivalent to 0.5 g Tazobactam in Water for Injection. Approximately 2 g Dextrose Hydrous added to adjust osmolality. Approximately 200 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 100 mL also contains approximately 1 mg Edetate Disodium Dihydrate added as a metal chelator. Dosage and Use: For intravenous use only. As directed by a physician. See package insert. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear. Piperacillin and Tazobactam Injection ZOSYN 4.5 g Rx only Piperacillin and Tazobactam Injection ZOSYN 4.5 g Rx only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50 mL Iso-osmotic Store at or below -20°C/-4°F. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration or 24 hours at room temperature. Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Dosage and Use: For intravenous use only. As directed by a physician. See Package Insert. Cautions: Do not add supplementary medication or additives. Must not be used in series connections. Check for minute leaks and solution clarity. Each 50 mL contains: Piperacillin Sodium equivalent to 2 g Piperacillin and Tazobactam Sodium equivalent to 0.25 g Tazobactam in Water for Injection. Approximately 1 g Dextrose Hydrous added to adjust osmolality. Approximately 100 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.5 mg Edetate Disodium Dihydrate added as a metal chelator. NDC 0338-9632-01 Single Dose Container Code 2G3582 Sterile Nonpyrogenic Rx only 07-34-00-2323 Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA 3 03389 63201 6 ZOSYN Piperacillin and Tazobactam Injection 2.25 g This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50 mL Iso-osmotic Store at or below -20°C/-4°F. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration or 24 hours at room temperature. Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Dosage and Use: For intravenous use only. As directed by a physician. See Package Insert. Cautions: Do not add supplementary medication or additives. Must not be used in series connections. Check for minute leaks and solution clarity. Each 50 mL contains: Piperacillin Sodium equivalent to 3 g Piperacillin and Tazobactam Sodium equivalent to 0.375 g Tazobactam in Water for Injection. Approximately 350 mg Dextrose Hydrous added to adjust osmolality. Approximately 150 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.75 mg Edetate Disodium Dihydrate added as a metal chelator. NDC 0338-9636-01 Single Dose Container Code 2G3583 Sterile Nonpyrogenic Rx only 07-34-00-2322 Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA 3 03389 63601 4 ZOSYN Piperacillin and Tazobactam Injection 3.375 g This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 100 mL Iso-osmotic Store at or below -20°C/-4°F. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration or 24 hours at room temperature. Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Dosage and Use: For intravenous use only. As directed by a physician. See Package Insert. Cautions: Do not add supplementary medication or additives. Must not be used in series connections. Check for minute leaks and solution clarity. Each 100 mL contains: Piperacillin Sodium equivalent to 4 g Piperacillin and Tazobactam Sodium equivalent to 0.5 g Tazobactam in Water for Injection. Approximately 2 g Dextrose Hydrous added to adjust osmolality. Approximately 200 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 100 mL also contains approximately 1 mg Edetate Disodium Dihydrate added as a metal chelator. NDC 0338-9638-01 Single Dose Container Code 2G3584 Sterile Nonpyrogenic Rx only 07-34-00-2321 Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA 3 03389 63801 8 Piperacillin and Tazobactam Injection ZOSYN 4.5 g This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda David Lewis Digitally signed by David Lewis Date: 11/19/2024 07:58:08AM GUID: 508da72000029f287fa31e664741b577 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T15:46:50.354206	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/050750Orig1s054lbl.pdf', 'application_number': 50750, 'submission_type': 'SUPPL ', 'submission_number': 54}
80,261	CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761416Orig1s000 LABELING FULL PRESCRIBING INFORMATION WARNING: EMBRYO-FETAL TOXICITY Embryo-Fetal Toxicity: Exposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. 1 INDICATIONS AND USAGE ZIIHERA is indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for treatment of unresectable or metastatic biliary tract cancer based on HER2- positive (IHC 3+) tumor specimens, as detected by an FDA-approved test [see Clinical Studies (14)]. Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Premedications Premedicate all patients 30 to 60 minutes prior to each dose of ZIIHERA to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.3)]: x Administer acetaminophen, an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone). 2.3 Recommended Dosage Recommended Dosage and Administration The recommended dosage of ZIIHERA is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until disease progression or unacceptable toxicity. Missed dose If a planned dose of ZIIHERA is delayed or missed, administer the dose as soon as possible; do not wait until the next planned dose. Adjust the administration schedule to maintain a 2-week interval between doses. 2.4 Dosage Modifications for Adverse Reactions x The recommended dosage reduction of ZIIHERA for adverse reactions is 15 mg/kg as described in Table 1. x Permanently discontinue ZIIHERA in patients who cannot tolerate 15 mg/kg. Reference ID: 5482738 Table 1 Dosage Modifications for Adverse Reactions Adverse Reaction Severity Treatment Modification Left Ventricular Dysfunction (LVD) [see Warnings and Precautions (5.2)] Absolute decrease of 16% points in LVEF from pre-treatment baseline or LVEF 50% and absolute decrease of 10% points below pre-treatment baseline x Withhold ZIIHERA for at least 4 weeks. x Repeat LVEF assessment within 4 weeks. x Resume ZIIHERA treatment within 4 to 8 weeks if LVEF returns to normal limits and the absolute decrease is 15% points from baseline. x Permanently discontinue ZIIHERA if LVEF has not recovered to within 15% points from pre- treatment baseline. Confirmed symptomatic congestive heart failure x Permanently discontinue ZIIHERA. Infusion-Related Reactions [see Warnings and Precautions (5.3)] Mild (Grade 1) x Reduce ZIIHERA infusion rate by 50%. x For subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated. Moderate (Grade 2) x Stop ZIIHERA infusion immediately. x Treat with appropriate therapy. x Resume ZIIHERA infusion at 50% of previous infusion rate once symptoms resolve. x For subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated. Severe (Grade 3) x Stop ZIIHERA infusion immediately. x Promptly treat with appropriate therapy; infusion should not be restarted during the same cycle even if signs and symptoms completely resolve. x Subsequent ZIIHERA infusions should be administered at 50% of previous infusion rate. x Permanently discontinue ZIIHERA for recurrent Grade 3 reaction. Life threatening (Grade 4) x Stop ZIIHERA infusion immediately and permanently discontinue. x Promptly treat with appropriate therapy. Reference ID: 5482738 Adverse Reaction Severity Treatment Modification Diarrhea [see Warnings and Precautions (5.4)] Mild/Moderate (Grade 1 or 2) x No dose modification of ZIIHERA is required. x Initiate appropriate medical therapy and monitor as clinically indicated. Severe (Grade 3) x Withhold ZIIHERA treatment until severity improves to Grade 1. x Initiate or intensify appropriate medical therapy and monitor as clinically indicated. x Administer subsequent ZIIHERA treatment at the same dose level or consider dose reduction to 15 mg/kg. x For recurrent Grade 3 symptoms, withhold ZIIHERA treatment and ensure medical management has been optimized. o Resume ZIIHERA treatment at a reduced dose of 15 mg/kg after severity improves to Grade 1. o Permanently discontinue ZIIHERA for recurrent Grade 3 symptoms that last > 3 days despite optimized medical management. Life threatening (Grade 4) x Permanently discontinue ZIIHERA Pneumonitis [see Adverse Reactions (6.1)] Confirmed Grade 2 x Permanently discontinue ZIIHERA. Other Adverse Reactions (excluding LVD, IRR, Diarrhea, and Pneumonitis) [see Adverse Reactions (6.1)] Mild/Moderate (Grades 1/2) x No dosage modification is required for ZIIHERA. x Initiate appropriate medical therapy and monitor as clinically indicated. Severe (Grade 3) x Withhold ZIIHERA treatment until severity improves to Grade 1. x Initiate appropriate medical therapy and monitor as clinically indicated. x Administer subsequent ZIIHERA treatment at the same dose; consider dose reduction to 15 mg/kg if Grade 3 symptoms recur. Life Threatening (Grade 4) x Permanently discontinue ZIIHERA, except as noted below. x Initiate appropriate medical therapy and monitor as clinically indicated. Reference ID: 5482738 Adverse Reaction Severity Treatment Modification x ZIIHERA treatment may be resumed at the same dose level for Grade 4 electrolyte imbalances or laboratory abnormalities that are corrected within 3 days of onset; do not resume until symptoms improve to Grade 1. x Permanently discontinue ZIIHERA for recurrent Grade 4 electrolyte imbalances or laboratory abnormalities. 2.5 Preparation and Administration Instructions Administer only as an intravenous infusion after ZIIHERA is reconstituted and diluted. Reconstitution x Calculate the recommended dose based on the patient’s weight to determine the number of vials needed. x Remove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature. x Reconstitute each 300 mg vial of ZIIHERA with 5.7 mL of Sterile Water for Injection by slowly directing the stream toward the inside of the wall of the vial, to obtain a final concentration of 50 mg/mL in an extractable volume of 6 mL. x Swirl the vial gently until completely dissolved. Do not shake or vigorously swirl. x Allow the reconstituted vial to settle to allow bubbles to dissipate. x Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted product should be a colorless to light yellow, clear to slightly opalescent solution with no visible particles. Discard the reconstituted vial if any discoloration or particulate matter is observed. x The product does not contain a preservative. Use the reconstituted ZIIHERA solution immediately or store the reconstituted ZIIHERA solution for up to 4 hours, either at room temperature (18°C to 24°C [64°F to 75°F]) or in a refrigerator (2°C to 8ºC [36°F to 46ºF]). Dilution x Withdraw the necessary volume for the calculated dose from each vial [see Dosage and Administration (2.3)]. x Slowly add the necessary dose volume to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection to prepare an infusion solution with a final concentration of the diluted solution between 0.4 mg/mL and 6 mg/mL. x Gently invert the infusion bag to mix. Do not shake. x The infusion solution must be a clear, colorless solution with no visible particles. Do not use if visible particles are observed or if the solution is discolored. x Discard any unused portion left in the vial(s). Reference ID: 5482738 x Use the infusion solution immediately upon dilution or store the infusion solution at room temperature (18°C to 24°C [64°F to 75°F]) for up to 12 hours or in the refrigerator (2ºC to 8ºC [36ºF to 46ºF]) for up to 24 hours. o These time limits include the beginning of reconstitution through the duration of infusion. o If these specified times are exceeded, discontinue the current infusion bag and prepare a new bag which contains the remaining dosage of ZIIHERA to be infused. x Compatibility with intravenous administration materials and the infusion solution has been demonstrated in the following materials: o Intravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) and ethylene-propylene copolymer. o Infusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP). Polyurethane (PUR), polyethylene-lined (PE-lined) acrylonitrile-butadiene-styrene (ABS). o Inline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF). o Closed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic c- polymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone and stainless steel (SS). Administration x Administer ZIIHERA as an intravenous infusion with a 0.2 or 0.22 micron filter. x Do not administer as an intravenous push or bolus. x Do not co-administer ZIIHERA and other intravenous drugs through the same intravenous line. Table 2 : Recommended ZIIHERA Infusion Durations Dose Infusion Duration First and Second 120-150 minutes Third and Fourth 90 minutes, if previous infusions were well-tolerated Subsequent 60 minutes, if previous infusions were well-tolerated 3 DOSAGE FORMS AND STRENGTHS For injection: 300 mg white lyophilized powder in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity Based on the mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Reference ID: 5482738 Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception while receiving ZIIHERA and for 4 months following the last dose of ZIIHERA. 5.2 Left Ventricular Dysfunction ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by greater than 10% and decreased to less than 50% in 4.3% of 233 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median time to first occurrence of left ventricular dysfunction was 5.6 months (range: 1.6 to 18.7 months). Left ventricular dysfunction resolved in 70% of patients. Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of adverse reactions [see Dosage and Administration (2.4)]. The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50% [see Dosage and Administration (2.4)]. 5.3 Infusion-Related Reactions ZIIHERA can cause infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with ZIIHERA as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients. IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within one day. Prior to each dose of ZIIHERA, administer premedications to prevent potential IRRs [see Dosage and Administration (2.2)]. Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. If an IRR occurs, slow, or stop the infusion, and administer appropriate medical management. Monitor patients until complete resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening infusion-related reactions [see Dosage and Administration (2.4)]. 5.4 Diarrhea ZIIHERA can cause severe diarrhea [see Adverse Reactions (6.1)]. Diarrhea was reported in 48% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Withhold or permanently discontinue ZIIHERA based on severity [see Dosage and Administration (2.4)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of the labeling: x Embyro-Fetal Toxicity [see Warnings and Precautions (5.1)] Reference ID: 5482738 x Left Ventricular dysfunction [see Warnings and Precautions (5.2)] x Infusion-Related Reactions [see Warnings and Precautions (5.3)] x Diarrhea [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population of ZIIHERA described in WARNINGS AND PRECAUTIONS reflect exposure in 233 patients administered ZIIHERA 20 mg/kg intravenously as a single agent in two single-arm, open-label studies (ZWI-ZW25-101 and HERIZON-BTC-01), which enrolled 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received ZIIHERA, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year. Biliary Tract Cancer The safety of ZIIHERA was evaluated in 80 patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer who received at least one prior gemcitabine-containing chemotherapy regimen in HERIZON-BTC-01 [See Clinical Studies (14)]. Patients received ZIIHERA 20 mg/kg by IV infusion once every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to ZIIHERA was 5.6 months (range: 0.5 to 27.2 months). Serious adverse reactions occurred in 53% of patients who received ZIIHERA. Serious adverse reactions in > 2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received ZIIHERA. Permanent discontinuation due to an adverse reaction occurred in 2.5% of patients who received ZIIHERA. Adverse reactions which resulted in permanent discontinuation in 1% of patients who received ZIIHERA included decreased ejection fraction and pneumonitis. Dosage interruptions due to an adverse reaction, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 41% of patients who received ZIIHERA. The most frequent adverse reactions (> 2% of patients) that required dosage interruption were diarrhea, increased alanine aminotransferase, increased aspartate aminotransferase, decreased ejection fraction, pneumonia, cholangitis, fatigue, biliary obstruction, abdominal pain, increased blood creatinine, and decreased potassium. Dosage reductions due to an adverse reaction occurred in 4% of patients who received ZIIHERA. Adverse reactions requiring dosage reductions in > 1% of patients were diarrhea, nausea, and decreased weight. The most common adverse reactions in patients receiving ZIIHERA ( 20%) were diarrhea, infusion- related reaction, abdominal pain, and fatigue. Table 3 summarizes the adverse reactions that occurred in HERIZON-BTC-01. Reference ID: 5482738 Table 3: Adverse Reactions ( 15%) in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA in HERIZON-BTC-01 Adverse Reaction* ZIIHERA N=80 All Grades (%) Grades 3 or 4 (%) Gastrointestinal disorders Diarrheaa 50 10 Abdominal painb 29 1 Nausea 18 1 Vomiting 15 1 Injury, poisoning and procedural complications Infusion-related reaction 35 1 General disorders and administration site conditions Fatiguec 24 4 Skin and subcutaneous tissue disorders Rashd 19 0 Metabolism and nutrition disorders Decreased appetite 16 0 * Graded per CTCAE version 5. a Diarrhea includes diarrhea and enteritis b Abdominal pain includes abdominal pain and abdominal pain upper c Fatigue includes asthenia and fatigue d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, rash, rash maculo- papular, and rash pustular Table 4 summarizes the laboratory abnormalities in HERIZON-BTC-01. Table 4: Laboratory Abnormalities ( 30%) that Worsened from Baseline in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA in HERIZON-BTC-01 Laboratory Abnormalities ZIIHERA* All Grades (%) Grades 3 or 4 (%) Hematology Hemoglobin decreased 88 14 Lymphocytes decreased 44 8 Chemistry Lactate dehydrogenase increased 55 0 Albumin decreased 53 0 Aspartate aminotransferase increased 47 10 Alanine aminotransferase increased 46 8 Alkaline phosphatase increased 41 5 Sodium decreased 35 10 Potassium decreased 34 5 *The denominator used to calculate the rate varied from 78 to 80 based on the number of patients with a baseline value and at least one post-treatment value. Reference ID: 5482738 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Use of ZIIHERA is not recommended during pregnancy (see CLINICAL CONSIDERATIONS). Advise patients of potential risks to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received ZIIHERA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care. 8.2 Lactation Risk Summary There are no data on the presence of zanidatamab-hrii in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for ZIIHERA treatment and any potential adverse effects on the breastfed child from ZIIHERA or from the underlying maternal condition. This consideration should also take into account the ZIIHERA half-life of approximately 21 days and a washout period of 4 months [see Clinical Pharmacology (12.3)]. 8.3 Females and Males of Reproductive Potential ZIIHERA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA [see Use in Specific Populations (8.1)]. Contraception Females ZIIHERA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose of ZIIHERA. Reference ID: 5482738 8.4 Pediatric Use Safety and efficacy of ZIIHERA have not been established in pediatric patients. 8.5 Geriatric Use Of the 80 patients who received ZIIHERA for unresectable or metastatic biliary tract cancer in HERIZON-BTC-01, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were aged 65-74 years old and 2 (3%) were aged 75 years or older [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these patients and younger adult patients. 11 DESCRIPTION Zanidatamab-hrii is a humanized, IgG-like, bispecific HER2-directed antibody. Zanidatamab-hrii is produced in Chinese hamster ovary cells via recombinant DNA technology and has a molecular weight of 124.8 kDa. ZIIHERA (zanidatamab-hrii) for injection is supplied as a sterile, preservative free, white lyophilized powder that requires reconstitution and dilution for intravenous use. Each single-dose vial of reconstituted product contains 300 mg of zanidatamab-hrii and the inactive ingredients: polysorbate 20 (0.63 mg), sodium succinate (4.3 mg), succinic acid (4.3 mg), and sucrose (567 mg). Following reconstitution with 5.7 mL Sterile Water for Injection, a solution containing 50 mg/mL zanidatamab-hrii is produced with a deliverable volume of 6 mL, with pH of 4.6. The resulting solution is diluted and administered by intravenous infusion. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zanidatamab-hrii is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo. 12.2 Pharmacodynamics Zanidatamab-hrii exposure-response relationships and the time course of the pharmacodynamic response are unknown. Cardiac Electrophysiology A mean increase in the QTc interval > 20 ms was not observed at the recommended approved dosage. 12.3 Pharmacokinetics Zanidatamab-hrii PK parameters are presented as means (percent coefficient of variation) following administration of ZIIHERA 20 mg/kg every 2 weeks after the 7th or later dose unless otherwise indicated. Reference ID: 5482738 Embryo-Fetal Toxicity Advise female patients of the potential risk to a fetus. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.3)]. Left Ventricular Dysfunction Advise patients that ZIIHERA can cause cardiac dysfunction and to contact a healthcare provider immediately for signs and symptoms of cardiac dysfunction [see Warnings and Precautions (5.2)]. Infusion-Related Reactions Advise patients of the risk of infusion-related reactions and to inform a healthcare provider immediately for symptoms of an infusion-related reaction [see Warnings and Precautions (5.3)]. Diarrhea Advise patients that ZIIHERA can cause diarrhea, which may be severe. Instruct patients how to manage diarrhea, and to contact their healthcare provider for sustained diarrhea that does not respond to supportive care [see Dosage and Administration (2.4), Warnings and Precautions (5.4)]. Distributed by: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 Manufactured by: Jazz Pharmaceuticals Ireland Limited Fifth Floor, Waterloo Exchange Waterloo Road, Dublin 4 Dublin, Ireland D04 E5W7 U.S. License No. 2167 Reference ID: 5482738 PATIENT INFORMATION ZIIHERA (zye HAYR rah) (zanidatamab-hrii) for injection, for intravenous use What is the most important information I should know about ZIIHERA? ZIIHERA can cause serious side effects, including: x harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ZIIHERA. o If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with ZIIHERA. o Females who are able to become pregnant should use birth control (contraception) during treatment with ZIIHERA and for 4 months after the last dose. See “What are the possible side effects of ZIIHERA?” for more information about side effects. What is ZIIHERA? ZIIHERA is a prescription medicine used to treat adults who have a type of bile duct (cholangiocarcinoma) or gallbladder cancer called biliary tract cancer (BTC), that is human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+). ZIIHERA may be used when your BTC: o was previously treated; o cannot be removed by surgery or has spread to other parts of your body (metastatic). Your healthcare provider will perform a test to make sure ZIIHERA is right for you. It is not known if ZIIHERA is safe and effective in children. Before receiving ZIIHERA, tell your healthcare provider about all of your medical conditions, including if you: x have or have had any heart problems x are breastfeeding or plan to breastfeed. It is not known if ZIIHERA passes into your breastmilk. Talk to your healthcare provider about the best way to feed your baby if you receive treatment with ZIIHERA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I receive ZIIHERA? x ZIIHERA is given through a vein by an intravenous (IV) infusion over 120 to 150 minutes for your first and second infusions. If you tolerate the first and second infusions well, your third and fourth infusions may be given to you over 90 minutes. Each additional infusion may be given to you over 60 minutes. x ZIIHERA is given every 2 weeks. x Your healthcare provider: o will give you medicines 30 to 60 minutes before each treatment to help prevent infusion-related reactions or make them less severe o may slow down, temporarily stop, or permanently stop your treatment with ZIIHERA if you have certain side effects o may do certain tests to check you for some side effects o will decide how many treatments you need x If you miss a dose, call your healthcare provider as soon as possible to reschedule your appointment. What are the possible side effects of ZIIHERA? ZIIHERA can cause serious side effects, including: x See “What is the most important information I should know about ZIIHERA?” x Heart problems that may affect how well your heart pumps blood. Your healthcare provider will check your heart function before and during treatment with ZIIHERA. Call your healthcare provider right away if you get any of the following signs and symptoms of a heart problem: o new or worsening shortness of breath o irregular heartbeat o feeling more tired than usual o sudden weight gain o swelling of your ankles or feet o dizziness or feeling light-headed o loss of consciousness x Infusion-related reactions, a common side effect that can happen during treatment with ZIIHERA. Your healthcare provider will check for side effects during your infusions. Tell your healthcare provider right away if you get any of the following symptoms during or after your infusions of ZIIHERA: o shortness of breath or trouble breathing o flushing o fever o nausea or vomiting Reference ID: 5482738 o chills o dizziness or feeling lightheaded o rash o chest discomfort x Diarrhea, a common side effect during treatment with ZIIHERA that may be severe. Your healthcare provider may prescribe an antidiarrheal medicine or other treatment, as needed. Other common side effects of ZIIHERA include stomach pain and feeling tired. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of ZIIHERA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of ZIIHERA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about ZIIHERA that is written for health professionals. What are the ingredients in ZIIHERA? Active ingredient: zanidatamab-hrii Inactive ingredients: polysorbate 20, sodium succinate, succinic acid, and sucrose Distributed by: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 Manufactured by: Jazz Pharmaceuticals Ireland Limited Fifth Floor, Waterloo Exchange Waterloo Road, Dublin 4 Dublin, Ireland D04 E5W7 U.S. License No. 2167 For more information, go to www.ZIIHERA.com or call 1-800-520-5568. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5482738 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ PAUL G KLUETZ 11/20/2024 04:56:33 PM Signature Page 1 of 1 Reference ID: 5482738	custom-source	2025-02-12T15:46:50.390605	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/761416Orig1s000Lbl.pdf', 'application_number': 761416, 'submission_type': 'ORIG ', 'submission_number': 1}
80,252	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use QSYMIA® safely and effectively. See full prescribing information for QSYMIA. QSYMIA (phentermine and topiramate extended-release capsules), for oral use, CIV Initial U.S. Approval: 2012 ---------------------------INDICATIONS AND USAGE--------------------------- QSYMIA is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate, indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with obesity (1) • Adults with overweight in the presence of at least one weight-related comorbid condition Limitations of Use: • The effect of QSYMIA on cardiovascular morbidity and mortality has not been established (1). • The safety and effectiveness of QSYMIA in combination with other products intended for weight loss, including prescription and over-the- counter drugs, and herbal preparations, have not been established (1). -----------------------DOSAGE AND ADMINISTRATION----------------------- • Take orally once daily in morning. Avoid administration in evening to prevent insomnia (2.2). • Recommended starting dosage is 3.75 mg/23 mg (phentermine mg/topiramate mg) daily for 14 days; then increase to 7.5 mg/46 mg daily (2.2). • Escalate dosage based on weight loss in adults or BMI reduction in pediatric patients. See the Full Prescribing Information for details regarding discontinuation or dosage escalation (2.2). • Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure (2.3). • Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe renal impairment or patients with moderate hepatic impairment (2.4, 2.5). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Extended-release capsules: (phentermine mg/topiramate mg) • 3.75 mg/23 mg (3) • 7.5 mg/46 mg (3) • 11.25 mg/69 mg (3) • 15 mg/92 mg (3) ------------------------CONTRAINDICATIONS-------------------------- • Pregnancy (4) • Glaucoma (4) • Hyperthyroidism (4) • Taking or within 14 days of stopping monoamine oxidase inhibitors (4) • Known hypersensitivity to any component of QSYMIA or idiosyncrasy to sympathomimetic amines (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • Embryo-Fetal Toxicity: Can cause fetal harm. In patients who can become pregnant, a negative pregnancy test is recommended before initiating QSYMIA and monthly during therapy; advise use of effective contraception. QSYMIA is available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS) (5.1). • Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue QSYMIA if symptoms develop (5.2). • Risk of Ophthalmologic Adverse Reactions: Acute myopia and secondary angle closure glaucoma have been reported. Immediately discontinue QSYMIA if symptoms develop. Consider QSYMIA discontinuation if visual field defects occur (5.3). • Mood and Sleep Disorders: Consider dosage reduction or discontinuation for clinically significant or persistent mood or sleep disorder symptoms (5.4). • Cognitive Impairment: May cause disturbances in attention or memory, or speech/language problems. Caution patients about operating automobiles or hazardous machinery when starting treatment (5.5). • Slowing of Linear Growth: Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected (5.6). • Metabolic Acidosis: Measure electrolytes before and during treatment. If persistent metabolic acidosis develops, reduce dosage or discontinue QSYMIA (5.7). • Decrease in Renal Function: Measure creatinine before and during treatment. For persistent creatinine elevations, reduce dosage or discontinue QSYMIA (5.8). • Serious Skin Reactions: QSYMIA should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related (5.13). ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions in: • Adults (incidence ≥ 5% and at least 1.5 times placebo) are: paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. • Pediatric patients aged 12 years and older (incidence ≥4% and greater than placebo) are: depression, dizziness, arthralgia, pyrexia, influenza, and ligament sprain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact VIVUS LLC, at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Oral Contraceptives: Altered exposure of progestin and estrogen may cause irregular bleeding, but not increased risk of pregnancy. Advise patients not to discontinue oral contraceptives if spotting occurs (7). • CNS Depressants Including Alcohol: May potentiate CNS depressant effects. Avoid excessive use of alcohol (7). • Non-potassium Sparing Diuretics: May potentiate hypokalemia. Measure potassium before and during treatment (7). -----------------------USE IN SPECIFIC POPULATIONS----------------------- • Lactation: Breastfeeding not recommended (8.2). See 17 for PATIENT COUNSELING INFORMATION and MEDICATION GUIDE Revised: 09/2024 Reference ID: 5481617 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Testing Prior to Initiation of QSYMIA 2.2 Recommended Dosage and Administration 2.3 Discontinuation of QSYMIA 15 mg/92 mg 2.4 Recommended Dosage in Patients with Renal Impairment 2.5 Recommended Dosage in Patients with Hepatic Impairment 3 DOSAGE FORM AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity 5.2 Suicidal Behavior and Ideation 5.3 Risk of Ophthalmological Adverse Reactions 5.4 Mood and Sleep Disorders 5.5 Cognitive Impairment 5.6 Slowing of Linear Growth 5.7 Metabolic Acidosis 5.8 Decrease in Renal Function 5.9 Risk of Seizures with Abrupt Withdrawal of QSYMIA 5.10 Kidney Stones 5.11 Oligohidrosis and Hyperthermia 5.12 Hypokalemia 5.13 Serious Skin Reactions 5.14 Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5481617 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE QSYMIA is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with obesity • Adults with overweight in the presence of at least one weight-related comorbid condition Limitations of Use • The effect of QSYMIA on cardiovascular morbidity and mortality has not been established. • The safety and effectiveness of QSYMIA in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Testing Prior to and During Treatment with QSYMIA Prior to QSYMIA initiation and during treatment with QSYMIA, the following is recommended: • Obtain a negative pregnancy test before initiating QSYMIA in patients who can become pregnant and monthly during QSYMIA therapy. QSYMIA is contraindicated during pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.3)]. • Obtain a blood chemistry profile that includes bicarbonate, creatinine, and potassium in all patients, and glucose in patients with type 2 diabetes mellitus on antidiabetic medication prior to initiating QSYMIA treatment and periodically during treatment [see Warnings and Precautions (5.7, 5.8, 5.12)]. 2.2 Recommended Dosage and Administration The recommended dosage, titration, and administration of QSYMIA are as follows: • Take QSYMIA orally once daily in the morning with or without food. Avoid administration of QSYMIA in the evening due to the possibility of insomnia. • The recommended starting dosage of QSYMIA is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA 7.5 mg/46 mg orally once daily. • After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, increase the dosage to QSYMIA 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg orally once daily. • After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, discontinue QSYMIA [see Dosage and Administration (2.3)], as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. • Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction. Reference ID: 5481617 2.3 Discontinuation of QSYMIA 15 mg/92 mg Discontinue QSYMIA 15 mg/92 mg gradually by taking QSYMIA 15 mg/92 mg orally once daily every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure [see Warnings and Precautions (5.9) and Drug Abuse and Dependence (9.3)]. 2.4 Recommended Dosage in Patients with Renal Impairment • The recommended dosage in patients with mild (CrCl greater or equal to 50 and less than 80 mL/min) renal impairment is the same as the recommended dosage for patients with normal renal function [see Warnings and Precautions (5.9), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. • In patients with severe [creatinine clearance (CrCl) less than 30 mL/min] or moderate (CrCl greater than or equal to 30 and less than 50 mL/min) renal impairment (CrCl calculated using the Cockcroft-Gault equation with actual body weight), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily. • Avoid use of QSYMIA in patients with end-stage renal disease on dialysis. 2.5 Recommended Dosage in Patients with Hepatic Impairment • The recommended dosage of QSYMIA in patients with mild hepatic impairment (Child-Pugh 5 - 6) is the same as the recommended dosage in patients with normal hepatic function [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. • In patients with moderate hepatic impairment (Child-Pugh score 7 - 9), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg orally once daily. • Avoid use of QSYMIA in patients with severe hepatic impairment (Child-Pugh score 10 - 15). 3 DOSAGE FORMS AND STRENGTHS QSYMIA extended-release capsules are available in four strengths (phentermine mg/topiramate mg): • 3.75 mg/23 mg - purple cap imprinted with VIVUS and purple body imprinted with 3.75/23 • 7.5 mg/46 mg - purple cap imprinted with VIVUS and yellow body imprinted with 7.5/46 • 11.25 mg/69 mg - yellow cap imprinted with VIVUS and yellow body imprinted with 11.25/69 • 15 mg/92 mg - yellow cap imprinted with VIVUS and white body imprinted with 15/92 4 CONTRAINDICATIONS QSYMIA is contraindicated in patients: • Who are pregnant [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] • With glaucoma [see Warnings and Precautions (5.3)] • With hyperthyroidism • Taking or within 14 days of stopping a monoamine oxidase inhibitors [see Drug Interactions (7)] • With known hypersensitivity to phentermine, topiramate or any of the excipients in QSYMIA, or idiosyncrasy to the sympathomimetic amines [see Adverse Reactions (6.2)]. Reference ID: 5481617 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity QSYMIA can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. A negative pregnancy test is recommended before initiating QSYMIA treatment in patients who can become pregnant and monthly during QSYMIA therapy. Advise patients who can become pregnant of the potential risk to a fetus and to use effective contraception during QSYMIA therapy [see Use in Specific Populations (8.1, 8.3)]. QSYMIA Risk Evaluation and Mitigation Strategy (REMS) Because of the teratogenic risk associated with QSYMIA therapy, QSYMIA is available through a limited program under the REMS. Under the QSYMIA REMS, only certified pharmacies may distribute QSYMIA. Further information is available at www.QSYMIAREMS.com or by telephone at 1-888-998-4887. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies (monotherapy and adjunctive therapy, median treatment duration 12 weeks) of 11 different AEDs across several indications showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. The estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in AED-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about AED effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age in the clinical trials analyzed. In a QSYMIA clinical trial of pediatric patients aged 12 years and older, 1 (0.6%) of the 167 QSYMIA-treated patients reported suicidal ideation and behavior which required hospitalization. No placebo-treated patients reported suicidal behavior or ideation. Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue QSYMIA in patients who experience suicidal thoughts or behaviors [see Warnings and Precautions (5.9)]. Avoid QSYMIA in patients with a history of suicidal attempts or active suicidal ideation. 5.3 Risk of Ophthalmologic Adverse Reactions Acute Myopia and Secondary Angle Closure Glaucoma A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Reference ID: 5481617 Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of QSYMIA as rapidly as possible in consultation with the treating physician. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision. Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment, consider discontinuing QSYMIA. 5.4 Mood and Sleep Disorders QSYMIA can cause mood disorders, including depression and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking QSYMIA [see Adverse Reactions (6.1)]. Consider dosage reduction or discontinuation of QSYMIA if clinically significant or persistent symptoms occur. Discontinue QSYMIA if patients have symptoms of suicidal ideation or behavior [see Warnings and Precautions (5.2)]. 5.5 Cognitive Impairment QSYMIA can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses of QSYMIA may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties [see Adverse Reactions (6.1)]. The concomitant use of alcohol or central nervous system (CNS) depressant drugs with QSYMIA may potentiate CNS depression or other centrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, light- headedness, impaired coordination, and somnolence. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain QSYMIA therapy does not affect them adversely. Caution patients against excessive alcohol intake while receiving QSYMIA. If cognitive dysfunction persists, consider dosage reduction or discontinuation of QSYMIA [see Warnings and Precautions (5.9)]. 5.6 Slowing of Linear Growth QSYMIA is associated with a reduction in height velocity (centimeters of height gained per year) in obese pediatric patients 12 to 17 years of age. In a 56-week study, average height increased from baseline in both QSYMIA- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in QSYMIA-treated compared to placebo-treated patients. Monitor height velocity in pediatric patients treated with QSYMIA. Consider dosage reduction or discontinuation of QSYMIA if pediatric patients are not growing or gaining height as expected [see Warnings and Precautions (5.9)]. Reference ID: 5481617 5.7 Metabolic Acidosis Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients treated with QSYMIA [see Adverse Reactions (6.1)]. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, or ketogenic diet) may be additive to the bicarbonate lowering effects of QSYMIA. Concomitant use of QSYMIA and a carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation [see Warnings and Precautions (5.10)]. Avoid use of QSYMIA with other carbonic anhydrase inhibitors. If concomitant use of QSYMIA with another carbonic anhydrase inhibitor is unavoidable, the patient should be monitored for the appearance or worsening of metabolic acidosis. Measure electrolytes including serum bicarbonate prior to starting QSYMIA and during QSYMIA treatment. In QSYMIA clinical trials, the peak reduction in serum bicarbonate typically occurred within 4 weeks of titration to the assigned dose, and in most patients, there was a correction of bicarbonate by week 56, without any dosage reduction. However, if persistent metabolic acidosis develops while taking QSYMIA, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.9)]. 5.8 Decrease in Renal Function QSYMIA can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular filtration rate). In clinical trials, peak increases in serum creatinine were observed after 4 to 8 weeks of treatment. On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. The changes in serum creatinine (and measured GFR) with short-term (4-weeks) QSYMIA treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known. Measure serum creatinine prior to starting QSYMIA and during QSYMIA treatment. If persistent elevations in creatinine occur, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.9), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)]. 5.9 Risk of Seizures with Abrupt Withdrawal of QSYMIA Abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of QSYMIA is medically required, appropriate monitoring is recommended. Patients discontinuing QSYMIA 15 mg/92 mg should be gradually tapered to reduce the possibility of precipitating a seizure [see Dosage and Administration (2.3) and Drug Abuse and Dependence (9.3)]. 5.10 Kidney Stones QSYMIA has been associated with kidney stone formation [see Adverse Reactions (6.1)]. Topiramate inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH. Patients on a ketogenic diet may be at increased risk for kidney stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated pediatric patients in a one-year, active-controlled study. Increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. Reference ID: 5481617 Avoid the use of QSYMIA with other drugs that inhibit carbonic anhydrase [see Drug Interactions (7)]. Advise patients to increase fluid intake (to increase urinary output), which may decrease the concentration of substances involved in kidney stone formation. 5.11 Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. The majority of the reports associated with topiramate have been in pediatric patients. Advise all patients and caregivers to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Patients on concomitant medications that predispose them to heat-related disorders may be at increased risk. 5.12 Hypokalemia QSYMIA can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when QSYMIA is used in conjunction with non-potassium sparing diuretics this may further potentiate potassium-wasting. Measure potassium before and during treatment with QSYMIA [see Adverse Reactions (6.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. 5.13 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. QSYMIA should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed, and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.14 Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5 This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.6)] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)] • Risk of Ophthalmologic Adverse Reactions [see Warnings and Precautions (5.3)] • Mood and Sleep Disorders [see Warnings and Precautions (5.4)] • Cognitive Impairment [see Warnings and Precautions (5.5)] • Slowing of Linear Growth [see Warnings and Precautions (5.6)] • Metabolic Acidosis [see Warnings and Precautions (5.7)] • Decrease in Renal Function [see Warnings and Precautions (5.8)] • Risk of Seizures with Abrupt Withdrawal of QSYMIA [see Warnings and Precautions (5.9)] • Kidney Stones [see Warnings and Precautions (5.10)] • Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.11)] • Hypokalemia [see Warnings and Precautions (5.12)] Reference ID: 5481617 • Serious Skin Reactions [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The data described herein reflect exposure to QSYMIA in two 1-year, randomized, double-blind, placebo- controlled, multicenter clinical trials and two supportive trials in 2,318 adult patients with overweight or obesity [936 (40%) patients with hypertension, 309 (13%) patients with type 2 diabetes mellitus, 808 (35%) patients with BMI greater than 40 kg/m2] exposed for a mean duration of 298 days. Data in this section also describe adverse reactions from a 1-year, randomized, double-blind, placebo-controlled multicenter clinical trial that evaluated 223 pediatric patients (12 to 17 years old) with obesity [see Clinical Studies (14)]. Adults Adverse reactions occurring at greater than or equal to 5% and at least 1.5 times placebo in adults include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated adults and more frequently than in the placebo group are shown in Table 1. Reference ID: 5481617 Table 1. Adverse Reactions Reported in ≥2% of QSYMIA-Treated Adults with Overweight or Obesity and More Frequently than Placebo in Overall Study Population of 1 Year Duration Adverse Reaction Placebo (N = 1561) % QSYMIA 3.75 mg/23 mg (N = 240) % QSYMIA 7.5 mg/46 mg (N = 498) % QSYMIA 15 mg/92 mg (N = 1,580) % Paraesthesia 2 4 14 20 Dry Mouth 3 7 14 19 Constipation 6 8 15 16 Upper Respiratory Tract Infection 13 16 12 14 Headache 9 10 7 11 Dysgeusia 1 1 7 9 Insomnia 5 5 6 9 Nasopharyngitis 8 13 11 9 Dizziness 3 3 7 9 Sinusitis 6 8 7 8 Nausea 4 6 4 7 Back Pain 5 5 6 7 Fatigue 4 5 4 6 Diarrhea 5 5 6 6 Vision Blurred 4 6 4 5 Bronchitis 4 7 4 5 Urinary Tract Infection 4 3 5 5 Cough 4 3 4 5 Influenza 4 8 5 4 Depression 2 3 3 4 Anxiety 2 3 2 4 Hypoesthesia 1 1 4 4 Irritability 1 2 3 4 Alopecia 1 2 3 4 Disturbance in Attention 1 0 2 4 Pain in Extremity 3 2 3 3 Muscle Spasms 2 3 3 3 Dyspepsia 2 2 2 3 Gastroesophageal Reflux Disease 1 1 3 3 Rash 2 2 2 3 Hypokalemia 0 0 1 3 Dry Eye 1 1 1 3 Gastroenteritis 2 1 2 3 Pharyngolaryngeal Pain 2 3 1 2 Paraesthesia Oral 0 0 1 2 Eye Pain 1 2 2 2 Nasal Congestion 1 2 1 2 Thirst 1 2 2 2 Sinus Congestion 2 3 3 2 Procedural Pain 2 2 2 2 Palpitations 1 1 2 2 Musculoskeletal Pain 1 1 3 2 Decreased Appetite 1 2 2 2 Neck Pain 1 1 2 1 Dysmenorrhea 0 2 0 1 Chest Discomfort 0 2 0 1 Reference ID: 5481617 Pediatric Patients Aged 12 Years and Older Adverse reactions occurring in pediatric patients treated with either QSYMIA 15 mg/92 mg or QSYMIA 7.5 mg/46 mg at greater than or equal to 4% and higher than placebo include depression, pyrexia, dizziness, arthralgia, influenza, and ligament sprain. Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated pediatric patients and more frequently than in the placebo group from a study in pediatric patients aged 12 years and older are shown in Table 2. Table 2. Adverse Reactions Reported in ≥2% of QSYMIA-Treated Pediatric Patients Aged 12 to 17 Years and More Frequently than Placebo during 56 Weeks of Treatment Adverse Reaction Placebo (N = 56) % QSYMIA 7.5 mg/46 mg (N = 54) % QSYMIA 15 mg/92 mg (N = 113) % Depression 0 2 4 Nausea 4 4 4 Pyrexia 2 2 4 Dizziness 0 2 4 Arthralgia 0 2 4 Paraesthesia 0 2 3 Anxiety 0 2 3 Abdominal Pain Upper 0 0 3 Fatigue 2 0 3 Ear Infection 0 2 3 Musculoskeletal Chest Pain 0 0 3 Influenza 0 4 2 Ligament Sprain 0 4 2 Increase in Heart Rate In adult and pediatric clinical trials, there was a higher incidence of heart rate elevations observed in QSYMIA- treated compared to placebo-treated patients. In an 8-week ambulatory blood pressure monitoring (ABPM) study in adults, QSYMIA increased the 24-hr average heart rate by 3.6 beats per minute (bpm) (95% CI 2.1, 5.2) compared to the placebo group [see Clinical Pharmacology (12.2)]. In clinical trials, a higher percentage of QSYMIA-treated adults and pediatric patients aged 12 years and older experienced heart rate increases from baseline of more than 5, 10, 15, and 20 bpm compared to placebo-treated patients. Table 3 and Table 4 provide the numbers and percentages of adult and pediatric patients, respectively, with elevations in heart rate in clinical studies of up to one year. Table 3. Number and Percentage of Adults with Overweight or Obesity with an Increase in Heart Rate at a Single Time Point from Baseline Placebo N=1561 n (%) QSYMIA 3.75 mg/23 mg N=240 n (%) QSYMIA 7.5 mg/46 mg N=498 n (%) QSYMIA 15 mg/92 mg N=1580 n (%) Greater than 5 bpm 1021 (65.4) 168 (70.0) 372 (74.7) 1228 (77.7) Greater than 10 bpm 657 (42.1) 120 (50.0) 251 (50.4) 887 (56.1) Greater than 15 bpm 410 (26.3) 79 (32.9) 165 (33.1) 590 (37.3) Greater than 20 bpm 186 (11.9) 36 (15.0) 67 (13.5) 309 (19.6) Reference ID: 5481617 Table 4. Number and Percentage of Pediatric Patients with an Increase in Heart Rate at a Single Time Point from Baseline Placebo N=56 n (%) QSYMIA 7.5 mg/46 mg N=54 n (%) QSYMIA 15 mg/92 mg N=113 n (%) Greater than 5 bpm 37 (66.1) 38 (70.4) 92 (81.4) Greater than 10 bpm 26 (46.4) 30 (55.6) 73 (64.6) Greater than 15 bpm 17 (30.4) 18 (33.3) 48 (42.5) Greater than 20 bpm 10 (17.9) 10 (18.5) 27 (23.9) Paraesthesia/Dysgeusia In adult clinical trials, reports of paraesthesia, characterized as tingling in hands, feet, or face, and dysgeusia, characterized as a metallic taste, occurred (see Table 1). Adverse reactions of paraesthesia were also reported in pediatric patients (see Table 2). QSYMIA-treated adult patients discontinued treatment due to these adverse reactions (1% for paraesthesia and 0.6% for dysgeusia); no pediatric patients discontinued treatment due to paraesthesia or dysgeusia. Mood and Sleep Disorders The proportion of adult patients in 1-year controlled trials of QSYMIA reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 10% with placebo. These events were further categorized into sleep disorders, anxiety, and depression. Reports of sleep disorders were typically characterized as insomnia and occurred in 8.1% and 11% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 5.8% of patients treated with placebo. Reports of anxiety occurred in 4.8% and 7.9% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo. Reports of depression/mood problems occurred in 3.8% and 7.6% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. Mood and sleep disorder adverse reactions occurred in patients with and without a history of depression. In a pediatric clinical trial, higher proportions of QSYMIA-treated patients reported one or more adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) compared to placebo- treated patients (see Table 2). Cognitive Disorders In the 1-year controlled trials of QSYMIA in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 5.0% for QSYMIA 7.5 mg/46 mg and 7.6% for QSYMIA 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/concentration, memory, and language (word-finding). These events occurred at any time during treatment with QSYMIA. Slowing of Linear Growth QSYMIA is associated with a reduction in height velocity (centimeters of height gained per year) in obese pediatric patients 12 to 17 years of age. In a 56-week study, average height increased from baseline in both QSYMIA- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in QSYMIA-treated compared to placebo-treated patients. Decrease in Bone Mineral Density Reference ID: 5481617 QSYMIA is associated with less bone mineral acquisition in pediatric patients 12 to 17 years of age. In a substudy (n=66) evaluating bone mineralization via dual-energy X-ray absorptiometry (DEXA), increases in bone mineral density (BMD) at the lumbar spine and total body less head (TBLH) were smaller in pediatric patients treated with QSYMIA compared to those treated with placebo after 1 year of treatment. Declines in BMD Z-scores of -0.5 or greater from baseline for TBLH were observed in 9% of QSYMIA 7.5 mg/46 mg- treated patients and 30% of QSYMIA 15 mg/92 mg-treated patients, compared to 0% of placebo-treated patients. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD was not correlated with decreased serum bicarbonate, which commonly occurs with QSYMIA treatment, or changes in body weight. No patient had a BMD Z-score that went below -2.0 during the trial. Similar findings were observed in a 1 year, active-controlled trial of topiramate in pediatric patients with another condition. Nephrolithiasis In the 1-year controlled trials of QSYMIA in adults, the incidence of nephrolithiasis was 0.2% for QSYMIA 7.5 mg/46 mg and 1.2% for QSYMIA 15 mg/92 mg, compared to 0.3% for placebo. Laboratory Abnormalities Serum Bicarbonate In the 1-year controlled trials of QSYMIA in adults, the incidence of persistent decreases in serum bicarbonate below the normal range (levels of less than 21 mEq/L at 2 consecutive visits or at the final visit) was 6.4% for QSYMIA 7.5 mg/46 mg and 12.8% for QSYMIA 15 mg/92 mg, compared to 2.1% for placebo. The incidence of persistent, markedly low serum bicarbonate values (levels of less than 17 mEq/L on 2 consecutive visits or at the final visit) was 0.2% for QSYMIA 7.5 mg/46 mg dose and 0.7% for QSYMIA 15 mg/92 mg dose, compared to 0.1% for placebo. In a pediatric clinical trial, 60 to 70% QSYMIA-treated patients had a persistent bicarbonate level below the normal range (<21 mEq/L) compared to 43% of placebo-treated patients. Serum Potassium In the 1-year controlled trials of QSYMIA in adults, the incidence of persistent low serum potassium values (less than 3.5 mEq/L at two consecutive visits or at the final visit) during the trial was 3.6% for QSYMIA 7.5 mg/46 mg dose and 4.9% for QSYMIA 15 mg/92 mg, compared to 1.1% for placebo. Of the subjects who experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium sparing diuretic. The incidence of markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L) at any time during the trial was 0.2% for QSYMIA 7.5 mg/46 mg dose and 0.7% for QSYMIA 15 mg/92 mg dose, compared to 0.0% for placebo. Persistent markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L at two consecutive visits or at the final visit) occurred in 0.2% receiving QSYMIA 7.5 mg/46 mg dose and 0.1% receiving QSYMIA 15 mg/92 mg dose, compared to 0.0% receiving placebo. Low serum potassium levels (<3.5 mEq/L) were not observed in a 56-week clinical trial of pediatric patients with obesity. Serum Creatinine In the 1-year controlled trials of QSYMIA in adults and pediatric patients, there was an increase in serum creatinine from baseline, peaking between Week 4 to 8 in adults and at Week 16 in pediatric patients. Serum creatinine values declined but remained elevated over baseline over 1 year of treatment. The incidence of increases in serum creatinine of greater than or equal to 0.3 mg/dL at any time during treatment in adults was 7.2% for QSYMIA 7.5 mg/46 mg and 8.4% for QSYMIA 15 mg/92 mg, compared to 2.0% for placebo; 17% of Reference ID: 5481617 pediatric patients treated with QSYMIA 7.5 mg/46 mg or QSYMIA 15 mg/92 mg and 0% of patients treated with placebo had a serum creatinine ≥0.3 mg/dL at any time post-randomization. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 2.0% of adult subjects receiving QSYMIA 7.5 mg/46 mg and 2.8% receiving QSYMIA 15 mg/92 mg, compared to 0.6% receiving placebo. Serum Ammonia Hyperammonemia with or without encephalopathy has been reported with topiramate. The risk for hyperammonemia with topiramate appears dose related and has been reported more frequently when concomitantly used with valproic acid [see Drug Interactions (7)]. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in clinical trials of another condition was 26% in patients taking topiramate at 100 mg/day (1.1 times the maximum recommended dosage of QSYMIA) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of QSYMIA), compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia (defined as 50% above the upper limit of normal reference range) at the 100 mg dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during post approval use of QSYMIA, phentermine, and topiramate. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. QSYMIA Psychiatric: suicidal ideation, suicidal behavior Ophthalmic: acute angle closure glaucoma, increased intraocular pressure Phentermine Allergic Reactions: urticaria Cardiovascular: elevation of blood pressure, ischemic events Central Nervous System: euphoria, psychosis, tremor Reproductive: changes in libido, impotence Topiramate Dermatologic: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus Gastrointestinal: pancreatitis Hepatic: hepatic failure (including fatalities), hepatitis Metabolic: hyperammonemia with or without encephalopathy has been reported with concomitant valproic acid [see Drug Interactions (7)], hypothermia Ophthalmic: maculopathy 7 DRUG INTERACTIONS Table 5 displays clinically significant drug interactions with QSYMIA. Reference ID: 5481617 Table 5. Clinically Significant Drug Interactions with QSYMIA Monoamine Oxidase Inhibitors Clinical Impact Concomitant use of phentermine with monoamine oxidase inhibitors (MAOIs) increases the risk of hypertensive crisis. Intervention Concomitant use of QSYMIA is contraindicated during MAOI treatment and within 14 days of stopping an MAOI. Oral Contraceptives Clinical Impact Co-administration of multiple-dose QSYMIA 15 mg/92 mg once daily with a single dose of oral contraceptive containing 35 µg ethinyl estradiol (estrogen component) and 1 mg norethindrone (progestin component), in obese otherwise healthy volunteers, decreased the exposure of ethinyl estradiol by 16% and increased the exposure of norethindrone by 22% [see Clinical Pharmacology (12.3)]. Although this interaction is not anticipated to increase the risk of pregnancy, irregular bleeding (spotting) may occur more frequently due to both the increased exposure to the progestin and lower exposure to the estrogen, which tends to stabilize the endometrium. Intervention Inform patients not to discontinue their combination oral contraceptive if spotting occurs, but to notify their health care provider if the spotting is troubling to them. CNS Depressants Including Alcohol Clinical Impact The concomitant use of alcohol or CNS depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Intervention Advise patients not to drive or operate machinery until they have gained sufficient experience on QSYMIA to gauge whether it adversely affects their mental performance, motor performance, and/or vision. Caution patients against excessive alcohol intake when taking QSYMIA. Consider QSYMIA dosage reduction or discontinuation if cognitive dysfunction persists [see Warnings and Precautions (5.5)] Non-Potassium Sparing Diuretics Clinical Impact Concurrent use of QSYMIA with non-potassium sparing diuretics may potentiate the potassium-wasting action of these diuretics. Concomitant administration of hydrochlorothiazide alone with topiramate alone has been shown to increase the Cmax and AUC of topiramate by 27% and 29%, respectively. Intervention When QSYMIA is used concomitantly with non-potassium-sparing diuretics, measure potassium before and during QSYMIA treatment [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)]. Antiepileptic Drugs Clinical Impact Concomitant administration of phenytoin or carbamazepine with topiramate in patients with epilepsy, decreased plasma concentrations of topiramate by 48% and 40%, respectively, when compared to topiramate given alone [see Clinical Pharmacology (12.3)]. Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid in patients has also been associated with hypothermia (with and without hyperammonemia). Reference ID: 5481617 Intervention Consider measuring blood ammonia in patients in whom the onset of hypothermia or encephalopathy has been reported [see Clinical Pharmacology (12.3)]. Carbonic Anhydrase Inhibitors Clinical Impact Concomitant use of topiramate with any other carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Intervention Avoid the use of QSYMIA with other drugs that inhibit carbonic anhydrase. If concomitant use of QSYMIA with another carbonic anhydrase inhibitor is unavoidable, monitor patient for the appearance or worsening of metabolic acidosis [see Warnings and Precautions (5.7, 5.10)]. Pioglitazone Clinical Impact A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and topiramate in a clinical trial. The clinical relevance of these observations is unknown. Intervention Consider increased glycemic monitoring when using pioglitazone and QSYMIA concomitantly [see Clinical Pharmacology (12.3)]. Amitriptyline Clinical Impact Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate. Intervention Any adjustments in amitriptyline dose when used with QSYMIA should be made according to the patient's clinical response and not on the basis of amitriptyline levels [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary QSYMIA is contraindicated in pregnant patients. The use of QSYMIA can cause fetal harm, and weight loss offers no clear clinical benefit to a pregnant patient (see Clinical Considerations). Available data from pregnancy registries and epidemiologic studies indicate an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being SGA in infants exposed in utero to topiramate (see Data). When phentermine and topiramate were co-administered to rats at doses of 3.75 and 25 mg/kg, respectively [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC)], or at the same dose to rabbits (approximately 0.1 times and 1 time, respectively, the clinical exposures at the MRHD based on AUC), there were no drug-related malformations. However, structural malformations, including craniofacial defects and reduced fetal weights occurred in offspring of multiple species of pregnant animals administered topiramate at clinically relevant doses (see Data). Advise pregnant women of the potential risk to a fetus. Clinical Considerations Disease Associated Maternal and/or Embryo/Fetal Risk Weight loss during pregnancy may result in fetal harm. Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to Reference ID: 5481617 the obligatory weight gain that occurs in maternal tissues during pregnancy. Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects. Fetal/Neonatal Adverse Reactions QSYMIA can cause metabolic acidosis [see Warnings and Precautions (5.7)]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Data Human Data Data evaluating the risk of major congenital malformations, oral clefts, and being SGA with topiramate exposure during pregnancy is available from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies. Major Congenital Malformations The NAAED Pregnancy Registry indicates an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference antiepileptic drug (AED) (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). Oral Clefts In the NAAED Pregnancy Registry, the prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Larger retrospective epidemiology studies showed that topiramate monotherapy exposure in pregnancy is associated with an approximately two to five-fold increased risk of oral clefts. The FORTRESS study found an excess risk of 1.5 (95% CI = -1.1 to 4.1) oral cleft cases per 1,000 infants exposed to topiramate during the first trimester. Small for Gestational Age Data from the NAAED Pregnancy Registry and population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED Pregnancy Registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the medical Birth Registry of Norway, a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group unexposed to AEDs. The long-term consequences of the SGA findings are not known. Reference ID: 5481617 Animal Data Phentermine/Topiramate Embryo-fetal development studies have been conducted in rats and rabbits with combination phentermine and topiramate treatment. Phentermine and topiramate co-administered to rats during the period of organogenesis (gestation day (GD) 6 through 17) caused reduced fetal body weights but did not cause fetal malformations at the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) estimates for each active ingredient]. In a similar study in rabbits in which the same doses were administered from GD 6 through 18, no effects on embryo-fetal development were observed at approximately 0.1 times (phentermine) and 1 time (topiramate) clinical exposures at the MRHD based on AUC. Significantly lower maternal body weight gain was recorded at these doses in rats and rabbits. A pre- and post-natal development study was conducted in rats with combination phentermine and topiramate treatment. There were no adverse maternal or offspring effects in rats treated throughout organogenesis and lactation with 1.5 mg/kg/day phentermine and 10 mg/kg/day topiramate (approximately 2- and 3-times clinical exposures at the MRHD, respectively, based on AUC). Treatment with higher doses of 11.25 mg/kg/day phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times maximum clinical doses based on AUC, respectively) caused reduced maternal body weight gain and offspring toxicity. Offspring effects included lower pup survival after birth, increased limb and tail malformations, reduced pup body weight and delayed growth, development, and sexual maturation without affecting learning, memory, or fertility and reproduction. The limb and tail malformations were consistent with results of animal studies conducted with topiramate alone. Phentermine Animal reproduction studies have not been conducted with phentermine. Limited data from studies conducted with the phentermine/topiramate combination indicate that phentermine alone was not teratogenic but resulted in lower body weight and reduced survival of offspring in rats at 5-fold the MRHD of QSYMIA, based on AUC. Topiramate Topiramate causes developmental toxicity, including teratogenicity, at clinically relevant doses in multiple animal species. Developmental toxicity, including teratogenicity, occurred at clinically relevant doses in multiple animal species in which topiramate was administered during the period of organogenesis (GD 6 – 15 in rodents, GD 6 – 18 in rabbits. In these studies, fetal malformations (primarily craniofacial defects such as cleft palate), limb malformations (ectrodactyly, micromelia, and amelia), rib/vertebral column anomalies, and/or reduced fetal weights were observed at dosages > 20 mg/kg in mice (approximately 2 times the MRHD of topiramate in QSYMIA 15 mg/92 mg on a mg/m2 basis), 20 mg/kg in rats (2 times the MRHD of QSYMIA based on estimated AUC), and 35 mg/kg in rabbits (2 times the MRHD based on estimated AUC). When rats were administered topiramate from GD 15 through lactation day 20, reductions in pre- and/or post-weaning weights occurred at dosages > 2 mg/kg (2 times the MRHD of QSYMIA based on estimated AUC). 8.2 Lactation Risk Summary Topiramate and phentermine are present in human milk. There are no data on the effects of topiramate and phentermine on milk production. Diarrhea and somnolence have been reported in breastfed infants with maternal use of topiramate. There are no data on the effects of phentermine in breastfed infants. Because of the Reference ID: 5481617 potential for serious adverse reactions, including changes in sleep, irritability, hypertension, vomiting, tremor, and weight loss in breastfed infants with maternal use of phentermine, advise patients that breastfeeding is not recommended during QSYMIA therapy. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended in patients who can become pregnant before initiating QSYMIA and monthly during QSYMIA therapy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Contraception Females QSYMIA can cause fetal harm when administered to a pregnant patient [see Use in Specific Populations (8.1)]. Advise patients who can become pregnant to use effective contraception during therapy with QSYMIA. For patients taking combined oral contraceptives (COCs), use of QSYMIA may cause irregular bleeding [see Drug Interactions (7)]. Advise patients not to discontinue taking their COC and to contact their health care provider. 8.4 Pediatric Use The safety and effectiveness of QSYMIA as an adjunct to a reduced-calorie diet and increased physical activity for weight reduction and long-term maintenance of body weight have been established in pediatric patients aged 12 years and older with obesity. Use of QSYMIA for this indication is supported by a 56-week, double-blind, placebo-controlled study in 223 pediatric patients aged 12 years and above, a pharmacokinetic study in pediatric patients, and studies in adults with obesity [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. In a pediatric clinical trial, there was one episode of serious suicidal ideation in a QSYMIA-treated patient requiring hospitalization and pharmacologic treatment [see Warnings and Precautions (5.2)]more patients treated with QSYMIA versus placebo reported adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) [see Warnings and Precautions (5.4). Increases in bone mineral density and linear growth were attenuated in QSYMIA- versus placebo-treated patients [see Warnings and Precautions (5.6)]. Serious adverse reactions seen in pediatric patients using topiramate include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones. The safety and effectiveness of QSYMIA in pediatric patients below the age of 12 years have not been established. 8.5 Geriatric Use In the QSYMIA clinical trials, a total of 254 (7%) of the patients were 65 to 69 years of age; no patients 70 years of age or older were enrolled. Clinical studies of QSYMIA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Reference ID: 5481617 8.6 Renal Impairment Compared to healthy volunteers with normal renal function, patients with moderate and severe renal impairment as estimated by the Cockcroft-Gault equation had higher exposures to phentermine and topiramate. The recommended dosage of QSYMIA in patients with mild renal impairment (CrCl greater or equal to 50 and less than 80 mL/min) is the same as the recommended dosage for patients with normal renal function. In patients with moderate (CrCl greater than or equal to 30 to less than 50 mL/min) and severe (CrCl less than 30 mL/min) renal impairment, the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily. QSYMIA has not been studied in patients with end-stage renal disease on dialysis. Avoid QSYMIA in this patient population [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment In patients with mild (Child-Pugh 5 - 6) and moderate (Child-Pugh 7 - 9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers with normal hepatic function. Exposure to topiramate was similar among patients with mild and moderate hepatic impairment and healthy volunteers. The recommended dosage of QSYMIA in patients with mild hepatic impairment (Child-Pugh 5 - 6) is the same as the recommended dosage in patients with normal hepatic function. In patients with moderate hepatic impairment, the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily. QSYMIA has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid QSYMIA in this patient population [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance QSYMIA contains phentermine, a Schedule IV controlled substance, and topiramate, which is not a controlled substance. 9.2 Abuse Phentermine has a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Phentermine is related chemically and pharmacologically to amphetamines. Amphetamines and other stimulant drugs have been extensively abused. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with impaired control over drug use and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times higher than recommended. Assess the risk of abuse prior to prescribing QSYMIA as part of a weight reduction and long-term maintenance of body weight program. 9.3 Dependence Physical dependence may occur in patients treated with QSYMIA. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. The following adverse reactions have been associated with the abrupt discontinuation of the individual components of QSYMIA: Reference ID: 5481617 • For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy [see Warnings and Precautions (5.9)]. • For phentermine, abrupt discontinuation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal of QSYMIA is required, appropriate medical monitoring is recommended. Patients discontinuing QSYMIA 15 mg/92 mg should be gradually tapered to reduce the possibility of precipitating a seizure [see Dosage and Administration (2.3)]. 10 OVERDOSAGE In the event of a significant overdose with QSYMIA, if the ingestion is recent, the stomach should be emptied immediately by gastric lavage or by induction of emesis. Appropriate supportive treatment should be provided according to the patient’s clinical signs and symptoms. In the event of an overdose of QSYMIA, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Acute overdose of phentermine may be associated with restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggressiveness, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmia, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. A severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. Management of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has been suggested for possible acute, severe hypertension, if this complicates phentermine overdosage. Topiramate overdose has resulted in severe metabolic acidosis. Other signs and symptoms include convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. A patient who ingested a dose between 96 and 110 gm topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Hemodialysis is an effective means of removing topiramate from the body. 11 DESCRIPTION QSYMIA extended-release capsules are comprised of immediate-release phentermine hydrochloride (expressed as the weight of the free base) and extended-release topiramate. QSYMIA contains phentermine hydrochloride, a sympathomimetic amine anorectic, and topiramate, a sulfamate-substituted monosaccharide. Phentermine Hydrochloride The chemical name of phentermine hydrochloride is α,α-dimethylphenethylamine hydrochloride. The molecular formula is C10H15N • HCl and its molecular weight is 185.7 (hydrochloride salt) or 149.2 (free base). Phentermine hydrochloride is a white, odorless, hygroscopic, crystalline powder that is soluble in water, methanol, and ethanol. Its structural formula is: Reference ID: 5481617 NH2 H3C CH3 HCl Topiramate Topiramate is 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate. The molecular formula is C12H21NO8S and its molecular weight is 339.4. Topiramate is a white to off-white crystalline powder with a bitter taste. It is freely soluble in methanol and acetone, sparingly soluble in pH 9 to pH 12 aqueous solutions and slightly soluble in pH 1 to pH 8 aqueous solutions. Its structural formula is: O O O O O O S O O NH2 QSYMIA QSYMIA (phentermine and topiramate extended-release capsules) is for oral administration and available in four dosage strengths: • 3.75 mg/23 mg (phentermine 3.75 mg and topiramate 23 mg) (equivalent to 4.67 mg of Phentermine Hydrochloride USP). • 7.5 mg/46 mg (phentermine 7.5 mg and topiramate 46 mg) (equivalent to 9.33 mg of Phentermine Hydrochloride USP). • 11.25 mg/69 mg (phentermine 11.25 mg and topiramate 69 mg) (equivalent to 14.0 mg of Phentermine Hydrochloride USP). • 15 mg/92 mg (phentermine 15 mg and topiramate 92 mg) (equivalent to 18.66 mg of Phentermine Hydrochloride USP). Each capsule contains the following inactive ingredients: FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and #6, ethylcellulose, gelatin, methylcellulose, microcrystalline cellulose, povidone, starch, sucrose, talc, titanium dioxide, and pharmaceutical black and white inks. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." The effect of phentermine on weight reduction and long-term maintenance of body weight is likely mediated by release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The exact mechanism of action is not known. The precise mechanism of action of topiramate on weight reduction and long-term maintenance of body weight is not known. Topiramate’s effect on weight reduction and long-term maintenance of body weight may be due to its effects on both appetite suppression and satiety enhancement, induced by a combination of pharmacologic effects including augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage- Reference ID: 5481617 gated ion channels, inhibition of AOBMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase. 12.2 Pharmacodynamics Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with drugs in this class. Cardiac Electrophysiology The effect of QSYMIA on the QTc interval was evaluated in a randomized, double-blind, placebo- and active- controlled (400 mg moxifloxacin), and parallel group/crossover thorough QT/QTc study. A total of 54 healthy subjects were administered QSYMIA 7.5 mg/46 mg at steady state and then titrated to QSYMIA 22.5 mg/138 mg at steady state. QSYMIA 22.5 mg/138 mg [a supra-therapeutic dose resulting in a phentermine and topiramate maximum concentration (Cmax) of 4- and 3- times higher than those at QSYMIA 7.5 mg/46 mg, respectively] did not affect cardiac repolarization as measured by the change from baseline in QTc. Glomerular Filtration Rate (GFR) Healthy obese males and females received QSYMIA daily for 4 weeks (3.75 mg/23 mg on Days 1 to 3, 7.5 mg/46 mg on Days 4 to 6, 11.25 mg/69 mg on Days 7 to 9, and 15 mg/92 mg on Days 10 to 28). The glomerular filtration rate (GFR) of these participants was assessed via iohexol clearance. On average, GFR decreased during QSYMIA treatment and returned to baseline within 4 weeks after discontinuing QSYMIA [see Warnings and Precautions (5.8)] Ambulatory Blood Pressure Monitoring The effect of QSYMIA on blood pressure as measured by 24-hr ABPM was evaluated in a randomized, double- blind, 3-arm (QSYMIA, placebo, and active phentermine comparator) study of adults with obesity or overweight and at least one weight-related comorbidity. The study had a treatment duration of 8 weeks, and the primary endpoint was the change from baseline to Week 8 in mean systolic blood pressure (SBP) as measured by 24-hr ABPM. QSYMIA 15 mg/92 mg did not demonstrate a pressor effect (see Table 6). At Week 8, placebo-adjusted mean (95% CI) treatment differences by 24-hr ABPM for QSYMIA 15 mg/92 mg were SBP -3.2 mmHg (-5.5, -0.9), DBP +1.2 mmHg (-0.2, +2.6), and heart rate (HR) +3.6 bpm (+2.1, +5.2). Placebo-adjusted mean weight loss was -3.9% (-4.9%, -3.0%) for QSYMIA 15 mg/92 mg and -3.8% (-4.7%, -2.9%) for phentermine 30 mg at Week 8. Reference ID: 5481617 Table 6. Ambulatory Blood Pressure Monitoring Results in Adults with Obesity or Overweight Treated with QSYMIA, Placebo, or Phentermine - Change from Baseline and Treatment Difference from Placebo and Phentermine at Week 8 APBM Measure Change from Baseline Treatment Difference Placebo (n=130) QSYMIA 15 mg/ 92 mg (n=122) Phentermine 30 mg (n=133) Qsymia – Placebo Qsymia - Phentermine Phentermine - Placebo SBP (mmHg) Mean (95% CI) -0.1 (-2.2, +1.9) -3.3 (-5.4, -1.2) +1.4 (-0.7, +3.4) -3.2 (-5.5, -0.9) -4.7 (-7.0, -2.5) +1.5 (-0.7, +3.7) DBP (mmHg) Mean (95% CI) -0.4 (-1.6, +0.9) +0.8 (-0.4, +2.1) +2.4 (+1.1, +3.6) +1.2 (-0.2, +2.6) -1.5 (-2.9, -0.2) +2.7 (+1.4, +4.1) HR (bpm) Mean (95% CI) -1.0 (-2.4, +0.4) +2.6 (+1.2, +4.0) +6.2 (+4.8, +7.6) +3.6 (+2.1, +5.2) -3.6 (-5.2, -2.1) +7.2 (+5.7, +8.8) SBP=systolic blood pressure; DBP=diastolic blood pressure; HR=heart rate; BPM=beats per minute; ABPM=ambulatory blood pressure monitoring; CI=confidence interval An analysis of covariance (ANCOVA) model was used in the per protocol population (observed and single imputation data) to evaluate change from baseline and between-group differences. 12.3 Pharmacokinetics Absorption Phentermine Upon oral administration of a single QSYMIA 15 mg/92 mg, the resulting mean plasma phentermine maximum concentration (Cmax), time to Cmax (Tmax), area under the concentration curve from time zero to the last time with measurable concentration (AUC0-t), and area under the concentration curve from time zero to infinity (AUC0-∞) are 49.1 ng/mL, 6 hr, 1990 ng⋅hr/mL, and 2000 ng⋅hr/mL, respectively. A high fat meal does not affect phentermine pharmacokinetics for QSYMIA 15 mg/92 mg. Phentermine pharmacokinetics are approximately dose-proportional from QSYMIA 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean phentermine accumulation ratios for AUC and Cmax are both approximately 2.5. Topiramate Upon oral administration of a single QSYMIA 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0-∞, are 1020 ng/mL, 9 hr, 61600 ng⋅hr/mL, and 68000 ng⋅hr/mL, respectively. A high fat meal does not affect topiramate pharmacokinetics for QSYMIA 15 mg/92 mg. Topiramate pharmacokinetics are approximately dose-proportional from QSYMIA 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean topiramate accumulation ratios for AUC and Cmax are both approximately 4.0. Distribution Phentermine Phentermine is 17.5% plasma protein bound. The estimated phentermine apparent volume of distribution (Vd/F) is 348 L via population pharmacokinetic analysis. Reference ID: 5481617 Topiramate Topiramate is 15 - 41% plasma protein bound over the blood concentration range of 0.5 to 250 µg/mL. The fraction bound decreased as blood topiramate increased. The estimated topiramate Vc/F (volume of the central compartment), and Vp/F (volume of the peripheral compartment) are 50.8 L, and 13.1 L, respectively, via population pharmacokinetic analysis. Elimination Metabolism and Excretion Phentermine Phentermine has two metabolic pathways, namely p-hydroxylation on the aromatic ring and N-oxidation on the aliphatic side chain. Cytochrome P450 (CYP) 3A4 primarily metabolizes phentermine but does not show extensive metabolism. Monoamine oxidase (MAO)-A and MAO-B do not metabolize phentermine. Seventy to 80% of a dose exists as unchanged phentermine in urine when administered alone. The mean phentermine terminal half-life is about 20 hours. The estimated phentermine oral clearance (CL/F) is 8.79 L/h via population pharmacokinetic analysis. Topiramate Topiramate does not show extensive metabolism. Six topiramate metabolites (via hydroxylation, hydrolysis, and glucuronidation) exist, none of which constitutes more than 5% of an administered dose. About 70% of a dose exists as unchanged topiramate in urine when administered alone. The mean topiramate terminal half-life is about 65 hours. The estimated topiramate CL/F is 1.17 L/h via population pharmacokinetic analysis. Specific Populations Patients with Renal Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of QSYMIA 15 mg/92 mg in adult patients with varying degrees of chronic renal impairment compared to healthy volunteers with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (greater or equal to 50 and less than 80 mL/min), moderate (greater than or equal to 30 and less than 50 mL/min), and severe (less than 30 mL/min). Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault equation. Compared to healthy volunteers, phentermine AUC0-inf was 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine Cmax was 2% to 15% higher. Compared to healthy volunteers, topiramate AUC0-inf was 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate Cmax was 6% to 17% higher. An inverse relationship between phentermine or topiramate Cmax or AUC and creatinine clearance was observed. QSYMIA has not been studied in patients with end-stage renal disease on dialysis [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of QSYMIA 15 mg/92 mg in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 - 6) and moderate (Child-Pugh score 7 - 9) hepatic impairment. In patients with mild and moderate hepatic impairment, phentermine AUC was 37% and 60% higher compared to healthy volunteers. Pharmacokinetics of topiramate was not affected in patients with mild and moderate hepatic impairment when compared with healthy Reference ID: 5481617 volunteers. QSYMIA has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15) [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)]. Pediatric Patients 12 to 17 years old A randomized, double-blind, placebo-controlled study was conducted to evaluate the population pharmacokinetics of QSYMIA using data from 37 pediatric patients (12 to 17 years of age) with obesity. QSYMIA dosages of 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg were studied. QSYMIA exposure in the pediatric patients appeared comparable to that in adults. Drug Interaction Studies In Vitro Assessment of Drug Interactions Phentermine Phentermine is not an inhibitor of CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, and is not an inhibitor of monoamine oxidases. Phentermine is not an inducer of CYP1A2, CYP2B6, and CYP3A4. Phentermine is not a P-glycoprotein substrate. Topiramate Topiramate is not an inhibitor of CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5. However, topiramate is a mild inhibitor of CYP2C19. Topiramate is a mild inducer of CYP3A4. Topiramate is not a P-glycoprotein substrate. Effects of Phentermine/Topiramate on Other Drugs Table 7 describes the effect of phentermine/topiramate on the pharmacokinetics of co-administered drugs. Reference ID: 5481617 Table 7. Effect of Phentermine/Topiramate on the Pharmacokinetics of Co-administered Drugs Phentermine/Topiramate Co-administered Drug and Dosing Regimen Drug and Dose (mg) Change in AUC Change in Cmax 15 mg/92 mg dose QD for 16 days Metformin 500 mg BID for 5 days ↑ 23% ↑ 16% 15 mg/92 mg dose QD for 21 days Sitagliptin 100 mg QD for 5 days ↓ 3% ↓ 9% *15 mg/92 mg dose QD for 15 days Oral contraceptive single dose norethindrone 1 mg ethinyl estradiol 35 mcg ↑ 16% ↓ 16% ↑ 22% ↓ 8% A single study examined the effect of multiple-dose QSYMIA 15 mg/92 mg once daily on the pharmacokinetics of multiple- dose 500 mg metformin twice daily and multiple-dose 100 mg sitagliptin once daily in 10 males and 10 females (mean BMI of 27.1 kg/m2 and range of 22.2 – 32.7 kg/m2). The study participants received metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively. The significance of these interactions is unknown. *See Drug Interactions (7) Effect of Other Drugs on Phentermine/Topiramate Table 8 describes the effect of other drugs on the pharmacokinetics of phentermine/topiramate. Table 8. Effect of Co-administered Drugs on the Pharmacokinetics of Phentermine/Topiramate Co-administered Drug and Dosing Regimen Phentermine/Topiramate Dose (mg) Change in AUC Change in Cmax Topiramate 92 mg single dose 15 mg phentermine single dose ↑ 42% ↑ 13% Phentermine 15 mg single dose 92 mg topiramate single dose ↑ 6% ↑ 2% Metformin 500 mg BID for 5 days 15 mg/92 mg dose QD for 16 days phentermine topiramate ↑ 5% ↓ 5% ↑ 7% ↓ 4% Sitagliptin 100 mg QD for 5 days 15 mg/92 mg dose QD for 21 days phentermine topiramate ↑ 9% ↓ 2% ↑ 10% ↓ 2% Probenecid 2 g QD 15 mg/92 mg dose QD for 11 days phentermine topiramate ↓ 0.3% ↑ 0.7% ↑ 4% ↑ 3% The same single study examined the effect of multiple-dose 500 mg metformin twice daily, a single-dose 2 g probenecid, and multiple-dose 100 mg sitagliptin once daily on the pharmacokinetics of multiple-dose phentermine/topiramate 15 mg/92 mg once daily in 10 males and 10 females (mean BMI of 27.1 kg/m2 and range of 22.2 – 32.7 kg/m2). The study participants received metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively. Effects of Topiramate Alone on Other Drugs and Effects of Other Drugs on Topiramate Antiepileptic Drugs Potential interactions between topiramate and standard antiepileptic (AED) drugs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. In Table 9, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone [see Drug Interactions (7)]. Reference ID: 5481617 Table 9. Summary of AED Interactions with Topiramate AED Co-administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increasea 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxideb NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease a Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramate Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady- state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions (7) and Warnings and Precautions (5.12)]. Pioglitazone A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate (96 mg twice daily) and pioglitazone (30 mg daily) when administered alone and concomitantly for 7 days. A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state (AUCτ,ss) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (Cmax,ss) was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite [see Drug Interactions (7)]. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes mellitus evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxyglyburide (M1), and 3-cis-hydroxyglyburide (M2), was reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Reference ID: 5481617 Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hours) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate [see Drug Interactions (7)]. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem hydrochloride extended-release with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in des- acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem hydrochloride extended-release resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg extended release) did not affect the pharmacokinetics of topiramate. Reference ID: 5481617 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Phentermine/Topiramate No animal studies have been conducted with the combination of phentermine/topiramate to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies performed individually with phentermine or topiramate, QSYMIA’s two active ingredients. Phentermine Phentermine was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in Chinese hamster lung (CHL-K1) cells, or an in vivo micronucleus assay. Rats were administered oral doses of 3, 10, and 30 mg/kg/day phentermine for 2 years. There was no evidence of carcinogenicity at the highest dose of phentermine (30 mg/kg) which is approximately 11 to 15 times the maximum recommended clinical dose of QSYMIA 15 mg/92 mg based on AUC exposure. No animal studies have been conducted with phentermine to determine the potential for impairment of fertility. Topiramate Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo. An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 2 to 4 times steady-state exposures measured in patients receiving topiramate monotherapy at the MRHD of QSYMIA 15 mg/92 mg. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 4 to 10 times the MRHD of QSYMIA based on AUC estimates). No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (approximately 4 to 8 times male and female MRHD exposures of QSYMIA based on AUC). 14 CLINICAL STUDIES Clinical Studies in Adults The effect of QSYMIA on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in two randomized, double-blind, placebo-controlled studies in patients with obesity (Study 1) and patients with obesity or overweight with two or more significant co-morbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment. There were two co-primary efficacy outcomes measured after 1 year of treatment (Week 56): 1) the percent weight loss from baseline; and 2) treatment response defined as achieving at least 5% weight loss from baseline. In Study 1 (NCT00554216), patients with obesity (BMI greater than or equal to 35 kg/m2) were randomized to receive 1 year of treatment with placebo (N=514), QSYMIA 3.75 mg/23 mg (N=241), or QSYMIA 15 mg/92 mg (N=512) in a 2:1:2 ratio. Patients ranged in age from 18-71 years old (mean age 43) and 83% Reference ID: 5481617 were female. Approximately 80% were White, 18% were Black or African American, and 15% were Hispanic or Latino ethnicity. At the beginning of the study the average weight and BMI of patients was 116 kg and 42 kg/m2, respectively. Patients with type 2 diabetes mellitus were excluded from participating in Study 1. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling. In Study 2 (NCT00553787), patients with overweight or obesity were randomized to receive 1 year of treatment with placebo (N=994), QSYMIA 7.5 mg/46 mg (N=498), or QSYMIA 15 mg/92 mg (N=995) in a 2:1:2 ratio. Eligible patients had to have a BMI greater than or equal to 27 kg/m2 and less than or equal to 45 kg/m2 (there was no lower limit on BMI for patients with type 2 diabetes mellitus) and two or more of the following obesity- related co-morbid conditions: • Elevated blood pressure (greater than or equal to 140/90 mmHg, or greater than or equal to 130/85 mmHg for diabetics) or requirement for greater than or equal to 2 antihypertensive medications; • Triglycerides greater than 200-400 mg/dL or were receiving treatment with 2 or more lipid-lowering agents; • Elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; and/or • Waist circumference greater than or equal to 102 cm for men or greater than or equal to 88 cm for females. Patients ranged in age from 19 to71 years of age (mean age 51) and 70% were female. Approximately 86% were White, 12% were Black or African American, and 13% were Hispanic or Latino ethnicity. The average weight and BMI of patients at the start of the study was 103 kg and 36.6 kg/m2, respectively. Approximately half (53%) of patients had hypertension at the start of the study. There were 388 (16%) patients with type 2 diabetes mellitus at the start of the study. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling. The percentage of randomized patients who withdrew from each study prior to week 56 was 40% in Study 1, and 31% in Study 2. Table 10 provides the results for weight loss at 1 year in Studies 1 and 2. After 1 year of treatment with QSYMIA, all dose levels resulted in statistically significant weight loss compared to placebo (see Table 10, Figure 1 and Figure 2). A statistically significant greater proportion of the patients randomized to QSYMIA than placebo achieved 5% and 10% weight loss. Reference ID: 5481617 Table 10. Weight Loss at One Year in Adult Patients in Studies 1 and 2 Analysis Method Study 1 (Obesity) Study 2 (Obesity or Overweight with Co-morbidities) Placebo QSYMIA 3.75 mg/23 mg QSYMIA 15 mg/92 mg Placebo QSYMIA 7.5 mg/46 mg QSYMIA 15 mg/92 mg ITT-LOCF (Primary) n = 498 n = 234 n = 498 n = 979 n = 488 n = 981 Weight (kg) Baseline mean (SD) 115.7 (21.4) 118.6 (21.9) 115.2 (20.8) 103.3 (18.1) 102.8 (18.2) 103.1 (17.6) % LS Mean Change from baseline (SE)** -1.6 (0.4) -5.1 (0.5)† -10.9 (0.4)†‡ -1.2 (0.3) -7.8 (0.4)† -9.8 (0.3)†‡ Difference from placebo (95% CI) 3.5 (2.4-4.7) 9.4 (8.4-10.3) 6.6 (5.8-7.4) 8.6 (8.0-9.3) Percentage of patients losing greater than or equal to 5% body weight 17% 45%† 67%†‡ 21% 62%† 70%†‡ Risk Difference vs. placebo (95% CI) 27.6 (20.4-34.8) 49.4 (44.1- 54.7) 41.3 (36.3- 46.3) 49.2 (45.4- 53.0) Percentage of patients losing greater than or equal to 10% body weight 7% 19%† 47%†‡ 7% 37%† 48%†‡ Risk Difference vs. placebo (95% CI) 11.4 (5.9-16.9) 39.8 (34.8- 44.7) 29.9 (25.3- 34.5) 40.3 (36.7- 43.8) SD=standard deviation; LS=least-squares; SE=standard error; CI=confidence interval * Uses all available data from subjects in ITT population, including data collected from subjects who discontinued drug but remained on study. Last Observation Carried Forward (LOCF) method used to impute missing data. † p < 0.0001 vs. placebo based on least-squares (LS) mean from an analysis of covariance. ‡ p < 0.01 vs. 3.75 mg/23 mg (Study 1) or 7.5 mg/46 mg (Study 2) dose. Type 1 error was controlled across all pairwise treatment comparisons. ** Adjusted for baseline bodyweight (Study 1) and baseline bodyweight and diabetic status (Study 2). Reference ID: 5481617 Figure 1. Study 1 Percent Weight Change from Baseline to Week 56 in Adults with Obesity Figure 2. Study 2 Percent Weight Change from Baseline to Week 56 in Adults with Obesity or Overweight with Co- morbidities The changes in cardiovascular, metabolic, and anthropometric risk factors associated with obesity from Study 1 and 2 are presented in Table 11 and Table 12. Reference ID: 5481617 Table 11. Least-Squares (LS) Mean† Change from Baseline and Treatment Difference from Placebo in Cardiometabolic Parameters in Adults Following One Year of Treatment in Study 1 (Obesity) Study 1 (Obesity) Placebo (N=498) QSYMIA 3.75 mg/23 mg (N=234) QSYMIA 15 mg/92 mg (N=498) QSYMIA – Placebo: LS Mean QSYMIA 3.75 mg/23 mg QSYMIA 15 mg/92 mg Heart Rate, bpm Baseline mean (SD) 73.2 (8.8) 72.3 (9.2) 73.1 (9.6) +1.1 +1.8 LS Mean Change (SE) -0.8 (0.5) +0.3 (0.6) +1.0 (0.5) Systolic Blood Pressure, mmHg Baseline mean (SD) 121.9 (11.5) 122.5 (11.1) 121.9 (11.6) -2.8 -3.8 LS Mean Change (SE) +0.9 (0.6) -1.8 (0.8) -2.9 (0.6) Diastolic Blood Pressure, mmHg Baseline mean (SD) 77.2 (7.9) 77.8 (7.5) 77.4 (7.7) -0.5 -1.9 LS Mean Change (SE) +0.4 (0.4) -0.1 (0.6) -1.5 (0.4) Total Cholesterol, % Baseline mean (SD) 194.3 (36.7) 196.3 (36.5) 192.7 (33.8) -1.9 -2.5 LS Mean Change (SE) -3.5 (0.6) -5.4 (0.9) -6.0 (0.6) LDL-Cholesterol, % Baseline mean (SD) 120.9 (32.2) 122.8 (33.4) 120.0 (30.1) -2.2 -2.8 LS Mean Change (SE) -5.5 (1.0) -7.7 (1.3) -8.4 (0.9) HDL-Cholesterol, % Baseline mean (SD) 49.5 (13.3) 50.0 (11.1) 49.7 (11.7) +0.5 +3.5 LS Mean Change (SE) +0.0 (0.8) +0.5 (1.1) +3.5 (0.8) Triglycerides, % Baseline mean (SD) 119.0 (39.3) 117.5 (40.3) 114.6 (37.1) -3.9 -14.3 LS Mean Change (SE) +9.1 (2.3) +5.2 (3.1) -5.2 (2.2) Fasting Glucose, mg/dL Baseline mean (SD) 93.1 (8.7) 93.9 (9.2) 93.0 (9.5) -1.2 -2.5 LS Mean Change (SE) +1.9 (0.5) +0.8 (0.7) -0.6 (0.5) Waist Circumference, cm Baseline mean (SD) 120.5 (14.0) 121.5 (15.2) 120.0 (14.7) -2.5* -7.8* LS Mean Change (SE) -3.1 (0.5) -5.6 (0.6) -10.9 (0.5) SD=standard deviation; SE=standard error * Statistically significant versus placebo based on the pre-specified method for controlling Type I error across multiple doses † Study 1 adjusted for baseline bodyweight Reference ID: 5481617 Table 12. Least-Squares (LS) Mean† Change from Baseline and Treatment Difference from Placebo in Cardiometabolic Parameters in Adults Following One Year of Treatment in Study 2 (Obese or Overweight with Comorbidities) Study 2 (Overweight and Obese with Comorbidities) Placebo (N=979) QSYMIA 7.5 mg/46 mg (N=488) QSYMIA 15 mg/92 mg (N=981) QSYMIA – Placebo: LS Mean QSYMIA 7.5 mg/46 mg QSYMIA 15 mg/92 mg Heart Rate, bpm Baseline mean (SD) 72.1 (9.9) 72.2 (10.1) 72.6 (10.1) +0.6 +1.7 LS Mean Change (SE) -0.3 (0.3) +0.3 (0.4) +1.4 (0.3) Systolic Blood Pressure, mmHg Baseline mean (SD) 128.9 (13.5) 128.5 (13.6) 127.9 (13.4) -2.3 -3.2 LS Mean Change (SE) -2.4 (0.48) -4.7 (0.63) -5.6 (0.5) Diastolic Blood Pressure, mmHg Baseline mean (SD) 81.1 (9.2) 80.6 (8.7) 80.2 (9.1) -0.7 -1.1 LS Mean Change (SE) -2.7 (0.3) -3.4 (0.4) -3.8 (0.3) Total Cholesterol, % Baseline mean (SD) 205.8 (41.7) 201.0 (37.9) 205.4 (40.4) -1.6 -3.0 LS Mean Change (SE) -3.3 (0.5) -4.9 (0.7) -6.3 (0.5) LDL-Cholesterol, % Baseline mean (SD) 124.2 (36.2) 120.3 (33.7) 123.9 (35.6) +0.4 -2.8 LS Mean Change (SE) -4.1 (0.9) -3.7 (1.1) -6.9 (0.9) HDL-Cholesterol, % Baseline mean (SD) 48.9 (13.8) 48.5 (12.8) 49.1 (13.8) +4.0 +5.6 LS Mean Change (SE) +1.2 (0.7) +5.2 (0.9) +6.8 (0.7) Triglycerides, % Baseline mean (SD) 163.5 (76.3) 161.1 (72.2) 161.9 (73.4) -13.3 -15.3 LS Mean Change (SE) +4.7 (1.7) -8.6 (2.2) -10.6 (1.7) Fasting Insulin, (µIU/mL) Baseline mean (SD) 17.8 (13.2) 18.0 (12.9) 18.4 (17.5) -4.2 -4.7 LS Mean Change (SE) +0.7 (0.8) -3.5 (1.1) -4.0 (0.8) Fasting Glucose, mg/dL Baseline mean (SD) 106.6 (23.7) 106.2 (21.0) 105.7 (21.4) -2.4 -3.6 LS Mean Change (SE) +2.3 (0.6) -0.1 (0.8) -1.3 (0.6) Waist Circumference, cm Baseline mean (SD) 113.4 (12.2) 112.7 (12.4) 113.2 (12.2) -5.2* -6.8* LS Mean Change (SE) -2.4 (0.3) -7.6 (0.4) -9.2 (0.3) SD=standard deviation; SE=standard error * Statistically significant versus placebo based on the pre-specified method for controlling Type I error across multiple doses † Study 2 adjusted for baseline bodyweight and diabetic status Among the 388 subjects with type 2 diabetes mellitus treated in Study 2, reductions in HbA1c from baseline (6.8%) were 0.1% for placebo compared to 0.4% and 0.4% with QSYMIA 7.5 mg/46 mg and QSYMIA 15 mg/92 mg, respectively. Clinical Studies in Pediatric Patients Aged 12 Years and Older The effect of QSYMIA on BMI in conjunction with reduced caloric intake and increased physical activity was evaluated in Study 3 (NCT03922945), a 56-week, randomized, double-blind, placebo-controlled study in pediatric patients (12 to 17 years of age) with BMI ≥ 95th percentile standardized by age and sex. Patients were randomized to receive treatment with placebo (N=56), QSYMIA 7.5 mg/46 mg (N=54), or QSYMIA 15 mg/92 mg (N=113) in a 1:1:2 ratio. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered a family-based lifestyle modification program for adolescents. Patients’ mean age was 14 years old, approximately 55% were female, 67% were White, 26% were Black or African American, and 33% were Hispanic or Latino ethnicity. At the beginning of the study, the average weight and BMI of patients was 106 kg and 38 kg/m2, respectively, with approximately 81% considered Reference ID: 5481617 severely obese (120% of the 95th percentile or greater for BMI standardized by age and sex). Thirty-eight (38%) of randomized patients withdrew from the study prior to week 56. The primary efficacy parameter was mean percent change in BMI. Table 13 provides results for BMI reduction at Week 56 in Study 3. After 56 weeks of treatment with QSYMIA, all dose levels resulted in statistically significant reduction in BMI compared to placebo (see Table 13, Figure 3). A greater proportion of patients randomized to QSYMIA than placebo achieved 5%, 10%, and 15% BMI reduction. Table 13. Change in BMI at Week 56 in Pediatric Patients Aged 12 to 17 Years in Study 3 (Obesity) Analysis Method Placebo QSYMIA 7.5 mg/46 mg QSYMIA 15 mg/92 mg ITT-Washout (Primary)* n = 56 n = 54 n = 113 BMI (kg/m2) Primary Efficacy Endpoint Baseline mean (SD) 36.4 (6.4) 36.9 (6.7) 39.0 (7.4) % LS Mean Change from baseline (SE) +3.3 (1.4) -4.8 (1.3) -7.1 (1.0) Difference from placebo (95% CI) -8.1 (-11.9, -4.3) -10.4 (-13.9, -7.0) Percentage of patients with a reduction of greater than or equal to 5% BMI 13.6% 44.0% 52.2% Difference vs. placebo (95% CI) 29.7% (11.2, 48.3) 38.6% (23.1, 54.1) Percentage of patients with a reduction of greater than or equal to 10% BMI 4.5% 33.5% 44.4% Difference vs. placebo (95% CI) 28.8% (13.6, 44.0) 40.5% (28.4, 52.6) Percentage of patients with a reduction of greater than or equal to 15% BMI 2.9% 13.6% 28.9% Difference vs. placebo (95% CI) 11.7% (1.3, 22.2) 27.4% (17.7, 37.1) SD=standard deviation; LS=least-squares; SE=standard error; CI=confidence interval Missing data were imputed using a washout multiple imputation method based on placebo response. Reference ID: 5481617 Figure 3. Study 3 Percent BMI Change from Baseline to Week 56 in Pediatric Patients Aged 12 to 17 Years with Obesity Reference ID: 5481617 The changes in cardiovascular, metabolic, and anthropometric risk factors associated with obesity from Study 3 are presented in Table 14. Table 14. Change from Baseline and Treatment Difference from Placebo in Cardiometabolic Parameters in Pediatric Patients Aged 12 to 17 Years Following 56 Weeks of Treatment in Study 3 (Obesity) Study 3 (Obesity) ITT Population Placebo (N=56) QSYMIA 7.5 mg/46 mg (N=54) QSYMIA 15 mg/92 mg (N=113) QSYMIA – Placebo QSYMIA 7.5 mg/46 mg QSYMIA 15 mg/92 mg Heart Rate, bpm Baseline mean (SD) 76.8 (9.9) 78.6 (9.6) 76.2 (9.6) -5.6 3.2 Mean Change (SD) 2.5 (12.4) -3.1 (8.4) 5.7 (11.4) Systolic Blood Pressure, mmHg Baseline mean (SD) 117.7 (10.4) 121.4 (9.2) 117.4 (10.2) -2.8 -1.0 LS Mean Change (SE) +2.9 (1.6) +0.1 (1.5) +1.8 (1.1) Diastolic Blood Pressure, mmHg Baseline mean (SD) 71.7 (8.3) 75.8 (6.7) 72.9 (7.3) -3.2 -2.2 LS Mean Change (SE) +3.4 (1.5) +0.2 (1.3) +1.2 (1.0) Total Cholesterol, mg/dL* Baseline mean (SD) 164.9 (30.9) 160.6 (26.1) 159.4 (32.7) -1.4 -1.2 Mean % Change (SD) -1.8 (10.7) -3.2 (13.1) -3.0 (14.5) LDL-Cholesterol, mg/dL* Baseline mean (SD) 94.1 (26.8) 89.4 (23.7) 90.2 (27.3) -3.9 -2.5 Mean % Change (SD) 0.2 (23.3) -3.7 (15.5) -2.3 (21.6) HDL-Cholesterol, mg/dL Baseline mean (SD) 47.2 (9.7) 47.2 (8.9) 46.7 (10.1) 6.4 5.0 LS Mean % Change (SE) -4.3 (15.1) +2.1 (11.5) +0.7 (9.6) Triglycerides, mg/dL Baseline mean (SD) 118.3 (46.1) 120.1 (61.6) 112.2 (63.2) -11.7 -11.2 LS Mean % Change (SE) +5.6 (8.4) -6.2 (8.0) -5.6 (7.2) HbA1c, %* Baseline mean (SD) 5.5 (0.3) 5.6 (0.4) 5.5 (0.4) -0.2 0.0 Mean Change (SD) -0.2 (0.2) -0.4 (0.3) -0.2 (0.3) Waist Circumference, cm Baseline mean (SD) 111.1 (14.0) 111.9 (15.5) 116.5 (16.8) -5.6 -7.6 LS Mean Change (SE) +0.6 (1.4) -5.0 (1.4) -7.0 (1.1) SD=standard deviation; SE=standard error Parameter was not pre-specified for inferential statistics; descriptive summary of change from baseline provided for subjects with non-missing data at baseline and Week 56. Reference ID: 5481617 16 HOW SUPPLIED/STORAGE AND HANDLING QSYMIA (phentermine and topiramate extended-release capsules) are available as follows (see Table 15): Table 15. QSYMIA Presentations Strength (phentermine mg/topiramate mg) Description How Supplied NDC 3.75 mg/23 mg extended-release capsules Purple cap imprinted with VIVUS, Purple body imprinted with 3.75/23 Unit of Use Bottle (14 capsules) 62541-201-14 Pharmacy Bottle (30 capsules) 62541-201-30 7.5 mg/46 mg extended-release capsules Purple cap imprinted with VIVUS, Yellow body imprinted with 7.5/46 Unit of Use Bottle (30 capsules) 62541-202-30 11.25 mg/69 mg extended-release capsules Yellow cap imprinted with VIVUS, Yellow body imprinted with 11.25/69 Pharmacy Bottle (30 capsules) 62541-203-30 15 mg/92 mg extended-release capsules Yellow cap imprinted with VIVUS, White body imprinted with 15/92 Unit of Use Bottle (30 capsules) 62541-204-30 3.75 mg/23 mg and 7.5 mg/46 mg extended-release capsules Purple cap imprinted with VIVUS, Purple body imprinted with 3.75/23 and Purple cap imprinted with VIVUS, Yellow body imprinted with 7.5/46 Starter Pack - Blister Configuration (28 Capsules) 62541-210-28 11.25 mg/69 mg and 15 mg/92 mg extended-release capsules Yellow cap imprinted with VIVUS, Yellow body imprinted with 11.25/69 Dose Escalation Pack – Blister Configuration (28 Capsules) 62541-220-28 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture. Reference ID: 5481617 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Inform patients who can become pregnant that QSYMIA can cause fetal harm and patients should avoid getting pregnant while taking QSYMIA [see Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.3)]. Advise patients who can become pregnant: • that pregnancy testing is recommended before initiating QSYMIA and monthly during therapy; • to use effective contraception during QSYMIA therapy; • who experience spotting while taking a combined oral contraceptive to notify their health care provider; • with a known or suspected pregnancy to stop QSYMIA immediately and notify their health care provider. Access to QSYMIA Advise patients that QSYMIA is only available through certified pharmacies that are enrolled in the QSYMIA certified pharmacy network. Advise patients on how to access QSYMIA through certified pharmacies. Additional information may be obtained via the website www.QSYMIAREMS.com or by telephone at 1-888- 998-4887. Suicidal Behavior and Ideation and Mood and Sleep Disorders Inform patients that QSYMIA can increase the risk of mood changes, sleep disorders, depression, and suicidal ideation. Advise patients to tell their health care provider(s) immediately if mood changes, depression, or suicidal ideation occur [see Warnings and Precautions (5.2, 5.4)]. Ophthalmologic Adverse Reactions Inform patients that QSYMIA can increase the risk of acute myopia, secondary angle closure glaucoma, and visual field defects. Advise patients to immediately report symptoms of severe and persistent eye pain or significant changes in their vision to their health care provider(s) [see Warnings and Precautions (5.3)]. Cognitive Impairment Inform patients that QSYMIA can cause confusion, concentration, and word-finding difficulties. Inform patients that the concomitant use of alcohol or central nervous system (CNS) depressant drugs with QSYMIA, may increase the risk of dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination and somnolence. Advise patients to tell their health care provider(s) about any changes in attention, concentration, memory, difficulty finding words, or other cognitive functions. Advise patients not to drive or operate machinery until they have gained sufficient experience on QSYMIA to gauge whether it adversely affects their mental performance, motor performance, and/or vision. Advise patients to avoid excessive alcohol intake while taking QSYMIA [see Warnings and Precautions (5.5)]. Slowing of Linear Growth Reference ID: 5481617 Discuss with the patient and caregiver that long-term QSYMIA treatment may attenuate growth as reflected by slower height increase in pediatric patients [see Warnings and Precautions (5.6)]. Metabolic Acidosis Inform patients that QSYMIA can increase the risk of metabolic acidosis. Advise patients to tell their health care provider(s) about any factors that can increase the risk of acidosis (e.g. prolonged diarrhea, surgery, and high protein/low carbohydrate diet, and/or concomitant medications such as carbonic anhydrase inhibitors) [see Warnings and Precautions (5.7)]. Risk of Seizures with Abrupt Withdrawal of QSYMIA Inform patients that abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. Advise patients not to abruptly stop QSYMIA without first talking to their health care provider(s) [see Dosage and Administration (2.3) and Warnings and Precautions (5.9)]. Kidney Stones Inform patients that use of QSYMIA has been associated with kidney stone formation. Advise patients to increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation. Advise patients to report symptoms of severe side or back pain, and/or blood in their urine to their health care provider(s) [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)]. Oligohidrosis and Hyperthermia Inform patients that oligohidrosis (decreased sweating) has been reported in association with the use of topiramate particularly in pediatric patients. Advise patients to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather [see Warnings and Precautions (5.11)]. Serious Skin Reactions Inform patients that serious skin reactions have been reported with use of topiramate. Inform patients of the signs of serious skin reactions and advise patients to report signs of a skin reaction to their health care provider(s) [see Warning and Precautions (5.13)]. Lactation Advise patients that breastfeeding is not recommended during QSYMIA treatment [see Use in Specific Populations (8.2)]. Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5 Inform patients that this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons [see Warnings and Precautions (5.14)]. How to Take QSYMIA Instruct patients on the dosage titration schedule of QSYMIA. Advise patients to take QSYMIA in the morning with or without food [see Dosage and Administration (2.2)]. Reference ID: 5481617 Manufactured for VIVUS LLC by Catalent Pharma Solutions, LLC 1100 Enterprise Drive Winchester, KY 40391 Copyright © 2012 - 2023 VIVUS LLC All rights reserved. VIVUS LLC 900 E. Hamilton Ave., Suite 550 Campbell, CA 95008 USA US Patent Numbers: 7,056,890; 7,553,818; 7,659,256; 7,674,776; 8,580,298; 8,580,299; 8,895,057; 8,895,058, 9,011,905; and 9,011,906 QSYMIA IS A REGISTERED TRADEMARK OF VIVUS LLC Reference ID: 5481617 RE-03-001-07 Risk Evaluation and Mitigation Strategy (REMS) Document Qsymia (phentermine and topiramate extended-release capsules) REMS I. Administrative Information Risk: Embryo-fetal toxicity Application Number: NDA 22580 (and authorized generic) Application Holder: VIVUS LLC Initial REMS Approval: 07/2012 Most Recent REMS Update: 11/2024 II. REMS Goal To inform certified pharmacies and patients of reproductive potential about: 1. The increased risk of embryo-fetal toxicity with major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) in a fetus exposed to Qsymia during the first trimester of pregnancy 2. The importance of pregnancy prevention for patients of reproductive potential receiving Qsymia 3. The need to discontinue Qsymia immediately if pregnancy occurs III. REMS Requirements VIVUS LLC must ensure that pharmacies and wholesalers-distributors comply with the following requirements: 1. Pharmacies that dispense Qsymia must: To become certified to dispense 1. Designate an Authorized Representative to carry out the certification process and oversee implementation and compliance with the REMS on behalf of the pharmacy. 2. Have the Authorized Representative successfully complete the Qsymia REMS Pharmacy Training. 3. Have the Authorized Representative enroll in the REMS on behalf of the pharmacy by completing and submitting the Pharmacy Enrollment Form to the REMS. 4. Train all relevant staff involved in dispensing on the risks associated with Qsymia and requirement to provide the Medication Guide and Risk of Birth Defects with Qsymia using the Qsymia REMS Pharmacy Training. 5. Establish processes and procedures to provide the Medication Guide and the Risk of Birth Defects with Qsymia to each patient each time Qsymia is dispensed. Reference ID: 5481617 RE-03-001-07 Before dispensing 6. Provide the patient with the Medication Guide and the Risk of Birth Defects with Qsymia through the processes and procedures established as a requirement of the REMS. To maintain certification to dispense 7. Have the new Authorized Representative enroll in the REMS by completing the Pharmacy Training and completing and submitting the Pharmacy Enrollment Form if the Authorized Representative changes. At all times 8. Not distribute, transfer, loan, or sell Qsymia. 9. Maintain records of standard operating procedures, training, and providing the Medication Guide and the Risk of Birth Defects with Qsymia. 10. Maintain and submit annual compliance reports to the REMS. 11. Comply with audits carried out by VIVUS LLC or a third party acting on behalf of VIVUS LLC to ensure that all processes and procedures are in place and are being followed. 2. Wholesalers-distributors that distribute Qsymia must: To be able to distribute 1. Establish processes and procedures to ensure that the drug is distributed only to certified pharmacies. At all times 2. Distribute only to certified pharmacies. 3. Maintain and submit annual compliance reports of adherence to distribution requirements of the REMS. 4. Comply with audits carried out by VIVUS LLC or a third party acting on behalf of VIVUS LLC to ensure that all processes and procedures are in place and are being followed. VIVUS LLC must provide training to pharmacies who dispense Qsymia. The training includes the following educational material: Qsymia REMS Pharmacy Training. The training must be available online and hard copy by mail or fax. To support REMS operations, VIVUS LLC must: 1. Establish and maintain a REMS website, www.QsymiaREMS.com. The REMS website must include the capability to complete pharmacy certification via fax or email, to locate certified pharmacies, and the option to print the Prescribing Information, Medication Guide, and REMS materials. The product website for consumers and healthcare providers must include prominent REMS-specific links to the REMS website. The REMS website must not link back to the promotional product website. 2. Make the REMS website fully operational and all REMS materials are available through the website within 90 calendar days of REMS modification. 3. Establish and maintain a Support Center for REMS participants at 1-888-998-4887 and a REMS Pharmacy Support Center for pharmacists at 1-855-302-6698. 4. Establish and maintain a validated, secure database of all REMS participants who are Reference ID: 5481617 RE-03-001-07 enrolled and/or certified in the Qsymia REMS. 5. Ensure pharmacies are able to become certified via fax or email. 6. Ensure that a Medication Guide is made available for dispensing with each Qsymia prescription. 7. Provide the Qsymia REMS Pharmacy Training and the Prescribing Information to pharmacies who (1) attempt to dispense Qsymia and are not yet certified or (2) inquire about how to become certified. 8. Notify pharmacies within 5 business days after they become certified in the REMS. 9. Provide authorized wholesalers-distributors access to the database of certified pharmacies. To ensure REMS participants’ compliance with the REMS, VIVUS LLC must: 10. Maintain adequate records to demonstrate that REMS requirements have been met, including, but not limited to records of: Qsymia distribution and dispensing, certification of pharmacies, and audits of REMS participants. These records must be readily available for FDA inspections. 11. Establish and maintain a plan for addressing noncompliance with REMS requirements. 12. Monitor pharmacies and wholesalers-distributors on an ongoing basis to ensure the requirements of the REMS are being met. Take corrective action if non-compliance is identified, including de-certification. 13. Audit certified pharmacies in accordance with the audit plan no later than 180 calendar days after they become certified and conduct ongoing audits of pharmacies in accordance with the audit plan to ensure that all REMS processes and procedures are in place, functioning, and support the REMS requirements. 14. Audit wholesalers-distributors no later than 180 calendar days after the wholesaler- distributor is authorized and every two years thereafter to ensure that all processes and procedures are in place, functioning, and support the REMS requirements. 15. Take reasonable steps to improve implementation of and compliance with the requirements in the Qsymia REMS based on monitoring and evaluation of the Qsymia REMS. IV. REMS Assessment Timetable VIVUS LLC must submit REMS Assessments at 6 months and 12 months from the date of initial approval of the REMS and annually thereafter. To facilitate inclusion of as much information as possible while allowing reasonable time to prepare the submission, the reporting interval covered by each assessment should conclude no earlier than 60 calendar days before the submission date for that assessment. VIVUS LLC must submit each assessment so that it will be received by the FDA on or before the due date. V. REMS Materials The following materials are part of the Qsymia REMS: Enrollment Forms Pharmacy 1. Pharmacy Enrollment Form Reference ID: 5481617 RE-03-001-07 Training and Educational Materials Pharmacy: 2. Qsymia REMS Pharmacy Training Patient: 3. Medication Guide 4. Risk of Birth Defects with Qsymia Other Materials 5. REMS Website VI. Statutory Elements This REMS is required under section 505-1 of the Federal Food, Drug and Cosmetic Act (FD&C Act) (21.U.S.C. 355-1) and consists of the following elements: • Medication Guide • Elements to Assure Safe Use: • Pharmacies and health care settings that dispense Qsymia are specially certified under 505-1(f)(3)(B) • Implementation System • Timetable for Submission of Assessments Reference ID: 5481617 Page 1 of 2 Qsymia® Risk Evaluation and Mitigation Strategy (REMS) Pharmacy Enrollment Form Because of the teratogenic risk associated with Qsymia therapy, Qsymia is available through a limited program under a REMS. Under the Qsymia REMS, only certified pharmacies may distribute Qsymia. I understand that my certified pharmacy and any retail chain pharmacy dispensing locations associated with my pharmacy must comply with the program requirements for certified pharmacies and the terms contained in this form. As the Authorized Representative, I must: • Carry out the certification process and oversee implementation and compliance with the Qsymia REMS on behalf of the pharmacy • Complete the Qsymia REMS Pharmacy Training • Complete the Pharmacy Enrollment Form and fax or email the form to the Qsymia REMS Pharmacy Support Center • Train all relevant staff involved in dispensing on the risks associated with Qsymia and the requirement to provide the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure using the Qsymia REMS Pharmacy Training • Establish processes and procedures to provide the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure to each patient each time Qsymia is dispensed Before dispensing, all pharmacy staff must: • Provide the patient with the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure through the processes and procedures established as a requirement of the REMS program At all times, all pharmacy staff must: • Not distribute, transfer, loan, or sell Qsymia • Maintain records of standard operating procedures, training, and providing the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure • Maintain and submit annual compliance reports to the Qsymia REMS • Comply with audits carried out by VIVUS to ensure that all processes and procedures are in place and are being followed • Have a new Authorized Representative enroll in the Qsymia REMS by completing the Qsymia REMS Pharmacy Training and the Pharmacy Enrollment Form Reference ID: 5481617 RE-03-031-01 © 2024 VIVUS LLC All rights reserved. 02/2024 Page 2 of 2 Authorized Representative to complete (all fields required): First Name Last Name Phone Number Fax Email Pharmacy Name Pharmacy Type (Corporate, Independent, Mail Order, Closed System) _________________________ Pharmacy DEA_____________ Pharmacy NCPDP__________ Pharmacy NPI ____________ Address City State Zip Code Signature Date Authorized Representative Please fax the completed form to the Qsymia REMS Pharmacy Support Center at 855-302-6699 or email the form to VivusUSREMS.sm@ppd.com. Once this form is successfully processed, you will receive a pharmacy enrollment confirmation via email from VIVUS. Your pharmacy will be considered certified to order, receive, and dispense Qsymia. Important Enrollment Information for Corporate Chain Entities with Retail Chain Pharmacy Dispensing Locations The Qsymia REMS Pharmacy Training for retail chain pharmacy dispensing locations is available through the Qsymia REMS website (www.QsymiaREMS.com). Once the Training and Knowledge Assessment are completed at a pharmacy dispensing location within your organization, it is the responsibility of the Authorized Representative to capture the following required pharmacy dispensing location information for each trained retail chain pharmacy dispensing location and submit the information to VIVUS: • Dispensing pharmacy address • Phone and fax numbers • Pharmacy DEA, NCPDP, and NPI numbers Once VIVUS receives, processes, and confirms the required retail chain pharmacy dispensing location information from the Authorized Representative, the pharmacy dispensing location will be considered certified and permitted to order, receive, and dispense Qsymia. If you have any questions or require additional information, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698. Reference ID: 5481617 www.QsymiaREMS.com 1 Qsymia® (phentermine and topiramate extended-release capsules) for oral use, CIV Pharmacy Training Overview The Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for Qsymia to ensure the beneﬁts of Qsymia outweigh the increased risk of teratogenicity. Purpose The goal of the Qsymia REMS is to inform certiﬁed pharmacies and patients of reproductive potential (PRP) about the: • Increased risk of embryo-fetal toxicity with major congenital malformations, including but not limited to cleft lip and/or cleft palate oral clefts) and of being mall for gestational age (SGA) in a fetus exposed to Qsymia during the ﬁrst trimester of pregnancy • Importance of pregnancy prevention for PRP • Need to discontinue Qsymia immediately if pregnancy occurs Complete the Qsymia Pharmacy Certiﬁcation in 3 easy steps: 1. Designate an Authorized Representative to carry out the certiﬁcation process and oversee implementation and compliance with the Qsymia REMS. 2. Read through the entirety of this Qsymia REMS Pharmacy Training and conﬁrm you understand the content by completing the Knowledge Assessment questions. - For dispensing locations of corporate chain pharmacies, your training and knowledge assessment will be managed by your corporate Authorized Representative. Please contact your corporate Authorized Representative for instructions on completing your training and knowledge assessment. 3. Complete the Pharmacy Enrollment Form and fax the form to the Qsymia REMS Pharmacy Support Center at 1-855- 302-6699 or email the form to VivusUSREMS.sm@ppd.com. Reference ID: 5481617 www.QsymiaREMS.com 2 Complete the Qsymia Pharmacy Training Indication and Patient Selection Qsymia is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with obesity • Adults with overweight in the presence of at least one weight-related comorbid condition Limitations of use: • The e^ect of Qsymia on cardiovascular morbidity and mortality has not been established. • The safety and e^ectiveness of Qsymia in combination with other products intended for weight loss including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. These training materials are being provided to assist pharmacists with understanding the risks of Qsymia and the pharmacy requirements under the REMS. Before you are eligible to dispense Qsymia, it is important to be aware of the increased risk of embryo-fetal toxicity associated with Qsymia therapy. The information presented in this training does not include a complete list of all risks and safety information on Qsymia. Before dispensing Qsymia, please read the accompanying Qsymia Prescribing Information, Qsymia Medication Guide, and the Risk of Birth Defects with Qsymia patient brochure. Further information is also available on the Website, www.QsymiaREMS.com, or by calling the Qsymia REMS Pharmacy Support Center at 1-855-302-6698. Reference ID: 5481617 www.QsymiaREMS.com 3 Qsymia is only dispensed through Certiﬁed Pharmacies To become a certiﬁed pharmacy, the Authorized Representative must: • Carry out the certiﬁcation process and oversee implementation and compliance with the Qsymia REMS on behalf of the pharmacy • Complete the Pharmacy Training • Complete the Pharmacy Enrollment Form and submit it to the Qsymia REMS • Train all relevant sta^ involved in dispensing on the risks associated with Qsymia and the requirement to provide the Medication Guide and Risk of Birth Defects with Qsymia patient brochure using the Pharmacy Training • Establish processes and procedures to provide the Medication Guide and Risk of Birth Defects with Qsymia patient brochure to each patient each time the drug is dispensed To become a certiﬁed pharmacy, the Authorized Representative must: • Provide the patient with the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure through the processes and procedures established as a requirement of the Qsymia REMS At all times, all pharmacy staV must: • Not distribute, transfer, loan, or sell Qsymia • Maintain records of standard operating procedures, training, and providing the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure • Maintain and submit annual compliance reports to the Qsymia REMS • Comply with audits carried out by VIVUS to ensure that all processes and procedures are in place and are being followed • Have a new Authorized Representative enroll in the Qsymia REMS by completing the Qsymia REMS Pharmacy Training and the Pharmacy Enrollment Form The list of certiﬁed pharmacies will be updated within 5 business days after a new pharmacy is certiﬁed and eligible to dispense. Prescribers and patients will be able to use a “Certiﬁed Pharmacy Locator” tool to identify certiﬁed pharmacies in their area and can be found at www.QsymiaREMS.com. Please note that Qsymia is not available outside this network of certiﬁed pharmacies. Reference ID: 5481617 www.QsymiaREMS.com 4 Counseling for Patients of Reproductive Potential Qsymia® can cause fetal harm. Advise patients of reproductive potential that labeling recommends: • Pregnancy testing prior to beginning Qsymia and monthly during therapy. Speciﬁc documentation of the result is not required at the pharmacy level. • Use of e^ective contraception consistently during Qsymia therapy because Qsymia can cause certain kinds of birth defects (oral clefts). Even patients who believe they cannot become pregnant should use e^ective contraception while taking Qsymia due to the potential for increased fertility associated with weight loss. • If a patient becomes pregnant while taking Qsymia, Qsymia should be discontinued immediately and the patient advised to notify their healthcare provider. Acceptable Contraception Methods For Patients of Reproductive Potential Option 1 Highly E^ective Methods to Use Alone Option 2 Acceptable Methods to Use Together Option 3 Acceptable Methods to Use Together Patients of reproductive potential are patients who have NOT had a hysterectomy, bilateral oophorectomy, or medically documented spontaneous ovarian failure, and have not gone through menopause. Menopause should be clinically conﬁrmed by an individual’s healthcare provider. Advise nursing mothers not to use Qsymia. Qsymia may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. OR OR Barrier Method • Diaphragm (with spermicide) • Cervical cap (with spermicide) Hormonal Contraception • Estrogen and progestin - Oral (the pill) - Transdermal patch - Vaginal ring • Progestin only - Oral - Injection • Intrauterine device (IUD) or intrauterine system (IUS) - Copper IUD - Levonorgestrel-releasing IUS • Progestin implant • Tubal sterilization • Male partner’s vasectomy One method from this list One method from this list One method from this list Barrier Method • Male condom (with or without spermicide) One method from this list Barrier Method • Diaphragm (with spermicide) • Cervical cap (with spermicide) • Male condom (with or without spermicide) One method from this list Reference ID: 5481617 www.QsymiaREMS.com 5 Counseling for All Patients • The Medication Guide and patient brochure contain important information that patients should read and become familiar with. • Qsymia should be taken in the morning, with or without food. • Avoid taking Qsymia in the evening due to the possibility of insomnia. • Advise patients to start treatment with Qsymia as follows: • Take one Qsymia capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) once each morning for the ﬁrst 14 days • After the ﬁrst 14 days, take one Qsymia 7.5 mg/46 mg capsule once each morning • Do not take Qsymia 3.75 mg/23 mg and Qsymia 7.5/46 mg capsules together • If an increase in Qsymia dose is prescribed, advise patients to increase the dose of Qsymia as follows: • Take one Qsymia 11.25 mg/69 mg capsule once each morning for 14 days • After the 14 days, take one Qsymia 15 mg/92 mg capsule once each morning • Do not take Qsymia 11.25 mg/69 mg and Qsymia 15 mg/92 mg capsules together • Advise patients NOT to stop Qsymia without talking with their healthcare provider as serious side e^ects such as seizures may occur. Additional information and tools Additional information and tools can be found at www.QsymiaREMS.com • Risk of Birth Defects with Qsymia patient brochure • Qsymia Prescribing Information • Qsymia Medication Guide For more information about Qsymia, contact VIVUS Medical Information at 1-888-998-4887 or visit www.Qsymia.com. For more information on the Qsymia REMS or pharmacy enrollment, contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 or visit www.QsymiaREMS.com. Reference ID: 5481617 www.QsymiaREMS.com 6 Important Safety Information Qsymia® is contraindicated in pregnancy; in patients with glaucoma; in hyperthyroidism; in patients receiving treatment or within 14 days following treatment with monoamine oxidase inhibitors (MAOIs); or in patients with hypersensitivity or idiosyncrasy to sympathomimetic amines, topiramate, or any of the inactive ingredients in Qsymia. Qsymia can cause fetal harm. Patients of reproductive potential should have a pregnancy test before treatment and monthly thereafter and use eEective contraception consistently during Qsymia therapy. If a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be informed of the potential hazard to the fetus. Topiramate, a component of Qsymia, increases the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue Qsymia in patients who experience suicidal thoughts or behaviors. Qsymia is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Acute angle closure glaucoma has been reported in patients treated with topiramate, a component of Qsymia. Symptoms include acute onset of decreased visual acuity and/or eye pain. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of Qsymia. Visual ﬁeld defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. Qsymia can cause mood disorders, including depression, and anxiety, as well as insomnia. Qsymia can cause cognitive dysfunction (e.g., impairment of concentration/attention, diEiculty with memory, and speech or language problems, particularly word-ﬁnding diEiculties). Since Qsymia has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles. Hyperchloremic, non-anion gap, metabolic acidosis has been reported in patients treated with Qsymia. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Qsymia. Qsymia can cause an increase in serum creatinine. If persistent elevations in creatinine occur while taking Qsymia, reduce the dose or discontinue Qsymia. Qsymia can cause slowing of linear growth. Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected. Qsymia can cause serious skin reactions and should be discontinued at the ﬁrst sign of a rash, unless the rash is clearly not drug- related. The most commonly observed side eEects in controlled clinical studies, ≥5% and at least 1.5 times placebo, include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. To report negative side eEects, contact VIVUS LLC at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Reference ID: 5481617 www.QsymiaREMS.com 7 Conﬁrm Understanding through the Knowledge Assessment Completing the Qsymia REMS Pharmacy Training Conﬁrm that you’ve read through and understand the Qsymia Pharmacy Training by completing the Knowledge Assessment questions and required Pharmacy Enrollment Form. Knowledge assessment questions (choose True or False): True False 1 The major risk for patients of reproductive potential (PRP) is that of embryo-fetal toxicity, including but not limited to the risk of cleft lip with or without cleft palate and of being small for gestational age. 2 If a patient thinks they are pregnant, they should continue taking Qsymia until the pregnancy is conﬁrmed 3 The Qsymia REMS speciﬁcally prohibits certiﬁed pharmacies from redistributing, transferring, loaning, or reselling Qsymia to another pharmacy distributor. 4 The Medication Guide and patient brochure Risk of Birth Defects with Qsymia should be dispensed only with new prescriptions. 5 Qsymia is not available outside the network of certiﬁed pharmacies. Reference ID: 5481617 www.QsymiaREMS.com 8 Pharmacy Knowledge Assessment Answers 1 of 5 True or False: The major risk for patients of reproductive potential (PRP) is that of embryo-fetal toxicity, including but limited to the risk of cleft lip with or without cleft palate and of being small for gestational age. 2 of 5 True or False: If a patient thinks they are pregnant, they should continue taking Qsymia until the pregnancy is conﬁrmed. 3 of 5 True or False: The Qsymia REMS speciﬁcally prohibits certiﬁed pharmacies from reselling or redistributing Qsymia to another pharmacy or distributor. 4 of 5 True or False: The Medication Guide and patient brochure Risk of Birth Defects with Qsymia should be dispensed only with new prescriptions. The correct answer is TRUE The major risk for patients of reproductive potential (PRP) is that of embryo-fetal toxicity, including but not limited to the risk of cleft lip with or without cleft palate and of being small for gestational age. The correct answer is FALSE If a patient believes they might be pregnant, they should stop taking Qsymia immediately and contact their healthcare provider. The correct answer is TRUE To be eligible for initial certiﬁcation, and to maintain ongoing certiﬁcation, pharmacies must agree and abide by the requirement that they not redistribute, transfer, loan, or resell Qsymia to any other pharmacy, distributor, physician’s o^ice, or any other location. Qsymia is only available through the network of certiﬁed pharmacies. The correct answer is FALSE A Medication Guide and patient brochure Risk of Birth Defects with Qsymia must be provided to the patient each time Qsymia is dispensed, whether the prescription being ﬁlled is a new prescription or a reﬁll. This is a condition of certiﬁcation, and systems must be in place to remind the pharmacist of this requirement each time they dispense a prescription for Qsymia. Reference ID: 5481617 www.QsymiaREMS.com 9 Pharmacy Knowledge Assessment Answers (Continued) 5 of 5 True or False: Qsymia is not available outside the network of certiﬁed pharmacies The correct answer is FALSE Qsymia is only available through the network of certiﬁed pharmacies ©2024 VIVUS LLC. All rights reserved. RE-XX-XXX-XX XX/2024 Reference ID: 5481617 MEDICATION GUIDE QSYMIA® (Kyoo sim ee uh) (phentermine and topiramate extended-release capsules) for oral use, CIV What is the most important information I should know about QSYMIA? QSYMIA can cause serious side effects, including: • Birth defects. If you take QSYMIA during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. Your baby may also be smaller than expected at birth. The long-term effects of this are not known. These defects can begin early in pregnancy, even before you know you are pregnant. Patients who are pregnant must not take QSYMIA. Patients who can become pregnant should: 1. Have a pregnancy test before taking QSYMIA and every month while taking QSYMIA. 2. Use effective birth control (contraception) consistently while taking QSYMIA. Talk to your health care provider about how to prevent pregnancy. If you become pregnant while taking QSYMIA, stop taking QSYMIA immediately and tell your health care provider right away. Health care providers and patients who become pregnant should report all cases of pregnancy to:  FDA MedWatch at 1-800-FDA-1088 Because of the risk for birth defects (cleft lip and cleft palate), QSYMIA is available through a restricted program called the QSYMIA Risk Evaluation and Mitigation Strategy (REMS). QSYMIA is only available through certified pharmacies that participate in the QSYMIA REMS program. Your health care provider can give you information about how to find a certified pharmacy. For more information, go to www.QSYMIAREMS.com or call 1-888-998-4887. • Suicidal thoughts or actions. Topiramate, an ingredient in QSYMIA, may cause you to have suicidal thoughts or actions. Call your health care provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood Do not stop QYSMIA without first talking to a health care provider. • Stopping QYSMIA suddenly can cause serious problems. • Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your health care provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your health care provider as scheduled. • Call your health care provider between visits as needed, especially if you are worried about symptoms. • Serious eye problems which include: o any sudden decrease in vision, with or without eye pain and redness, o a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These problems can lead to permanent vision loss if not treated. Tell your health care provider right away if you have any new eye symptoms. QSYMIA can have other serious side effects. See “What are the possible side effects of QSYMIA?” What is QSYMIA? • QSYMIA is a prescription medicine that contains phentermine and topiramate extended-release. QSYMIA may help adults and children 12 years and older with obesity, or some adults with overweight who also have weight-related Reference ID: 5481617 medical problems, to help them lose excess body weight and keep the weight off. • QSYMIA should be used with a reduced calorie diet and increased physical activity. • It is not known if QSYMIA changes your risk of heart problems or stroke or of death due to heart problems or stroke. • It is not known if QSYMIA is safe and effective when taken with other prescription and over-the-counter medicines, or herbal weight loss products. • It is not known if QSYMIA is safe and effective in children under 12 years old. • QSYMIA is a federally controlled substance (CIV) because it contains phentermine and can be abused or lead to drug dependence. Keep QSYMIA in a safe place, to protect it from theft. Never give your QSYMIA to anyone else, because it may cause death or harm them. Selling or giving away QSYMIA is against the law. Who should not take QSYMIA? Do not take QSYMIA if you: • are pregnant, planning to become pregnant, or become pregnant during QSYMIA treatment. • have glaucoma. • have thyroid problems (hyperthyroidism). • are taking certain medicines called monoamine oxidase inhibitors (MAOIs) or have taken MAOIs in the past 14 days. • are allergic to topiramate, sympathomimetic amines such as phentermine, or any of the ingredients in QSYMIA. See the end of this Medication Guide for a complete list of ingredients in QSYMIA. Before taking QSYMIA, tell your health care provider about all of your medical conditions, including if you: • have or have had depression, mood problems, or suicidal thoughts or behavior. • have eye problems, especially glaucoma. See “Who should not take QSYMIA?” • have a history of too much acid in the blood (metabolic acidosis) or a condition that puts you at higher risk for metabolic acidosis such as o chronic diarrhea, surgery, a diet high in fat and low in carbohydrates (ketogenic diet), weak, brittle, or soft bones (osteoporosis, osteomalacia (rickets), osteopenia), or decreased bone density. • have kidney problems, kidney stones, or are getting kidney dialysis. • have liver problems. • have seizures or convulsions (epilepsy). • are breastfeeding or plan to breastfeed. QSYMIA can pass into your breast milk and may harm your baby. You and your health care provider should decide if you will take QSYMIA or breastfeed. You should not do both. Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. QSYMIA taken with other medicines may affect how each medicine works and may cause side effects. Especially tell your health care provider if you take: • Birth control pills. Tell your health care provider if your menstrual bleeding changes while you are taking birth control pills that contain both estrogen and progestin (combination oral contraceptives) and QSYMIA. • Water pills (diuretics) such as hydrochlorothiazide (HCTZ). • Any medicines that impair or decrease your thinking, concentration, or muscle coordination. • Carbonic anhydrase inhibitors such as ZONEGRAN (zonisamide), DIAMOX (acetazolamide) or NEPTAZANE (methazolamide). • Seizure medicines such as Valproic acid (DEPAKENE or DEPAKOTE). Ask your health care provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them to show your health care provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking to your health care provider. How should I take QSYMIA? • Your health care provider should start you on a diet and exercise program when you start taking QSYMIA. Stay on this program while you are taking QSYMIA. • Take QSYMIA exactly as your health care provider tells you to take it. • Do not change your dose without talking to your health care provider. • Take QSYMIA daily in the morning. • QSYMIA can be taken with or without food. • If you miss a dose of QSYMIA, wait until the next morning to take your usual dose of QSYMIA. Do not double your dose. • To start treatment with QSYMIA o Take 1 QSYMIA 3.75 mg (phentermine)/23 mg (topiramate) capsule (Figure A) 1 time each morning for the first 14 days. o After taking QSYMIA 3.75 mg/23 mg capsule for 14 days, then take 1 QSYMIA 7.5 mg/46 mg capsule (Figure B) 1 time each morning. • After taking QSYMIA for 12 weeks o Your health care provider may tell you to increase your dose of QSYMIA if you do not lose a certain amount of Reference ID: 5481617 weight or do not have a certain decrease in BMI for children 12 years and older, within the first 12 weeks of treatment at the recommended dose. • If your health care provider increases the dose of QSYMIA o Take 1 QSYMIA 11.25 mg/69 mg capsule (Figure C) 1 time each morning for 14 days. o After taking 14 days of QSYMIA 11.25 mg/69 mg capsule, then take 1 QSYMIA 15 mg/92 mg capsule (Figure D) 1 time each morning. • Stopping QSYMIA treatment Your health care provider should tell you to stop taking QSYMIA if you have not lost a certain amount of weight or do not have a certain decrease in BMI for children 12 years and older, after an additional 12 weeks of treatment on the higher dose. Do not stop taking QSYMIA without talking to your health care provider. Stopping QSYMIA suddenly can cause serious problems, such as seizures. Your health care provider will tell you how to stop taking QSYMIA slowly. If you take too much QSYMIA, call your health care provider or Poison Help line at 1-800-222-1222 or go to the nearest emergency room right away. What should I avoid while taking QSYMIA? • Do not get pregnant while taking QSYMIA. See “What is the most important information I should know about QSYMIA.” • Do not drink too much alcohol while taking QSYMIA. QSYMIA and alcohol can affect each other causing side effects such as sleepiness or dizziness. • Do not drive a car, operate heavy machinery, or do other dangerous activities until you know how QSYMIA affects you. QSYMIA can slow your thinking and motor skills and may affect vision. What are the possible side effects of QSYMIA? QSYMIA can cause serious side effects, including: • See “What is the most important information I should know about QSYMIA?” • Mood changes and trouble sleeping. QSYMIA may cause depression or mood problems, and trouble sleeping. Tell your health care provider if symptoms occur. • Concentration, memory, and speech difficulties. QSYMIA may affect how you think and cause confusion, problems with concentration, attention, memory, or speech. Tell your health care provider if symptoms occur. • Slowing of growth. QSYMIA may slow the increase in height in children 12 years and older, when used for a long time. • Increases of acid in bloodstream (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia (rickets), osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: o feel tired o not feel hungry (loss of appetite) o feel changes in heartbeat o have trouble thinking clearly Your health care provider should do a blood test to measure the level of acid in your blood before and during your treatment with QSYMIA. • Decrease in kidney function. QSYMIA may cause a decrease in kidney function. Your health care provider should do a blood test to measure your kidney function before and during treatment with QSYMIA. • Possible seizures if you stop taking QSYMIA too fast. Seizures may happen in people who may or may not have had seizures in the past if you stop QSYMIA too fast. Your health care provider will tell you how to stop taking QSYMIA slowly. • Kidney stones. Drink plenty of fluids when taking QSYMIA to help decrease your chances of getting kidney stones. If you get severe side or back pain, or blood in your urine, call your health care provider. Reference ID: 5481617 • Decreased sweating and increased body temperature (fever). People should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. • Low potassium. QSYMIA can increase your risk of low potassium levels. Your health care provider should do a blood test to measure the level of potassium in your blood before and during treatment with QSYMIA. • Serious skin reactions. QSYMIA may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson Syndrome). QSYMIA may also cause a rash with blisters and peeling skin over much of the body that may cause death (Toxic Epidermal Necrolysis). Call your health care provider right away if you develop a skin rash or blisters. • Allergic reaction to FD&C Yellow No. 5. QSYMIA capsules contain the inactive ingredient FD&C Yellow No. 5 (tartrazine) which can cause allergic-type reactions (including bronchial asthma) in certain people, especially people who also have an allergy to aspirin. Common side effects of QSYMIA in adults include: • numbness or tingling in the hands, arms, feet, or face (paraesthesia) • dizziness • change in the way foods taste or loss of taste (dysgeusia) • trouble sleeping (insomnia) • constipation • dry mouth Common side effects of QSYMIA in children 12 years and older include: • depression • dizziness • joint pain • fever • flu • ankle sprain Tell your health care provider if you have any side effect that bothers you or does not go away. These are not all of the possible side effects of QSYMIA. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You can also report side effects to VIVUS at 1-888-998-4887. How should I store QSYMIA? • Store QSYMIA at room temperature between 68°F to 77°F (20°C to 25°C). • Keep QSYMIA in a tightly closed container. • Keep QSYMIA dry and away from moisture. Keep QSYMIA and all medicines out of the reach of children. General Information about the safe and effective use of QSYMIA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use QSYMIA for a condition for which it was not prescribed. Do not give QSYMIA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or health care provider for information about QSYMIA that is written for health professionals. What are the ingredients in QSYMIA? Active Ingredient: phentermine hydrochloride and topiramate extended-release. Inactive Ingredients: FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and #6, ethylcellulose, gelatin, methylcellulose, microcrystalline cellulose, povidone, starch, sucrose, talc, titanium dioxide, and pharmaceutical black and white inks. Copyright © 2024 VIVUS LLC All rights reserved. VIVUS LLC 900 E. Hamilton Ave., Suite 550 Campbell, CA 95008 USA US Patent Numbers: 7,056,890; 7,553,818; 7,659,256; 7,674,776; 8,580,298; 8,580,299; 8,895,057; 8,895,058; 9,011,905; and 9,011,906. QSYMIA is a registered trademark of VIVUS LLC. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2024 ME-03-001- Reference ID: 5481617 Risk of Birth Defects with Qsymia (phentermine and topiramate extended-release capsules), CIV Please read the following important safety information about the use of Qsymia in patients who can become pregnant. You are considered a patient who can become pregnant if this applies to you: • You have never had a hysterectomy (uterus removed), surgical sterilization (tubes tied), or both ovaries removed and • You have not gone through menopause. Menopause should be confirmed by your healthcare provider 1) Qsymia can increase the risk of birth defects including: • Cleft lip and cleft palate (as shown in the picture) Your baby may also be smaller than expected at birth; the long-term effects of this are not known These defects happen early in pregnancy, sometimes even before you know you are pregnant 2) You should have a pregnancy test taken BEFORE starting treatment with Qsymia and EVERY MONTH after that while on treatment • Talk with your healthcare provider about when and where to have your pregnancy testing performed • If you have a positive pregnancy test, or you miss a period, or you think you might be pregnant, you must not start Qsymia, or if you are already taking Qsymia, you should stop it immediately and tell your healthcare provider right away 3) While you are on Qsymia therapy, you should use effective birth control methods every time you have sex with a male • Certain birth control methods are effective when used alone. Other birth control methods are not as effective by themselves, so you should use a second method of birth control Talk to your healthcare provider to help decide what birth control options are best for you. Please see the chart on the back to review birth control options. cleft lip • • Reference ID: 5481617 Please read the accompanying Qsymia® Medication Guide as it contains additional important safety information about your treatment. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Qsymia, talk to your healthcare provider or pharmacist, contact VIVUS Medical Information at 1-888-998-4887, or visit the Website www.QsymiaREMS.com. © 2024 VIVUS LLC All rights reserved. 02/2024 RE-03-005-07 Your Birth Control Options OPTION 1 Highly Effective Methods to Use Alone One method from this list OPTION 2 Acceptable Methods to Use Together One method from this list OPTION 3 Acceptable Methods to Use Together One method from this list One method from this list Barrier Method • Diaphragm (with spermicide) • Cervical cap (with spermicide) • Male condom (with or without spermicide) Hormonal Contraception • Estrogen and progestin – Oral (the pill) – Transdermal patch – Vaginal ring • Progestin only – Oral – Injection One method from this list Barrier Method • Male condom (with or without spermicide) Barrier Method • Diaphragm (with spermicide) • Cervical cap (with spermicide) • Intrauterine device (IUD) or intrauterine system (IUS) – Copper IUD – Levonorgestrel-releasing IUS • Progestin implant • Tubal sterilization • Male partner’s vasectomy OR OR Keep in mind, even the most effective birth control methods can fail. But your chances of getting pregnant are lowest if the methods you choose are always used correctly and every time you have sex. Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Home Prescribing Information Materials for Patients Risk of Birth Defects with Qsymia patient brochure Medication Guide These materials can be downloaded and printed. ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 A Risk Evaluation and Mitigation Strategy (REMS) is a strategy to manage known or potential serious risks associated with a drug product and is required by the Food and Drug Administration (FDA) to ensure that the benefits of a drug outweigh its risks. The FDA has required a REMS for Qsymia. The goal of the Qsymia REMS is to inform certified pharmacies and patients of reproductive potential about the: • Increased risk of embryo-fetal toxicity with major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) in a fetus exposed to Qsymia during the first trimester of pregnancy • Importance of pregnancy prevention for patients of reproductive potential receiving Qsymia • Need to discontinue Qsymia immediately if pregnancy occurs Dispensed to Patients Through Certified Pharmacies Qsymia is available only through certified pharmacies. Click Here to learn more. Risk Evaluation and Mitigation Strategy (REMS) Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Welcome to Qsymia® (phentermine and topiramate extended-release capsules) CIV Pharmacy Training Qsymia REMS Pharmacy Training is designed to provide pharmacists with an understanding of the risks of Qsymia and the pharmacy requirements under the REMS. Qsymia REMS Pharmacy Training is necessary to dispense Qsymia. Complete the Qsymia REMS Pharmacy Certification in 3 easy steps: 1. Designate an Authorized Representative to carry out the certification process and oversee implementation and compliance with the Qsymia REMS. 2. Read through the entirety of this Qsymia REMS Pharmacy Training and confirm you understand the content by completing the Knowledge Assessment questions. 3. Complete the Pharmacy Enrollment Form and fax the form to the Qsymia REMS Pharmacy Support Center at 1-855-302-6699 or email the form to VivusUSREMS.sm@ppd.com. Start Qsymia Pharmacy Training ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Download and print Qsymia REMS Pharmacy Training. Pharmacy Training Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Pharmacy Training Indication and Patient Selection Qsymia is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with obesity • Adults with overweight in the presence of at least one weight-related comorbid condition Limitations of use: • The effect of Qsymia on cardiovascular morbidity and mortality has not been established. • The safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. Next Page: 1 of 6 ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Pharmacy Training Increased Risk of Embryo-Fetal Toxicity • Qsymia is contraindicated in pregnant patients because the use of Qsymia can cause fetal harm and weight loss offers no clear benefit to a pregnant patient • Available data indicate an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) Studies evaluating the risk of major congenital malformations and/or oral clefts with exposure to topiramate during the first trimester of pregnancy include the following: • The North American Anti-Epileptic Drug (NAAED) Pregnancy Registry (2010) analysis • A retrospective observational study using 4 U.S. electronic healthcare databases (FORTRESS) • A case-control study using data from the Slone Epidemiology Center Birth Defects Study (BDS, 1997-2009) and the Centers for Disease Control's (CDC's) National Birth Defects Prevention Study (NBDPS, 1996-2007) • The UK Epilepsy and Pregnancy Register The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). An increase in oral clefts was observed with all dose strengths of topiramate. These data show that exposure to topiramate in pregnancy is associated with a 2- to 5-fold increase in risk of oral clefts. The FORTRESS study found an excess risk of 1.5 (95% CI = -1.1 to 4.1) oral cleft cases per 1,000 infants exposed to topiramate during the first trimester. Other data sources confirm the increased risk of oral clefts with topiramate exposure during pregnancy (i.e., animal studies and Adverse Event Reporting System data for topiramate). Small for Gestational Age • Data from the NAAED Pregnancy Registry and population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). • In the NAAED Pregnancy Registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. • In the medical Birth Registry of Norway, a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group unexposed to AEDs; the long-term consequences of the SGA findings are not known. Page: 2 of 6 Next Back ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Pharmacy Training Qsymia is Only Available Through Certified Pharmacies To become a certified pharmacy, the Authorized Representative must: • Carry out the certification process and oversee implementation and compliance with the Qsymia REMS on behalf of the pharmacy • Complete the Pharmacy Training • Complete the Pharmacy Enrollment Form and submit it to the Qsymia REMS • Train all relevant staff involved in dispensing on the risks associated with Qsymia and the requirement to provide the Medication Guide and Risk of Birth Defects with Qsymia patient brochure using the Pharmacy Training • Establish processes and procedures to provide the Medication Guide and Risk of Birth Defects with Qsymia patient brochure to each patient each time the drug is dispensed Before dispensing, all pharmacy staff must: • Provide the patient with the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure through the processes and procedures established as a requirement of the Qsymia REMS At all times, all pharmacy staff must: • Not distribute, transfer, loan, or sell Qsymia • Maintain records of standard operating procedures, training, and providing the Medication Guide and the Risk of Birth Defects with Qsymia patient brochure • Maintain and submit annual compliance reports to the Qsymia REMS • Comply with audits carried out by VIVUS to ensure that all processes and procedures are in place and are being followed • Have a new Authorized Representative enroll in the Qsymia REMS by completing the Qsymia REMS Pharmacy Training and the Pharmacy Enrollment Form The list of certified pharmacies will be updated within 5 business days after a new pharmacy is certified and eligible to dispense. Prescribers and patients will be able to use a "Certified Pharmacy Locator" tool to identify certified pharmacies in their area. Next Back ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Page: 3 of 6 Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Pharmacy Training Counseling for Patients of Reproductive Potential Qsymia can cause fetal harm. Advise patients of reproductive potential that labeling recommends: • Pregnancy testing prior to beginning Qsymia and monthly during therapy. Specific documentation of the result is not required at the pharmacy level. • Use of effective contraception consistently during Qsymia therapy because Qsymia can cause certain kinds of birth defects (oral clefts). Even patients who believe they cannot become pregnant should use effective contraception while taking Qsymia due to the potential for increased fertility associated with weight loss. • If a patient becomes pregnant while taking Qsymia, Qsymia should be discontinued immediately and the patient advised to notify their healthcare provider. *Patients of reproductive potential are patients who have NOT had a hysterectomy, bilateral oophorectomy, or medically documented spontaneous ovarian failure, and have not gone through menopause. Menopause should be clinically confirmed by an individual's healthcare provider. Advise nursing mothers not to use Qsymia. Qsymia may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Next Back ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Page: 4 of 6 Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Pharmacy Training Counseling for All Patients • The Medication Guide and patient brochure contain important information that patients should read and become familiar with. • Qsymia should be taken in the morning, with or without food. • Avoid taking Qsymia in the evening due to the possibility of insomnia. • Advise patients to start treatment with Qsymia as follows: ○ Take one Qsymia capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) once each morning for the first 14 days. ○ After the first 14 days is complete, take one Qsymia 7.5 mg/46 mg capsule once each morning ○ Do not take Qsymia 3.75 mg/23 mg and Qsymia 7.5 mg/46 mg capsules together • If an increase in Qsymia dose is prescribed after medical evaluation, advise patients to increase the dose of Qsymia as follows: ○ Take one Qsymia 11.25 mg/69 mg capsule once each morning for 14 days ○ After the 14 days is complete, take one Qsymia 15 mg/92 mg capsule once each morning ○ Do not take Qsymia 11.25 mg/69 mg and Qsymia 15 mg/92 mg capsules together • Advise patients NOT to stop Qsymia without talking with their HCP as serious side effects such as seizures may occur. Next Back ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Page: 5 of 6 Additional Information and Tools Additional information and tools can be found at www.QsymiaREMS.com • Risk of Birth Defects with Qsymia patient brochure • Qsymia Prescribing Information • Qsymia Medication Guide For more information on Qsymia, contact VIVUS Medical Information at 1-888-998-4887 or visit www.Qsymia.com. For more information on the Qsymia REMS, or for information on pharmacy enrollment, contact the Qsymia REMS Phamacy Support Center at 1-855-302-6698 or visit www.QsymiaREMS.com. Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Pharmacy Training Important Safety Information Qsymia is contraindicated in pregnancy; in patients with glaucoma; in hyperthyroidism; in patients receiving treatment or within 14 days following treatment with monoamine oxidase inhibitors (MAOIs); or in patients with hypersensitivity or idiosyncrasy to sympathomimetic amines, topiramate, or any of the inactive ingredients in Qsymia. Qsymia can cause fetal harm. Patients of reproductive potential should have a pregnancy test before treatment and monthly thereafter and use effective contraception consistently during Qsymia therapy. If a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be informed of the potential hazard to the fetus. Topiramate increases the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue Qsymia in patients who experience suicidal thoughts or behaviors. Qsymia is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Acute angle closure glaucoma has been reported in patients treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or eye pain. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of Qsymia. Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. Qsymia can cause mood disorders, including depression, and anxiety, as well as insomnia. Qsymia can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Since Qsymia has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles. Hyperchloremic, non-anion gap, metabolic acidosis has been reported in patients treated with Qsymia. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Qsymia. Qsymia can cause an increase in serum creatinine. If persistent elevations in creatinine occur while taking Qsymia, reduce the dose or discontinue Qsymia. Qsymia can cause slowing of linear growth. Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected. Qsymia can cause serious skin reactions and should be discontinued at the first sign of a rash, unless the rash is clearly not drug- related. The most commonly observed side effects in controlled clinical studies, ≥5% and at least 1.5 times placebo, include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. To report negative side effects, contact VIVUS LLC at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Back ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Page: 6 of 6 Reference ID: 5481617 ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Information for Pharmacists Qsymia REMS Pharmacy Support Center Phone: 1-855-302-6698 Qsymia is only available through certified pharmacies. Certified pharmacies must follow the requirements of the Qsymia REMS . Steps for pharmacy certification: 1. Designate an Authorized Representative to carry out the certification process and oversee implementation and compliance with the Qsymia REMS. 2. Read through the entirety of this Qsymia REMS Pharmacy Training and confirm you understand the content by completing the Knowledge Assessment questions. 3. Complete the Pharmacy Enrollment Form and submit it to the Qsymia REMS. Search for Certified Pharmacies Search now. Information for Pharmacists Prescribing Information Materials for Pharmacists Pharmacy Enrollment Form Medication Guide Risk of Birth Defects with Qsymia patient brochure These materials can be downloaded and printed. Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Qsymia Certified Pharmacy Network Qsymia is also available by mail order through the Qsymia Home Delivery Network: P: 1-844-777-9642 F: 1-844-678-8444 P: 1-877-487-8800 F: 1-800-332-9581 P: 1-800-273-3455 F: 1-800-406-8976 ©2024 VIVUS LLC All rights reserved. RE-03-010-XX XX/2024 VIVUS LLC Corporate Site Privacy Policy Terms of Use Contact Us For assistance, please contact the Qsymia REMS Pharmacy Support Center at 1-855-302-6698 Enter your ZIP Code Search Enter your zip code to locate a certified pharmacy within 20 miles of your zip code. Search for a Certified Pharmacy near you Reference ID: 5481617 Pharmacy Training Information for Pharmacists Qsymia Certified Pharmacy Network Risk of Birth Defects Patient Brochure Home Risk Evaluation and Mitigation Strategy (REMS) Qsymia Medication Guide Qsymia Prescribing Information \| Qsymia Important Safety Information \| Authorized Generic Medication Guide Authorized Generic Prescribing Information \| Qsymia Certified Pharmacy Network Search for a Qsymia® Certified Pharmacy Retail Location ©2024 VIVUS LLC All rights reserved. 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80,269	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LENVIMA safely and effectively. See full prescribing information for LENVIMA. LENVIMA® (lenvatinib) capsules, for oral use Initial U.S. Approval: 2015 ----------------------------INDICATIONS AND USAGE--------------------------- LENVIMA is a kinase inhibitor that is indicated: Differentiated Thyroid Cancer (DTC) • For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). (1.1) Renal Cell Carcinoma (RCC) • In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC). (1.2) • In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. (1.2) Hepatocellular Carcinoma (HCC) • For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). (1.3) Endometrial Carcinoma (EC) • In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.4, 2.1) ----------------------DOSAGE AND ADMINISTRATION------------------------- Single Agent Therapy: • DTC: The recommended dosage is 24 mg orally once daily. (2.3) • HCC: The recommended dosage is based on actual body weight: 12 mg orally once daily for patients greater than or equal to 60 kg or 8 mg orally once daily for patients less than 60 kg. (2.5) Combination Therapy: • EC: The recommended dosage is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. (2.6) • RCC: The recommended dosage is: o 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. (2.4) o 18 mg orally once daily with everolimus 5 mg orally once daily. (2.4) Modify the recommended daily dose for certain patients with renal or hepatic impairment. (2.8, 2.9) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Capsules: 4 mg and 10 mg. (3) -------------------------------CONTRAINDICATIONS------------------------------ None. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ • Hypertension: Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade 3 hypertension despite optimal antihypertensive therapy. Discontinue for Grade 4 hypertension. (2.7, 5.1) • Cardiac Dysfunction: Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold or discontinue for Grade 3 cardiac dysfunction. Discontinue for Grade 4 cardiac dysfunction. (2.7, 5.2) • Arterial Thromboembolic Events: Discontinue following an arterial thromboembolic event. (2.7, 5.3) • Hepatotoxicity: Monitor liver function prior to treatment and periodically during treatment. Withhold or discontinue for Grade 3 or 4 hepatotoxicity. Discontinue for hepatic failure. (2.7, 5.4) • Renal Failure or Impairment: Withhold or discontinue for Grade 3 or 4 renal failure or impairment. (2.7, 5.5) • Proteinuria: Monitor for proteinuria prior to treatment and periodically during treatment. Withhold for 2 or more grams of proteinuria per 24 hours. Discontinue for nephrotic syndrome. (2.7, 5.6) • Diarrhea: May be severe and recurrent. Promptly initiate management for severe diarrhea. Withhold or discontinue based on severity. (2.7, 5.7) • Fistula Formation and Gastrointestinal Perforation: Discontinue in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation. (2.7, 5.8) • QT Interval Prolongation: Monitor and correct electrolyte abnormalities. Withhold for QT interval greater than 500 ms or for 60 ms or greater increase in baseline QT interval. (2.7, 5.9) • Hypocalcemia: Monitor blood calcium levels at least monthly and replace calcium as necessary. Withhold or discontinue based on severity. (2.7, 5.10) • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold for RPLS until fully resolved or discontinue. (2.7, 5.11) • Hemorrhagic Events: Withhold or discontinue based on severity. (2.7, 5.12) • Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to treatment and monthly during treatment. (5.13) • Impaired Wound Healing: Withhold LENVIMA for at least 1 week before elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established. (5.14) • Osteonecrosis of the Jaw: Consider preventive dentistry prior to treatment with LENVIMA. Avoid invasive dental procedures, if possible, particularly in patients at higher risk. (5.15) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.16, 8.1, 8.3) ------------------------------ADVERSE REACTIONS------------------------------- • In DTC, the most common adverse reactions (incidence ≥30%) for LENVIMA are hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. (6.1) • In RCC: o The most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, decreased weight, dysphonia, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, hemorrhagic events, vomiting, constipation, hepatotoxicity, headache, and acute kidney injury. (6.1) o The most common adverse reactions (incidence ≥30%) for LENVIMA and everolimus are diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and proteinuria. (6.1) • In HCC, the most common adverse reactions (incidence ≥20%) for LENVIMA are hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. (6.1) • In EC, the most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, decreased weight, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------USE IN SPECIFIC POPULATIONS---------------------- • Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 Reference ID: 5482835 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Differentiated Thyroid Cancer 1.2 Renal Cell Carcinoma 1.3 Hepatocellular Carcinoma 1.4 Endometrial Carcinoma 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Important Dosage Information 2.3 Recommended Dosage for Differentiated Thyroid Cancer (DTC) 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) 2.5 Recommended Dosage for Hepatocellular Carcinoma (HCC) 2.6 Recommended Dosage for Endometrial Carcinoma (EC) 2.7 Dosage Modifications for Adverse Reactions 2.8 Dosage Modifications for Severe Renal Impairment 2.9 Dosage Modifications for Severe Hepatic Impairment 2.10 Capsule Administration and Preparation of Suspension for Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension 5.2 Cardiac Dysfunction 5.3 Arterial Thromboembolic Events 5.4 Hepatotoxicity 5.5 Renal Failure or Impairment 5.6 Proteinuria 5.7 Diarrhea 5.8 Fistula Formation and Gastrointestinal Perforation 5.9 QT Interval Prolongation 5.10 Hypocalcemia 5.11 Reversible Posterior Leukoencephalopathy Syndrome 5.12 Hemorrhagic Events 5.13 Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction 5.14 Impaired Wound Healing 5.15 Osteonecrosis of the Jaw (ONJ) 5.16 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Drugs That Prolong the QT Interval 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Differentiated Thyroid Cancer 14.2 Renal Cell Carcinoma 14.3 Hepatocellular Carcinoma 14.4 Endometrial Carcinoma (EC) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482835 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Differentiated Thyroid Cancer LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 1.2 Renal Cell Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). LENVIMA, in combination with everolimus, is indicated for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy. 1.3 Hepatocellular Carcinoma LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.4 Endometrial Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MSI or MMR status in tumor specimens [see Clinical Studies (14.4)]. Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved test for the selection of patients who are not MSI-H is not currently available. 2.2 Important Dosage Information • Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration (2.8, 2.9)]. • Take LENVIMA once daily, with or without food, at the same time each day [see Clinical Pharmacology (12.3)]. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration. 2.3 Recommended Dosage for Differentiated Thyroid Cancer (DTC) The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity. Reference ID: 5482835 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) First-Line Treatment of Patients with Advanced RCC The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. Previously Treated RCC The recommended dosage of LENVIMA is 18 mg in combination with 5 mg everolimus orally once daily until disease progression or until unacceptable toxicity. Refer to the everolimus prescribing information for recommended everolimus dosing information. 2.5 Recommended Dosage for Hepatocellular Carcinoma (HCC) The recommended dosage of LENVIMA is based on actual body weight: • 12 mg for patients greater than or equal to 60 kg or • 8 mg for patients less than 60 kg. Take LENVIMA orally once daily until disease progression or until unacceptable toxicity. 2.6 Recommended Dosage for Endometrial Carcinoma (EC) The recommended dosage of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. 2.7 Dosage Modifications for Adverse Reactions Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of LENVIMA for adverse reactions. Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions Adverse Reaction Severity a Dosage Modifications for LENVIMA Hypertension [see Warnings and Precautions (5.1)] Grade 3 • Withhold for Grade 3 that persists despite optimal antihypertensive therapy. • Resume at reduced dose when hypertension is controlled at less than or equal to Grade 2. Grade 4 • Permanently discontinue. Grade 3 • Withhold until improves to Grade 0 to 1 or baseline. Reference ID: 5482835 Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions Adverse Reaction Severity a Dosage Modifications for LENVIMA Cardiac Dysfunction [see Warnings and Precautions (5.2)] • Resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Grade 4 • Permanently discontinue. Arterial Thromboembolic Event [see Warnings and Precautions (5.3)] Any Grade • Permanently discontinue. Hepatotoxicity [see Warnings and Precautions (5.4)] Grade 3 or 4 • Withhold until improves to Grade 0 to 1 or baseline. • Either resume at a reduced dose or discontinue depending on severity and persistence of hepatotoxicity. • Permanently discontinue for hepatic failure. Renal Failure or Impairment [see Warnings and Precautions (5.5)] Grade 3 or 4 • Withhold until improves to Grade 0 to 1 or baseline. • Resume at a reduced dose or discontinue depending on severity and persistence of renal impairment. Proteinuria [see Warnings and Precautions (5.6)] 2 g or greater proteinuria in 24 hours • Withhold until less than or equal to 2 grams of proteinuria per 24 hours. • Resume at a reduced dose. • Permanently discontinue for nephrotic syndrome. Gastrointestinal Perforation [see Warnings and Precautions (5.8)] Any Grade • Permanently discontinue. Fistula Formation [see Warnings and Precautions (5.8)] Grade 3 or 4 • Permanently discontinue. QT Prolongation [see Warnings and Precautions (5.9)] Greater than 500 ms or greater than 60 ms increase from baseline • Withhold until improves to less than or equal to 480 ms or baseline. • Resume at a reduced dose. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.11)] Any Grade • Withhold until fully resolved. • Resume at a reduced dose or discontinue depending on severity and persistence of neurologic symptoms. Reference ID: 5482835 Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions Adverse Reaction Severity a Dosage Modifications for LENVIMA Other Adverse Reactions [see Warnings and Precautions (5.7, 5.10, 5.12)] Persistent or intolerable Grade 2 or 3 adverse reaction Grade 4 laboratory abnormality • Withhold until improves to Grade 0 to 1 or baseline. • Resume at reduced dose. Grade 4 adverse reaction • Permanently discontinue. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Table 2: Recommended Dosage Reductions of LENVIMA for Adverse Reactions Indication First Dosage Reduction To Second Dosage Reduction To Third Dosage Reduction To DTC 20 mg once daily 14 mg once daily 10 mg once daily RCC 14 mg once daily 10 mg once daily 8 mg once daily Endometrial Carcinoma 14 mg once daily 10 mg once daily 8 mg once daily HCC • Actual weight 60 kg or greater 8 mg once daily 4 mg once daily 4 mg every other day • Actual weight less than 60 kg 4 mg once daily 4 mg every other day Discontinue Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Pembrolizumab When administering LENVIMA in combination with pembrolizumab, modify the dosage of one or both drugs as appropriate. Withhold, dose reduce, or discontinue LENVIMA as shown in Table 1. Refer to pembrolizumab prescribing information for additional dose modification information. Reference ID: 5482835 Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Everolimus When administering LENVIMA in combination with everolimus, withhold or reduce the LENVIMA dose first and then the everolimus dose for adverse reactions of both LENVIMA and everolimus. Refer to the everolimus prescribing information for additional dose modification information. 2.8 Dosage Modifications for Severe Renal Impairment The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is [see Warnings and Precautions (5.5), Use in Specific Populations (8.6)]: • Differentiated thyroid cancer: 14 mg orally once daily • Renal cell carcinoma: 10 mg orally once daily • Endometrial carcinoma: 10 mg orally once daily 2.9 Dosage Modifications for Severe Hepatic Impairment The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is [see Warnings and Precautions (5.4), Use in Specific Populations (8.7)]: • Differentiated thyroid cancer: 14 mg taken orally once daily • Renal cell carcinoma: 10 mg taken orally once daily • Endometrial carcinoma: 10 mg orally once daily 2.10 Capsule Administration and Preparation of Suspension for Administration Administration Oral: Capsule or Suspension Capsule • Swallow LENVIMA capsules whole at the same time each day with or without food [see Clinical Pharmacology (12.3)]. Do not crush or chew the LENVIMA capsules. Suspension • Prepare [see Preparation below] oral suspension with water or apple juice and administer at the same time each day with or without food [see Clinical Pharmacology (12.3)]. Feeding Tube Administration Suspension • Prepare [see Preparation below] suspension for feeding tube administration with water and administer at the same time each day with or without food [see Clinical Pharmacology (12.3)]. Reference ID: 5482835 Preparation of Suspension • Place the required number of capsules, up to a maximum of 5, in a small container (approximately 20 mL capacity) or syringe (20 mL). Do not break or crush capsules. • Add 3 mL of liquid to the container or syringe. Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until capsules are fully disintegrated and administer the entire contents. • Next, add an additional 2 mL of liquid to the container or syringe using a second syringe or dropper, swirl or shake and administer. Repeat this step at least once and until there is no visible residue to ensure all of the medication is taken. • If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time. If LENVIMA suspension is not used at the time of preparation, LENVIMA suspension may be stored in a refrigerator at 36ºF to 46ºF (2ºC to 8ºC) for a maximum of 24 hours in a covered container. If not administered within 24 hours, the suspension should be discarded. Note: Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube). 3 DOSAGE FORMS AND STRENGTHS Capsules: • 4 mg: yellowish-red body and yellowish-red cap, marked in black ink with “Є” on cap and “LENV 4 mg” on body. • 10 mg: yellow body and yellowish-red cap, marked in black ink with “Є” on cap and “LENV 10 mg” on body. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in SELECT and Grade 4 hypertension was not reported in REFLECT. In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205 (RCC), hypertension was reported in 42% of patients and the median time to onset of new or worsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients. Systolic blood pressure ≥160 mmHg occurred in 29% of patients and diastolic blood pressure ≥100 mmHg occurred in 21% [see Adverse Reactions (6.1)]. Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or Reference ID: 5482835 permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.7)]. 5.2 Cardiac Dysfunction Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, cardiac failure, ventricular hypokinesia, or decrease in left or right ventricular ejection fraction of more than 20% from baseline) occurred in 3% of LENVIMA-treated patients. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.7)]. 5.3 Arterial Thromboembolic Events Among patients receiving LENVIMA or LENVIMA with everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in Study 205 (RCC), 2% of patients in REFLECT (HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials [see Adverse Reactions (6.1)]. Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%). Permanently discontinue LENVIMA following an arterial thrombotic event [see Dosage and Administration (2.7)]. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 5.4 Hepatotoxicity Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated patients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Two percent of patients discontinued LENVIMA and 0.2% discontinued sorafenib due to hepatic encephalopathy and 1% of patients discontinued LENVIMA or sorafenib due to hepatic failure [see Adverse Reactions (6.1)]. Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.7)]. Reference ID: 5482835 5.5 Renal Failure or Impairment Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patients receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in each study. In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade 3 in 10% of patients [see Adverse Reactions (6.1)]. Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity [see Dosage and Administration (2.7)]. 5.6 Proteinuria Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMA with everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus [see Adverse Reactions (6.1)]. Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.7)]. 5.7 Diarrhea Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred in 49% of patients, including Grade 3 in 6%. In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction [see Adverse Reactions (6.1)]. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.7)]. 5.8 Fistula Formation and Gastrointestinal Perforation Of 799 patients treated with LENVIMA or LENVIMA with everolimus in SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula [see Dosage and Administration (2.7)]. 5.9 QT Interval Prolongation In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In Study 205 (RCC), Reference ID: 5482835 QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA with everolimus and QTc interval >500 ms occurred in 6%. In REFLECT (HCC), QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%. Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose of LENVIMA upon recovery based on severity [see Dosage and Administration (2.7)]. 5.10 Hypocalcemia In SELECT (DTC), Grade 3 to 4 hypocalcemia occurred in 9% of patients receiving LENVIMA. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction. In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated with LENVIMA with everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients [see Adverse Reactions (6.1)]. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA depending on severity [see Dosage and Administration (2.7)]. 5.11 Reversible Posterior Leukoencephalopathy Syndrome Across clinical studies of 1823 patients who received LENVIMA as a single agent [see Adverse Reactions (6.1)], reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 0.3%. Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA depending on severity and persistence of neurologic symptoms [see Dosage and Administration (2.7)]. 5.12 Hemorrhagic Events Serious including fatal hemorrhagic events can occur with LENVIMA. Across SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients receiving LENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA, including 7 fatal hemorrhagic events [see Adverse Reactions (6.1)]. Serious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treated with LENVIMA in clinical trials and in the post-marketing setting. In post-marketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials. Reference ID: 5482835 Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA based on the severity [see Dosage and Administration (2.7)]. 5.13 Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction LENVIMA impairs exogenous thyroid suppression. In SELECT (DTC), 88% of all patients had a baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA with everolimus in Study 205 (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205 [see Adverse Reactions (6.1)]. Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment. Treat hypothyroidism according to standard medical practice. 5.14 Impaired Wound Healing Impaired wound healing has been reported in patients who received LENVIMA [see Adverse Reactions (6.2)]. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established. 5.15 Osteonecrosis of the Jaw (ONJ) Osteonecrosis of the Jaw (ONJ) has been reported in patients receiving LENVIMA [see Adverse Reactions (6.1)]. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. 5.16 Embryo-Fetal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Reference ID: 5482835 Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Hypertension [see Warnings and Precautions (5.1)] • Cardiac Dysfunction [see Warnings and Precautions (5.2)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.3)] • Hepatotoxicity [see Warnings and Precautions (5.4)] • Renal Failure and Impairment [see Warnings and Precautions (5.5)] • Proteinuria [see Warnings and Precautions (5.6)] • Diarrhea [see Warnings and Precautions (5.7)] • Fistula Formation and Gastrointestinal Perforation [see Warnings and Precautions (5.8)] • QT Interval Prolongation [see Warnings and Precautions (5.9)] • Hypocalcemia [see Warnings and Precautions (5.10)] • Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.11)] • Hemorrhagic Events [see Warnings and Precautions (5.12)] • Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction [see Warnings and Precautions (5.13)] • Impaired Wound Healing [see Warnings and Precautions (5.14)] • Osteonecrosis of the Jaw (ONJ) [see Warnings and Precautions (5.15)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions reflect exposure to LENVIMA as a single agent in 261 patients with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 406 patients with endometrial carcinoma (Study 309), LENVIMA with everolimus in 62 patients with RCC (Study 205), and LENVIMA with pembrolizumab in 352 patients with RCC (CLEAR). Safety data obtained in 1823 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions. Among the 1823 patients who received LENVIMA as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily, and the median duration of exposure was 5.6 months. The data below reflect exposure to LENVIMA in 1557 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205; CLEAR; Study 309), and a randomized, placebo-controlled trial (SELECT). The median duration of exposure to LENVIMA across Reference ID: 5482835 these five studies ranged from 6 to 16 months. The demographic and exposure data for each clinical trial population are described in the subsections below. Differentiated Thyroid Cancer The safety of LENVIMA was evaluated in SELECT, in which patients with radioactive iodine-refractory differentiated thyroid cancer were randomized (2:1) to LENVIMA (n=261) or placebo (n=131) [see Clinical Studies (14.1)]. The median treatment duration was 16.1 months for LENVIMA. Among 261 patients who received LENVIMA, median age was 64 years, 52% were females, 80% were White, 18% were Asian, and 2% were Black; and 4% were Hispanic/Latino. The most common adverse reactions observed in LENVIMA-treated patients (≥30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA; 18% of patients discontinued LENVIMA for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). Table 3 presents adverse reactions occurring at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the study. Table 3: Adverse Reactions Occurring in Patients with a Between-Group Difference of ≥5% in All Grades or ≥2% in Grades 3 and 4 in SELECT (DTC) Adverse Reaction LENVIMA 24 mg N=261 Placebo N=131 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Vascular Hypertensiona 73 44 16 4 Hypotension 9 2 2 0 Gastrointestinal Diarrhea 67 9 17 0 Nausea 47 2 25 1 Stomatitisb 41 5 8 0 Vomiting 36 2 15 0 Abdominal painc 31 2 11 1 Constipation 29 0.4 15 1 Oral paind 25 1 2 0 Dry mouth 17 0.4 8 0 Dyspepsia 13 0.4 4 0 General Fatiguee 67 11 35 4 Edema peripheral 21 0.4 8 0 Musculoskeletal and Connective Tissue Arthralgia/Myalgiaf 62 5 28 3 Reference ID: 5482835 Table 3: Adverse Reactions Occurring in Patients with a Between-Group Difference of ≥5% in All Grades or ≥2% in Grades 3 and 4 in SELECT (DTC) Adverse Reaction LENVIMA 24 mg N=261 Placebo N=131 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Metabolism and Nutrition Decreased appetite 54 7 18 1 Decreased weight 51 13 15 1 Dehydration 9 2 2 1 Nervous System Headache 38 3 11 1 Dysgeusia 18 0 3 0 Dizziness 15 0.4 9 0 Renal and Urinary Proteinuria 34 11 3 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 32 3 1 0 Rashg 21 0.4 3 0 Alopecia 12 0 5 0 Hyperkeratosis 7 0 2 0 Respiratory, Thoracic and Mediastinal Dysphonia 31 1 5 0 Cough 24 0 18 0 Epistaxis 12 0 1 0 Psychiatric Insomnia 12 0 3 0 Infections Urinary tract infection 11 1 5 0 Dental and oral infectionsh 10 1 1 0 Cardiac Electrocardiogram QT prolonged 9 2 2 0 a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes macular rash, maculo-papular rash, generalized rash, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection Clinically important adverse reactions occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% were pulmonary embolism (3%, including fatal reports vs 2%, respectively) and osteonecrosis of the jaw (0.4% vs 0%, respectively). Laboratory abnormalities with a difference of ≥2% in Grade 3 – 4 events and at a higher incidence in the LENVIMA arm are presented in Table 4. Reference ID: 5482835 Table 4: Laboratory Abnormalities with a Difference of ≥2% in Grade 3 - 4 Events and at a Higher Incidence in the LENVIMA Arma, b in SELECT (DTC) Laboratory Abnormality LENVIMA 24 mg Placebo Grades 3-4 (%) Grades 3-4 (%) Chemistry Hypocalcemia 9 2 Hypokalemia 6 1 Increased aspartate aminotransferase (AST) 5 0 Increased alanine aminotransferase (ALT) 4 0 Increased lipase 4 1 Increased creatinine 3 0 Hematology Thrombocytopenia 2 0 a With at least 1 grade increase from baseline b Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA (n = 253 to 258), Placebo (n = 129 to 131) The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia. First-Line Treatment of Renal Cell Carcinoma in Combination with Pembrolizumab (CLEAR) The safety of LENVIMA in combination with pembrolizumab was investigated in CLEAR [see Clinical Studies (14.2)]. Patients received LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks (n=352), or LENVIMA 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of LENVIMA and pembrolizumab was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of Reference ID: 5482835 LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%). Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with LENVIMA and pembrolizumab in CLEAR. Table 5: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=352 Sunitinib 50 mg N=340 Adverse Reactions All Grades (%) Grade 3- 4 (%) All Grades (%) Grade 3- 4 (%) General Fatiguea 63 9 56 8 Gastrointestinal Diarrheab 62 10 50 6 Stomatitisc 43 2 43 2 Nausea 36 3 33 1 Abdominal paind 27 2 18 1 Vomiting 26 3 20 1 Constipation 25 1 19 0 Musculoskeletal and connective tissue Musculoskeletal paine 58 4 41 3 Endocrine Hypothyroidismf 57 1 32 0 Vascular Hypertensiong 56 29 43 20 Hemorrhagic eventsh 27 5 26 4 Metabolism Decreased appetitei 41 4 31 1 Skin and subcutaneous tissue Rashj 37 5 17 1 Palmar-plantar erythrodysaesthesia syndromek 29 4 38 4 Respiratory, thoracic, and mediastinal Reference ID: 5482835 Table 5: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=352 Sunitinib 50 mg N=340 Adverse Reactions All Grades (%) Grade 3- 4 (%) All Grades (%) Grade 3- 4 (%) Dysphonia 30 0 4 0 Renal and urinary Proteinurial 30 8 13 3 Acute kidney injurym 21 5 16 2 Investigations Weight decreased 30 8 9 0 Hepatobiliary Hepatotoxicityn 25 9 21 5 Nervous system Headache 23 1 16 1 a Includes asthenia, fatigue, lethargy and malaise b Includes diarrhea and gastroenteritis c Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitis d Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, and upper abdominal pain e Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non- cardiac chest pain, pain in extremity, and pain in jaw f Includes hypothyroidism, increased blood thyroid stimulating hormone and secondary hypothyroidism g Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressure h Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include: Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis , hematoma , hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage , increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, and upper gastrointestinal hemorrhage i Includes decreased appetite and early satiety j Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular k Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema l Includes hemoglobinuria, nephrotic syndrome, and proteinuria m Includes acute kidney injury, azotaemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininaemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic Reference ID: 5482835 Table 5: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=352 Sunitinib 50 mg N=340 Adverse Reactions All Grades (%) Grade 3- 4 (%) All Grades (%) Grade 3- 4 (%) n Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune- mediated hepatitis, liver function test increased, liver injury, transaminases increased, and gamma- glutamyltransferase increased Clinically relevant adverse reactions (<20%) that occurred in patients receiving LENVIMA/pembrolizumab were myocardial infarction (3%) and angina pectoris (1%). Table 6: Laboratory Abnormalities in ≥20% (All Grades) of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200 mg Sunitinib 50 mg Laboratory Abnormalitya All Grades %b Grades 3-4 %b All Grades %b Grade 3-4 %b Chemistry Hypertriglyceridemia 80 15 71 15 Hypercholesterolemia 64 5 43 1 Increased lipase 61 34 59 28 Increased creatinine 61 5 61 2 Increased amylase 59 17 41 9 Increased aspartate aminotransferase (AST) 58 7 57 3 Hyperglycemia 55 7 48 3 Increased alanine aminotransferase (ALT) 52 7 49 4 Hyperkalemia 44 9 28 6 Hypoglycemia 44 2 27 1 Hyponatremia 41 12 28 9 Decreased albumin 34 0.3 22 0 Increased alkaline phosphatase 32 4 32 1 Hypocalcemia 30 2 22 1 Hypophosphatemia 29 7 50 8 Hypomagnesemia 25 2 15 3 Reference ID: 5482835 Table 6: Laboratory Abnormalities in ≥20% (All Grades) of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200 mg Sunitinib 50 mg Laboratory Abnormalitya All Grades %b Grades 3-4 %b All Grades %b Grade 3-4 %b Increased creatine phosphokinase 24 6 36 5 Hypermagnesemia 23 2 22 3 Hypercalcemia 21 1 11 1 Hematology Lymphopenia 54 9 66 15 Thrombocytopenia 39 2 73 13 Anemia 38 3 66 8 Leukopenia 34 1 77 8 Neutropenia 31 4 72 16 a With at least 1 grade increase from baseline b Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA/pembrolizumab (n= 343 to 349) and sunitinib (n= 329 to 335). Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed in 3 patients on rechallenge in patients receiving LENVIMA and 10 patients receiving both LENVIMA and pembrolizumab. Previously Treated Renal Cell Carcinoma in Combination with Everolimus (Study 205) The safety of LENVIMA was evaluated in Study 205, in which patients with unresectable advanced or metastatic renal cell carcinoma (RCC) were randomized (1:1:1) to LENVIMA 18 mg orally once daily with everolimus 5 mg orally once daily (n=51), LENVIMA 24 mg orally once daily (n=52), or everolimus 10 mg orally once daily (n=50) [see Clinical Studies (14.2)]. This data also includes patients on the dose escalation portion of the study who received LENVIMA with everolimus (n=11). The median treatment duration was 8.1 months for LENVIMA with everolimus. Among 62 patients who received LENVIMA with everolimus, the median age was 61 years, 71% were men, and 98% were White. The most common adverse reactions observed in the LENVIMA with everolimus-treated group (≥30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and proteinuria. The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA with everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA with everolimus-treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Reference ID: 5482835 Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA with everolimus-treated group. Table 7 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus arm. Study 205 was not designed to demonstrate a statistically significant difference in adverse reaction rates for LENVIMA in combination with everolimus, as compared to everolimus for any specific adverse reaction listed in Table 7. Table 7: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC) LENVIMA 18 mg with Everolimus 5 mg N=62 Everolimus 10 mg N=50 Adverse Reactions Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Endocrine Hypothyroidism 24 0 2 0 Gastrointestinal Diarrhea 81 19 34 2 Vomiting 48 7 12 0 Nausea 45 5 16 0 Stomatitis/Oral inflammationa 44 2 50 4 Abdominal painb 37 3 8 0 Oral painc 23 2 4 0 Dyspepsia/Gastro-esophageal reflux 21 0 12 0 Constipation 16 0 18 0 General Fatigued 73 18 40 2 Peripheral edema 42 2 20 0 Pyrexia/Increased body temperature 21 2 10 2 Metabolism and Nutrition Decreased appetite 53 5 18 0 Decreased weight 34 3 8 0 Musculoskeletal and Connective Tissue Arthralgia/Myalgiae 55 5 32 0 Musculoskeletal chest pain 18 2 4 0 Nervous System Headache 19 2 10 2 Psychiatric Insomnia 16 2 2 0 Renal and Urinary Proteinuria/Urine protein present 31 8 14 2 Renal failure eventf 18 10 12 2 Respiratory, Thoracic and Mediastinal Cough 37 0 30 0 Dyspnea/Exertional dyspnea 35 5 28 8 Reference ID: 5482835 Table 7: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC) LENVIMA 18 mg with Everolimus 5 mg N=62 Everolimus 10 mg N=50 Adverse Reactions Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Dysphonia 18 0 4 0 Skin and Subcutaneous Tissue Rashg 35 0 40 0 Vascular Hypertension/Increased blood pressure 42 13 10 2 Hemorrhagic eventsh 32 6 26 2 a Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration b Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain c Includes gingival pain, glossodynia, and oropharyngeal pain d Includes asthenia, fatigue, lethargy and malaise e Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgia f Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic, renal failure, renal failure acute, and renal impairment g Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash, and septic rash h Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip hemorrhage, renal hematoma, and scrotal hematocele In Table 8, Grade 3-4 laboratory abnormalities occurring in ≥3% of patients in the LENVIMA with everolimus arm are presented. Table 8: Grade 3-4 Laboratory Abnormalities Occurring in ≥3% of Patients in the LENVIMA with Everolimus Arma,b in Study 205 (RCC) Laboratory Abnormality LENVIMA 18 mg with Everolimus 5 mg Everolimus 10 mg Grades 3-4 (%) Grades 3-4 (%) Chemistry Hypertriglyceridemia 18 18 Increased lipase 13 12 Hypercholesterolemia 11 0 Hyponatremia 11 6 Hypophosphatemia 11 6 Hyperkalemia 6 2 Hypocalcemia 6 2 Hypokalemia 6 2 Increased aspartate aminotransferase (AST) 3 0 Increased alanine aminotransferase (ALT) 3 2 Increased alkaline phosphatase 3 0 Hyperglycemia 3 16 Increased creatine kinase 3 4 Reference ID: 5482835 Table 8: Grade 3-4 Laboratory Abnormalities Occurring in ≥3% of Patients in the LENVIMA with Everolimus Arma,b in Study 205 (RCC) Laboratory Abnormality LENVIMA 18 mg with Everolimus 5 mg Everolimus 10 mg Grades 3-4 (%) Grades 3-4 (%) Hematology Lymphopenia 10 20 Anemia 8 16 Thrombocytopenia 5 0 a With at least 1 grade increase from baseline b Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA with Everolimus (n = 62), Everolimus (n = 50). Hepatocellular Carcinoma The safety of LENVIMA was evaluated in REFLECT, which randomized (1:1) patients with unresectable hepatocellular carcinoma (HCC) to LENVIMA (n=476) or sorafenib (n=475) [see Clinical Studies (14.3)]. The dose of LENVIMA was 12 mg orally once daily for patients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with a baseline body weight of <60 kg. The dose of sorafenib was 400 mg orally twice daily. Duration of treatment was ≥6 months in 49% and 32% of patients in the LENVIMA and sorafenib groups, respectively. Among the 476 patients who received LENVIMA in REFLECT, the median age was 63 years, 85% were men, 28% were White and 70% were Asian. The most common adverse reactions observed in the LENVIMA-treated patients (≥20%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. The most common serious adverse reactions (≥2%) in LENVIMA-treated patients were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reduction or interruption in 62% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to adverse reactions occurred in 20% of patients in the LENVIMA-treated group. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). Table 9 summarizes the adverse reactions that occurred in ≥10% of patients receiving LENVIMA in REFLECT. REFLECT was not designed to demonstrate a statistically significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 9. Reference ID: 5482835 Table 9: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in REFLECT (HCC) Adverse Reaction LENVIMA 8 mg/12 mg N=476 Sorafenib 800 mg N=475 Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Endocrine Hypothyroidisma 21 0 3 0 Gastrointestinal Diarrhea 39 4 46 4 Abdominal painb 30 3 28 4 Nausea 20 1 14 1 Vomiting 16 1 8 1 Constipation 16 1 11 0 Ascitesc 15 4 11 3 Stomatitisd 11 0.4 14 1 General Fatiguee 44 7 36 6 Pyrexiaf 15 0 14 0.2 Peripheral edema 14 1 7 0.2 Metabolism and Nutrition Decreased appetite 34 5 27 1 Decreased weight 31 8 22 3 Musculoskeletal and Connective Tissue Arthralgia/Myalgiag 31 1 20 2 Nervous System Headache 10 1 8 0 Renal and Urinary Proteinuriah 26 6 12 2 Respiratory, Thoracic and Mediastinal Dysphonia 24 0.2 12 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 27 3 52 11 Rashi 14 0 24 2 Vascular Hypertensionj 45 24 31 15 Hemorrhagic eventsk 23 4 15 4 a Includes hypothyroidism, blood thyroid stimulating hormone increased. b Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain c Includes ascites and malignant ascites d Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, and stomatitis e Includes asthenia, fatigue, lethargy and malaise f Includes increased body temperature, pyrexia g Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, and myalgia Reference ID: 5482835 Table 9: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in REFLECT (HCC) Adverse Reaction LENVIMA 8 mg/12 mg N=476 Sorafenib 800 mg N=475 Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) h Includes proteinuria, increased urine protein, protein urine present i Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash and rash j Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertension k Includes all hemorrhage terms. Hemorrhage terms that occurred in 5 or more subjects in either treatment group include: epistaxis, hematuria, gingival bleeding, hemoptysis, esophageal varices hemorrhage, hemorrhoidal hemorrhage, mouth hemorrhage, rectal hemorrhage and upper gastrointestinal hemorrhage In Table 10, Grade 3-4 laboratory abnormalities occurring in ≥2% of patients in the LENVIMA arm in REFLECT (HCC) are presented. Table 10: Grade 3-4 Laboratory Abnormalities Occurring in ≥2% of Patients in the LENVIMA Arma,b in REFLECT (HCC) Laboratory Abnormality LENVIMA (%) Sorafenib (%) Chemistry Increased GGT 17 20 Hyponatremia 15 9 Hyperbilirubinemia 13 10 Increased aspartate aminotransferase (AST) 12 18 Increased alanine aminotransferase (ALT) 8 9 Increased alkaline phosphatase 7 5 Increased lipase 6 17 Hypokalemia 3 4 Hyperkalemia 3 2 Decreased albumin 3 1 Increased creatinine 2 2 Hematology Thrombocytopenia 10 8 Lymphopenia 8 9 Neutropenia 7 3 Anemia 4 5 a With at least 1 grade increase from baseline b Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA (n=278 to 470) and sorafenib (n=260 to 473) Reference ID: 5482835 Endometrial Carcinoma The safety of LENVIMA in combination with pembrolizumab was investigated in Study 309, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.4)]. Patients with endometrial carcinoma that are pMMR or not MSI-H received LENVIMA 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks (n=342); or received doxorubicin or paclitaxel (n= 325). For patients with pMMR or not MSI-H status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to LENVIMA was 6.7 months (range: 1 day to 26.8 months). Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (≥1 %) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in patients receiving LENVIMA in Study 309. Reference ID: 5482835 Table 11: Adverse Reactions in ≥20% of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC) Endometrial Carcinoma (pMMR or not MSI-H) LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342 Doxorubicin or Paclitaxel N=325 Adverse Reaction All Gradesa (%) Grades 3-4 (%) All Gradesa (%) Grades 3-4 (%) Endocrine Hypothyroidismb 67 0.9 0.9 0 Vascular Hypertensionc 67 39 6 2.5 Hemorrhagic eventsd 25 2.6 15 0.9 General Fatiguee 58 11 54 6 Gastrointestinal Diarrheaf 55 8 20 2.8 Nausea 49 2.9 47 1.5 Vomiting 37 2.3 21 2.2 Stomatitisg 35 2.6 26 1.2 Abdominal painh 34 2.6 21 1.2 Constipation 27 0 25 0.6 Musculoskeletal and Connective Tissue Musculoskeletal disordersi 53 5 27 0.6 Metabolism Decreased appetitej 44 7 21 0 Investigations Decreased weight 34 10 6 0.3 Renal and Urinary Proteinuriak 29 6 3.4 0.3 Infections Urinary tract infectionl 31 5 13 1.2 Nervous System Headache 26 0.6 9 0.3 Respiratory, Thoracic and Mediastinal Dysphonia 22 0 0.6 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesiam 23 2.9 0.9 0 Rashn 20 2.3 4.9 0 Reference ID: 5482835 Table 11: Adverse Reactions in ≥20% of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC) Endometrial Carcinoma (pMMR or not MSI-H) LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342 Doxorubicin or Paclitaxel N=325 Adverse Reaction All Gradesa (%) Grades 3-4 (%) All Gradesa (%) Grades 3-4 (%) a Graded per NCI CTCAE v4.03 b Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism, and secondary hypothyroidism c Includes hypertension, blood pressure increased, hypertensive crisis, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, and blood pressure fluctuation d Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, injection site hemorrhage, melena, purpura, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, coital bleeding, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, and vessel puncture site bruise e Includes fatigue, asthenia, malaise, and lethargy f Includes diarrhea and gastroenteritis g Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, and tongue ulceration h Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, and epigastric discomfort i Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw j Includes decreased appetite and early satiety k Includes proteinuria, protein urine present, hemoglobinuria l Includes urinary tract infection, cystitis, and pyelonephritis m Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema, and skin reaction n Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, and application site rash Reference ID: 5482835 Table 12: Laboratory Abnormalities Worsened from Baselinea Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC) Endometrial Carcinoma (pMMR or not MSI-H) LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342 Doxorubicin or Paclitaxel N=325 Laboratory Testb All Gradesc (%) Grades 3-4 (%) All Gradesc (%) Grades 3-4 (%) Chemistry Hypertriglyceridemia 70 6 45 1.7 Hypoalbuminemia 60 2.7 42 1.6 Increased aspartate aminotransferase 58 9 23 1.6 Hyperglycemia 58 8 45 4.4 Hypomagnesemia 46 0 27 1.3 Increased alanine aminotransferase 55 9 21 1.2 Hypercholesteremia 53 3.2 23 0.7 Hyponatremia 46 15 28 7 Increased alkaline phosphatase 43 4.7 18 0.9 Hypocalcemia 40 4.7 21 1.9 Increased lipase 36 14 13 3.9 Increased creatinine 35 4.7 18 1.9 Hypokalemia 34 10 24 5 Hypophosphatemia 26 8 17 3.2 Increased amylase 25 7 8 1 Hyperkalemia 23 2.4 12 1.2 Increased creatine kinase 19 3.7 7 0 Increased bilirubin 18 3.6 6 1.6 Hematology Lymphopenia 51 18 66 23 Thrombocytopenia 50 8 30 4.7 Anemia 49 8 84 14 Leukopenia 43 3.5 83 43 Neutropenia 34 8 80 60 a With at least 1 grade increase from baseline b Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: LENVIMA/pembrolizumab (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). c Graded per NCI CTCAE v4.03 Reference ID: 5482835 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LENVIMA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: pancreatitis, increased amylase General: impaired wound healing Hepatobiliary: cholecystitis Renal and Urinary: nephrotic syndrome Vascular: arterial (including aortic) aneurysms, dissections, and rupture 7 DRUG INTERACTIONS 7.1 Drugs That Prolong the QT Interval LENVIMA has been reported to prolong the QT/QTc interval. Avoid coadministration of LENVIMA with medicinal products with a known potential to prolong the QT/QTc interval [see Warnings and Precautions (5.9)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits (see Data). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% post-implantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the recommended clinical dose of 24 mg based on BSA). At the 0.03 mg/kg dose, increased post- implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose Reference ID: 5482835 level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). 8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk; however, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than those in maternal plasma (see Data). Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment with LENVIMA and for 1 week after the last dose. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher [based on area under the curve (AUC)] in milk compared to maternal plasma. 8.3 Females and Males of Reproductive Potential Based on animal data and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating LENVIMA [see Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with LENVIMA and for 30 days after the last dose. Infertility LENVIMA may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established. The safety and efficacy of LENVIMA alone and in combination were investigated but not established in four open label studies (NCT02432274, NCT04154189, NCT04447755, NCT03245151) in 232 patients aged 2 to <17 years with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma. Hypothyroidism and pneumothorax were observed at a higher rate in pediatric patients compared to that of adult patients. The pharmacokinetics (PK) of lenvatinib in pediatric patients were within range of values previously observed in adults at the approved recommended dose of 24 mg. Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth Reference ID: 5482835 retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the human exposure based on AUC at the recommended clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats. 8.5 Geriatric Use Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in SELECT, 45% were ≥65 years of age and 11% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 352 patients with renal cell carcinoma (RCC) who received LENVIMA with pembrolizumab in CLEAR, 45% were ≥65 years of age and 13% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Of the 62 patients with RCC who received LENVIMA with everolimus in Study 205, 36% were ≥65 years of age. Conclusions are limited due to the small sample size, but there appeared to be no overall differences in safety or effectiveness between these subjects and younger subjects. Of the 476 patients with hepatocellular carcinoma (HCC) who received LENVIMA in REFLECT, 44% were ≥65 years of age and 12% were ≥75 years of age. No overall differences in safety or effectiveness were observed between patients ≥65 and younger subjects. Patients ≥75 years of age showed reduced tolerability to LENVIMA. Of 406 adult patients with endometrial carcinoma (EC) who were treated with LENVIMA in combination with pembrolizumab in Study 309, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. 8.6 Renal Impairment No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose of LENVIMA for patients with RCC, DTC, or endometrial carcinoma and severe renal impairment [see Dosage and Administration (2.7)]. There is no recommended dose of LENVIMA for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate or severe hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations Reference ID: 5482835 may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C). Reduce the dose of lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Death due to multiorgan dysfunction occurred in a patient who received a single dose of LENVIMA 120 mg orally. 11 DESCRIPTION LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3- chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is: Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.3. LENVIMA capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively. The inactive ingredients are: calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and talc. In addition, the capsule shell contains ferric oxide red, ferric oxide yellow, hypromellose, and titanium dioxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRA), KIT, and RET. Lenvatinib also exhibited antiproliferative activity Reference ID: 5482835 in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 alpha (FRS2) phosphorylation. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone. 12.2 Pharmacodynamics Exposure-Response Relationships In a multicenter randomized (1:1) double blind trial of 152 patients with radioactive iodine (RAI)-refractory DTC, a dose-response relationship for overall response rate (ORR) was observed over the dose range of 18 mg (0.75 times the recommended dose of 24 mg) and 24 mg. A higher ORR was observed at the recommended lenvatinib dose. No dose-response relationships for adverse reactions, serious adverse reactions, adverse reactions leading to study drug discontinuation, and adverse reactions leading to study drug interruption were observed over the same dose range. 12.3 Pharmacokinetics In patients with solid tumors administered single and multiple doses of LENVIMA once daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 mg (0.1 times the recommended clinical dose of 24 mg) to 32 mg (1.33 times the recommended clinical dose of 24 mg) with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg). Geometric mean Cmax and AUC values at steady state for RCC, DTC and HCC are summarized in the Table 13. Table 13: Lenvatinib Cmax and AUC in Patients with Solid Tumorsa Tumor Type Dose Parameter N Geometric Mean %CV RCC 18 mg Cmax (ng/mL) 350 267 36.7 AUC (ng∙h/mL) 350 3148 42.5 20 mg Cmax (ng/mL) 346 275 32.6 AUC (ng∙h/mL) 346 3135 41.3 DTC 24 mg Cmax (ng/mL) 251 323 33.3 AUC (ng∙h/mL) 251 3483 34.7 HCC (body weight < 60 kg) 8 mg Cmax (ng/mL) 150 154 25.4 AUC (ng∙h/mL) 150 1835 34.0 HCC (body weight ≥ 60 kg) 12 mg Cmax (ng/mL) 318 172 23.1 AUC (ng∙h/mL) 318 2013 29.3 a Model-predicted steady-state pharmacokinetic parameters are presented. Absorption The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Reference ID: 5482835 Food Effect Administration with a high fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours. Distribution Model-predicted geometric mean steady state volume of distribution is 97 L (%CV, 30.2%). Protein binding of lenvatinib is 97% to 99%, which is independent of concentration, and is not impacted by hepatic or renal function. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro. Elimination The terminal elimination half-life of lenvatinib was approximately 28 hours. Metabolism The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion Ten days after a single administration of radiolabeled lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively. Specific Populations Age (18 to 92 years), sex, race/ethnicity (White, Black and Asian), tumor types (DTC, RCC, HCC and other tumor types) and renal impairment (creatinine clearance: 15-89 mL/min) did not have a significant effect on apparent oral clearance (CL/F). Subjects with end stage renal disease were not studied. Patients with Hepatic Impairment The pharmacokinetics of lenvatinib following a single 10 mg dose were evaluated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of a single 5 mg dose were evaluated in subjects with severe (Child-Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively. Apparent oral clearance of lenvatinib in patients with HCC and mild hepatic impairment was similar to patients with HCC and moderate hepatic impairment. Body Weight Lenvatinib exposures in patients with HCC in REFLECT were comparable between those weighing <60 kg who received a starting dose of 8 mg and those ≥60 kg who received a starting dose of 12 mg. Drug Interaction Studies Effect of Other Drugs on Lenvatinib CYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg daily for 18 days) increased lenvatinib (administered as a single 5 mg dose on Day 5) AUC by 15% and Cmax by 19%. Reference ID: 5482835 P-gp Inhibitor: Rifampicin (600 mg as a single dose) increased lenvatinib (24 mg as a single dose) AUC by 31% and Cmax by 33%. CYP3A and P-gp Inducers: Rifampicin (600 mg daily for 21 days) decreased lenvatinib (24 mg as a single dose on Day 15) AUC by 18%. The Cmax was unchanged. Population pharmacokinetic analysis demonstrated that neither everolimus nor pembrolizumab meaningfully affect the pharmacokinetics of lenvatinib. In Vitro Studies with Transporters: Lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, MATE2-K, or the bile salt export pump (BSEP). Effect of Lenvatinib on Other Drugs CYP2C8 Substrate: There is no projected significant drug-drug interaction risk between lenvatinib and repaglinide. CYP3A4 Substrate: Co-administration of lenvatinib with midazolam had no effect on the pharmacokinetics of midazolam. Population pharmacokinetic analysis demonstrated that lenvatinib does not meaningfully affect the pharmacokinetics of either everolimus or pembrolizumab. In Vitro Studies with Substrates of CYP or UDP-glucuronosyltransferase (UGT): Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Lenvatinib does not inhibit CYP2A6 and CYP2E1. Lenvatinib induces CYP3A, but it does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme in tissues. Lenvatinib does not inhibit UGT1A6, UGT2B7 or aldehyde oxidase. Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7. In Vitro Studies with Substrates of Transporters: Lenvatinib does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay. No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the AUC at the recommended clinical dose of 24 mg once daily. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the AUC at the recommended clinical dose of 24 mg once daily, respectively. In addition, in monkeys, a Reference ID: 5482835 decreased incidence of menstruation was reported at lenvatinib exposures lower than those observed in humans at the recommended clinical dose of 24 mg once daily. 14 CLINICAL STUDIES 14.1 Differentiated Thyroid Cancer A multicenter, randomized (2:1), double-blind, placebo-controlled study (SELECT; NCT01321554) was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review. Radioactive iodine (RAI)-refractory was defined as 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity >600 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry. Patients were randomized to receive LENVIMA 24 mg once daily (n=261) or placebo (n=131) until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age. The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Independent review confirmation of disease progression was required prior to discontinuing patients from the randomization phase of the study. Other efficacy outcome measures included objective response rate (ORR) and overall survival (OS). Patients in the placebo arm could receive LENVIMA following independent review confirmation of disease progression. Of the 392 patients randomized, 51% were male, the median age was 63 years, 40% were 65 years or older, 79% were White, 54% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, and 24% had received 1 prior VEGF/VEGFR-targeted therapy. Metastases were present in 99% of the patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. The histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. In the LENVIMA arm, 67% of patients did not demonstrate iodine uptake on any RAI scan compared to 77% in the placebo arm. Additionally, 59% of patients on the LENVIMA arm and 61% of patients on placebo arm progressed, according to RECIST 1.1, within 12 months of prior I 131 therapy; 19.2% of patients on the LENVIMA arm and 17.6% of patients on placebo arm received prior cumulative activity of >600 mCi or 22 GBq I 131, with the last dose administered at least 6 months prior to study entry. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq). A statistically significant prolongation in PFS was demonstrated in LENVIMA-treated patients compared to those receiving placebo (Table 14 and Figure 1). Upon confirmation of progression, 83% of patients that were randomly assigned to placebo crossed over to receive open-label LENVIMA. Reference ID: 5482835 Table 14: Efficacy Results in Differentiated Thyroid Cancer in SELECT LENVIMA N=261 Placebo N=131 Progression-Free Survival (PFS)a Number of events (%) 107 (41) 113 (86) Progressive disease 93 (36) 109 (83) Death 14 (5) 4 (3) Median PFS in months (95% CI) 18.3 (15.1, NE) 3.6 (2.2, 3.7) Hazard ratio (95% CI)b 0.21 (0.16, 0.28) p-valuec <0.001 Objective Response Ratea Objective response rate 65% 2% (95% CI) (59%, 71%) (0%, 4%) Complete response 2% 0% Partial response 63% 2% p-valued <0.001 Overall Survival (OS)e Number of deaths (%) 71 (27) 47 (36) Median OS in months (95% CI) NE (22.1, NE) NE (20.3, NE) Hazard ratio (95% CI)b 0.73 (0.50, 1.07) p-valueb 0.10 a Independent radiologic review b Estimated with Cox proportional hazard model stratified by region (Europe vs North America vs other), age group (≤65 years vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1) c Log-rank test stratified by region (Europe vs North America vs other), age group (≤65 years vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1) d Cochran-Mantel-Haenszel chi-square test e NE = Not estimable Figure 1: Kaplan-Meier Curves for Progression-Free Survival in SELECT Reference ID: 5482835 14.2 Renal Cell Carcinoma First-Line Treatment of Patients with RCC in Combination with Pembrolizumab CLEAR The efficacy of LENVIMA in combination with pembrolizumab was investigated in CLEAR (NCT02811861), a multicenter, open-label, randomized trial that enrolled 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America and Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable, intermediate and poor risk). Patients were randomized (1:1:1) to one of the following treatment arms: • LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks up to 24 months. • LENVIMA 18 mg orally once daily in combination with everolimus 5 mg orally once daily. • Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks. Treatment continued until unacceptable toxicity or disease progression. Administration of LENVIMA with pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Pembrolizumab dosing was continued for a maximum of 24 months; however, treatment with LENVIMA could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks. The study population characteristics were: median age of 62 years (range: 29 to 88 years); 42% age 65 or older, 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%). The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. At the protocol-specified interim analysis, LENVIMA in combination with pembrolizumab demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. An updated OS analysis was conducted when approximately 304 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 15 and Figures 2 and 3 summarize the efficacy results for CLEAR. Reference ID: 5482835 Table 15: Efficacy Results in Renal Cell Carcinoma Per IRC in CLEAR LENVIMA 20 mg with Pembrolizumab 200 mg N=355 Sunitinib 50 mg N=357 Progression-Free Survival (PFS) Number of events, n (%) 160 (45%) 205 (57%) Progressive disease 145 (41%) 196 (55%) Death 15 (4%) 9 (3%) Median PFS in months (95% CI) 23.9 (20.8, 27.7) 9.2 (6.0, 11.0) Hazard Ratioa (95% CI) 0.39 (0.32, 0.49) p-valueb <0.0001 Overall Survival (OS) Number of deaths, n (%) 80 (23%) 101 (28%) Median OS in months (95% CI) NR (33.6, NE) NR (NE, NE) Hazard Ratioa (95% CI) 0.66 (0.49, 0.88) p-valueb 0.0049 Updated OS Number of deaths, n (%) 149 (42%) 159 (45%) Median OS in months (95% CI) 53.7 (48.7, NE) 54.3 (40.9, NE) Hazard Ratioa (95% CI) 0.79 (0.63, 0.99) Objective Response Rate (Confirmed) Objective response rate, n (%) 252 (71%) 129 (36%) (95% CI) (66, 76) (31, 41) Complete response rate 16% 4% Partial responses rate 55% 32% p-valuec <0.0001 Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR. Data cutoff date = 28 Aug 2020, Updated OS cutoff date = 31 July 2022 CI = confidence interval; NE= Not estimable; NR= Not reached a Hazard ratio is based on a Cox Proportional Hazards Model, stratified by geographic region and MSKCC prognostic groups. b Two-sided p-value based on stratified log-rank test. c Two-sided p-value based upon CMH test. Reference ID: 5482835 Figure 2: Kaplan-Meier Curves for Progression-Free Survival in CLEAR L + P = LENVIMA + Pembrolizumab; S = Sunitinib. Figure 3: Kaplan-Meier Curves for Updated Overall Survival in CLEAR L + P = LENVIMA + Pembrolizumab; S = Sunitinib. Reference ID: 5482835 KEYNOTE-B61 The efficacy of LENVIMA in combination with pembrolizumab was investigated in a multicenter, single-arm study, KEYNOTE-B61 (NCT04704219), that enrolled 160 patients with advanced/metastatic non-clear cell RCC in the first-line setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received LENVIMA 20 mg orally once daily in combination with pembrolizumab 400 mg every 6 weeks for up to 24 months or until unacceptable toxicity or disease progression. LENVIMA could be continued as a single agent beyond 24 months until unacceptable toxicity or disease progression. Administration of LENVIMA with pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit. Among the 158 treated patients, the baseline characteristics were: median age of 60 years (range: 24 to 87 years); 71% male; 86% White, 8% Asian, and 3% Black; <1% Hispanic or Latino; 22% and 78% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; histologic subtypes were 59% papillary, 18% chromophobe, 4% translocation, <1% medullary, 13% unclassified, and 6% other; patient distribution by IMDC risk categories was 35% favorable, 54% intermediate, and 10% poor. Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%). The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures included DOR as assessed by BICR using RECIST 1.1. Efficacy results are summarized in Table 16. Table 16: Efficacy Results in Study (NCT04704219) Endpoint LENVIMA 20 mg and pembrolizumab 400 mg every 6 weeks n=158 Objective Response Rate (Confirmed) ORR, (95% CI) 51% (43, 59) Complete response 8% Partial response 42% Duration of Response Median in months (range) 19.5 (1.5+, 23.5+) CI = confidence interval * Based on Kaplan-Meier estimates + Denotes ongoing response Previously Treated RCC in Combination with Everolimus (Study 205) The efficacy was evaluated in a multicenter, randomized (1:1:1) study (Study 205: NCT01136733), in which 153 patients with advanced or metastatic renal cell carcinoma who have previously received anti-angiogenic therapy received LENVIMA 18 mg orally once daily with everolimus 5 mg orally once daily, LENVIMA 24 mg orally once daily, or everolimus 10 mg orally once daily. Patients were required to have histological confirmation of clear cell RCC and ECOG PS of 0 or 1. Patients were stratified by hemoglobin level (≤ or Reference ID: 5482835 >13 g/dL for males and ≤ or >11.5 g/dL for females) and corrected serum calcium (≥10 mg/dL vs. < 10 mg/dL). The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST 1.1. Of the 101 patients randomized to the LENVIMA with everolimus arm or everolimus arm, 72% were male, the median age was 60 years, 31% were older than 65 years, and 96% were White. Metastases were present in 95% of the patients and unresectable advanced disease was present in 5%. All patients had a baseline ECOG PS of either 0 (54%) or 1 (46%) with similar distribution across these two treatment arms. MSKCC favorable, intermediate, and poor-risk categories were observed, respectively, in 24%, 37%, and 39% of patients in the LENVIMA with everolimus arm and 24%, 38%, and 38% of patients in the everolimus arm. Efficacy results from Study 205 are summarized in Table 17 and Figures 4 and 5. The treatment effect of the combination on PFS was supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.43 (95% CI: 0.24, 0.75) compared with the everolimus arm. Table 17: Efficacy Results in Renal Cell Carcinoma Per Investigator Assessment in Study 205 LENVIMA 18 mg with Everolimus 5 mg N=51 Everolimus 10 mg N=50 Progression-Free Survival (PFS)a Number of events, n (%) 26 (51) 37 (74) Progressive disease 21 (41) 35 (70) Death 5 (10) 2 (4) Median PFS in months (95% CI) 14.6 (5.9, 20.1) 5.5 (3.5, 7.1) Hazard Ratio (95% CI)b LENVIMA with Everolimus vs Everolimus 0.37 (0.22, 0.62) - Overall Survival (OS)c Number of deaths, n (%) 32 (63) 37 (74) Median OS in months (95% CI) 25.5 (16.4, 32.1) 15.4 (11.8, 20.6) Hazard Ratio (95% CI)b LENVIMA with Everolimus vs Everolimus 0.67 (0.42, 1.08) - Objective Response Rate (Confirmed) Objective response rate, n (%) 19 (37) 3 (6) (95% CI) (24, 52) (1, 17) Number of complete responses, n (%) 1 (2) 0 Number of partial responses (%) 18 (35) 3 (6) Tumor assessments were based on RECIST v1.1 criteria for progression but only confirmed responses are included for ORR. Data cutoff date = 13 Jun 2014 CI = confidence interval a Point estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation. b Hazard ratio is based on a stratified Cox regression model including treatment as a covariate factor and hemoglobin and corrected serum calcium as strata. c Data cutoff date = 31 Jul 2015 Reference ID: 5482835 Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Study 205 Figure 5: Kaplan-Meier Curves for Overall Survival in Study 205 Reference ID: 5482835 14.3 Hepatocellular Carcinoma The efficacy of LENVIMA was evaluated in a randomized, open-label, multicenter, international study (REFLECT; NCT01761266) conducted in patients with previously untreated unresectable hepatocellular carcinoma (HCC). The study enrolled adults with Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) Stage C or B HCC who were ineligible for local liver-directed therapy; had an ECOG PS of 0 or 1; had received no prior systemic therapy for HCC; and had at least one measurable target lesion according to modified RECIST for HCC. Patients were randomized (1:1) to receive LENVIMA (12 mg for baseline body weight ≥60 kg or 8 mg for baseline body weight <60 kg) orally once daily or sorafenib 400 mg orally twice daily until radiological disease progression or unacceptable toxicity. Randomization was stratified by region (Western vs Asia Pacific), presence of macroscopic portal vein invasion or extrahepatic spread (yes vs no), ECOG PS (0 vs 1), and body weight (<60 kg vs ≥60 kg). The major efficacy outcome measure was overall survival (OS). REFLECT was designed to show the non-inferiority of LENVIMA to sorafenib for OS. Additional efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR) according to modified RECIST for HCC. A total of 954 patients were randomized, 478 to the LENVIMA arm and 476 to the sorafenib arm. The demographics of the study population were: median age of 62 years (range: 20 to 88 years); 84% male; 69% Asian and 29% White; 63% ECOG PS of 0; and 69% weighed ≥60 kg. Of the 590 (62%) patients with at least one site of documented distant metastatic disease, 52% had lung metastasis, 45% had lymph node metastasis, and 16% had bone metastasis. Macroscopic portal vein invasion, extra-hepatic spread, or both were present in 70% of patients. HCC was categorized as Child-Pugh A and BCLC Stage C in 79% and Child-Pugh A and BCLC Stage B in 21% of patients. Seventy-five percent (75%) of patients had radiographic evidence of cirrhosis at baseline. Investigator-documented primary risk factors for the development of HCC were hepatitis B (50%), hepatitis C (23%), alcohol use (6%), other (7%), and unknown (14%). REFLECT demonstrated that LENVIMA was non-inferior to sorafenib for OS. REFLECT did not demonstrate a statistically significant improvement in OS for patients randomized to LENVIMA as compared to those in the sorafenib arm. LENVIMA was statistically significantly superior to sorafenib for PFS and ORR. Efficacy results are summarized in Table 18 and Figure 6. Reference ID: 5482835 Table 18: Efficacy Results in Hepatocellular Carcinoma in REFLECT LENVIMA N= 478 Sorafenib N=476 Overall Survival Number of deaths (%) 351 (73) 350 (74) Median OS in months (95% CI) 13.6 (12.1, 14.9) 12.3 (10.4, 13.9) Hazard Ratio (95% CI)a 0.92 (0.79, 1.06) Progression-Free Survivalb (mRECIST) Number of Events (%) 311 (65) 323 (68) Median PFS in months (95% CI) 7.3 (5.6, 7.5) 3.6 (3.6, 3.7) Hazard Ratio (95% CI) 0.64 (0.55, 0.75) p-value <0.001 Objective Response Rateb (mRECIST) Objective response rate 41% 12% Complete responses, n (%) 10 (2.1) 4 (0.8) Partial responses, n (%) 184 (38.5) 55 (11.6) 95% CI (36%, 45%) (10%, 16%) p-value <0.001 Progression-Free Survivalb (RECIST 1.1) Number of Events (%) 307 (64) 320 (67) Median PFS in months (95% CI) 7.3 (5.6, 7.5) 3.6 (3.6, 3.9) Hazard Ratio (95% CI) 0.65 (0.56, 0.77) Objective Response Rateb (RECIST 1.1) Objective response rate 19% 7% Complete responses, n (%) 2 (0.4) 1 (0.2) Partial responses, n (%) 88 (18.4) 30 (6.3) 95% CI (15%, 22%) (4%, 9%) CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HR = hazard ratio; OS = overall survival. a Based on stratified Cox-model. Non-inferiority margin for HR (LENVIMA vs sorafenib) is 1.08. b Per independent radiology review. Reference ID: 5482835 Figure 6: Kaplan-Meier Curves for Overall Survival in REFLECT 14.4 Endometrial Carcinoma (EC) The efficacy of LENVIMA in combination with pembrolizumab was investigated in Study 309 (NCT03517449), a multicenter, open-label, randomized, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were pMMR (using the VENTANA MMR RxDx Panel test) or not MSI-H were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomized (1:1) to one of the following treatment arms: • LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks. • Investigator’s choice consisting of either doxorubicin 60 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off. Treatment with LENVIMA and pembrolizumab continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for pembrolizumab, a maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR and DOR, as assessed by BICR. Among the 697 pMMR or not MSI-H patients, 346 patients were randomized to LENVIMA in combination with pembrolizumab, and 351 patients were randomized to investigator’s choice of doxorubicin (n=254) or paclitaxel (n=97). The population characteristics of these Reference ID: 5482835 patients were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy. Efficacy results for these patients are summarized in Table 19 and Figures 7 and 8. Table 19: Efficacy Results in Endometrial Carcinoma in Study 309 Endometrial Carcinoma (pMMR or not MSI-H) Endpoint LENVIMA with pembrolizumab N=346 Doxorubicin or Paclitaxel N=351 OS Number (%) of patients with event 165 (48%) 203 (58%) Median in months (95% CI) 17.4 (14.2, 19.9) 12.0 (10.8, 13.3) Hazard ratioa (95% CI) 0.68 (0.56, 0.84) p-valueb 0.0001 PFSc Number (%) of patients with event 247 (71%) 238 (68%) Median in months (95% CI) 6.6 (5.6, 7.4) 3.8 (3.6, 5.0) Hazard ratioa (95% CI) 0.60 (0.50, 0.72) p-valueb <0.0001 Objective Response Rate ORRc (95% CI) 30% (26, 36) 15% (12,19) Complete response 5% 3% Partial response 25% 13% p-valued <0.0001 Duration of Response N=105 N=53 Median in months (range) 9.2 (1.6+, 23.7+) 5.7 (0.0+, 24.2+) a Based on the stratified Cox regression model b Based on stratified log-rank test c Per independent radiology review d Based on Miettinen and Nurminen method stratified by ECOG performance status, geographic region, and history of pelvic radiation Reference ID: 5482835 Figure 7: Kaplan-Meier Curves for Overall Survival in Study 309 (pMMR or not MSI-H) Figure 8: Kaplan-Meier Curves for Progression-Free Survival in Study 309 (pMMR or not MSI-H) Reference ID: 5482835 16 HOW SUPPLIED/STORAGE AND HANDLING LENVIMA 4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on the body. LENVIMA 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on the body. LENVIMA capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows: • NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card). • NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card). • NDC 62856-718-30: 18 mg, carton with 6 cards NDC 62856-718-05 (five 10 mg capsules and ten 4 mg capsules per card). • NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card). • NDC 62856-712-30: 12 mg, carton with 6 cards NDC 62856-712-05 (fifteen 4 mg capsules per card). • NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card). • NDC 62856-708-30: 8 mg, carton with 6 cards NDC 62856-708-05 (ten 4 mg capsules per card). • NDC 62856-704-30: 4 mg, carton with 6 cards NDC 62856-704-05 (five 4 mg capsules per card). Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypertension Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated [see Warnings and Precautions (5.1)]. Cardiac Dysfunction Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction [see Warnings and Precautions (5.2)]. Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke [see Warnings and Precautions (5.3)]. Reference ID: 5482835 Hepatotoxicity Advise patients that they will need to undergo laboratory tests to monitor liver function and to report any new symptoms indicating hepatic toxicity or failure [see Warnings and Precautions (5.4)]. Proteinuria and Renal Failure/Impairment Advise patients that they will need to undergo regular laboratory tests to monitor kidney function and protein in the urine [see Warnings and Precautions (5.5, 5.6)]. Diarrhea Advise patients when to start standard anti-diarrheal therapy and to maintain adequate hydration. Advise patients to contact their healthcare provider if they are unable to maintain adequate hydration [see Warnings and Precautions (5.7)]. Fistula Formation and Gastrointestinal Perforation Advise patients that LENVIMA can increase the risk of fistula formation or gastrointestinal perforation and to seek immediate medical attention for severe abdominal pain [see Warnings and Precautions (5.8)]. QTc Interval Prolongation Advise patients who are at risk for QTc prolongation that they will need to undergo regular ECGs. Advise all patients that they will need to undergo laboratory tests to monitor electrolytes [see Warnings and Precautions (5.9)]. Hypocalcemia Advise patients of the risks of hypocalcemia, that they will need to undergo laboratory tests to monitor calcium levels, and the potential requirement for calcium supplementation [see Warnings and Precautions (5.10)]. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Advise patients of the signs and symptoms of RPLS and to contact their healthcare provider for new onset or worsening neurological function [see Warnings and Precautions (5.11)]. Hemorrhagic Events Advise patients that LENVIMA can increase the risk for bleeding and to contact their healthcare provider for bleeding or symptoms of severe bleeding [see Warnings and Precautions (5.12)]. Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction Advise patients that LENVIMA can cause hypothyroidism and that their thyroid function should be monitored regularly during treatment [see Warnings and Precautions (5.13)]. Impaired Wound Healing Advise patients that LENVIMA may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.14)]. Osteonecrosis of the Jaw (ONJ) Advise patients regarding good oral hygiene practices and to have preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA. Reference ID: 5482835 Inform patients being treated with LENVIMA, particularly those who are at high risk for ONJ, to avoid invasive dental procedures, if possible, and to inform their healthcare provider of any planned dental procedures [see Warnings and Precautions (5.15)]. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with ONJ. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.16), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women to discontinue breastfeeding during treatment with LENVIMA and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Distributed by: Eisai Inc. Nutley, NJ 07110 LENVIMA® is a registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015-2024 Eisai Inc. Reference ID: 5482835 PATIENT INFORMATION LENVIMA® (lehn-veema) (lenvatinib) capsules What is LENVIMA? LENVIMA is a prescription medicine that is used to treat people with certain kinds of cancer. • LENVIMA is used by itself to treat differentiated thyroid cancer (DTC), a type of thyroid cancer that can no longer be treated with radioactive iodine and is progressing. • LENVIMA is used to treat adults with a type of kidney cancer called advanced renal cell carcinoma (RCC): o along with the medicine pembrolizumab as your first treatment when your kidney cancer has spread or cannot be removed by surgery. o along with the medicine everolimus after one course of treatment with another anti-cancer medicine (anti- angiogenic therapy). • LENVIMA is used by itself as the first treatment for a type of liver cancer called hepatocellular carcinoma (HCC) when it cannot be removed by surgery. • LENVIMA is used along with another medicine called pembrolizumab to treat advanced endometrial carcinoma (EC), a type of uterine cancer: o when a laboratory test shows that your tumor is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), and o you have received anti-cancer treatment, and it is no longer working, and o your cancer cannot be cured by surgery or radiation. The safety and efficacy of LENVIMA have not been established in children. Before you take LENVIMA, tell your healthcare provider about all of your medical conditions, including if you: • have high blood pressure • have heart problems • have a history of blood clots in your arteries (type of blood vessel), including stroke, heart attack, or change in vision • have or have had liver or kidney problems • have a history of a tear (perforation) in your stomach or intestine, or an abnormal connection between two or more body parts (fistula) • have headaches, seizures, or vision problems • have any bleeding problems • plan to have surgery, a dental procedure, or have had a recent surgery. You should stop taking LENVIMA at least 1 week before planned surgery. See “What are the possible side effects of LENVIMA?” • are pregnant or plan to become pregnant. LENVIMA can harm your unborn baby. Females who are able to become pregnant: o Your healthcare provider should do a pregnancy test before you start treatment with LENVIMA. o You should use an effective method of birth control (contraception) during treatment with LENVIMA and for 30 days after the last dose of LENVIMA. Talk with your healthcare provider about birth control methods you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LENVIMA. • are breastfeeding or plan to breastfeed. It is not known if LENVIMA passes into your breast milk. Do not breastfeed during treatment with LENVIMA and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you are taking, or have taken, an osteoporosis medicine. Know the medicines you take. Keep a list of your medicines to show to your healthcare provider and pharmacist when you get a new medicine. Reference ID: 5482835 How should I take LENVIMA? • Take LENVIMA exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much LENVIMA to take and when to take it. Your healthcare provider may change your dose during treatment, stop treatment for some time, or completely stop treatment with LENVIMA if you have side effects. • Take LENVIMA 1 time each day at the same time, with or without food. • If you miss a dose of LENVIMA, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take the next dose at your regular time. • Swallow LENVIMA capsules whole. Do not crush or chew the LENVIMA capsules. • If you cannot swallow LENVIMA capsules whole, LENVIMA capsules can be mixed with water or apple juice, then taken by mouth, or mixed with water and given through a feeding tube. • If you take too much LENVIMA, call your healthcare provider or go to the nearest hospital emergency room right away. How to take LENVIMA by mouth if you cannot swallow whole capsules: o Place your daily dose, up to 5 capsules, in a small container or oral syringe (approximately 20 mL capacity). o Add 3 mL of water or apple juice to the container or oral syringe. Wait 10 minutes for the capsule shell (outer surface) to dissolve completely, then stir or shake the mixture for 3 minutes until capsules are fully dissolved. Do not break or crush the capsules. o Drink the liquid mixture or use an oral syringe to take directly into the mouth. o Next, using a second syringe, add an additional 2 mL of liquid to the container or oral syringe (cap the first oral syringe before adding the additional water) then swirl or shake and take the liquid mixture. Repeat this step at least one time and until you cannot see any of the LENVIMA mixture left in the container or oral syringe to make sure all of the medicine is taken. o If 6 capsules are required for your daily dose, follow the above instructions using 3 capsules at a time. How to give LENVIMA through a feeding tube: • LENVIMA should be given in feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube). o Place your daily dose, up to 5 capsules, in a syringe (20 mL capacity). o Add 3 mL of water to the syringe. Wait 10 minutes for the capsule shell (outer surface) to dissolve completely, then stir or shake the mixture for 3 minutes until capsules are fully dissolved. Do not break or crush the capsules. o Give the mixture through a feeding tube. o Next, cap the syringe and remove the plunger. Use a second syringe and add an additional 2 mL of liquid to the syringe. Swirl or shake and give the mixture in the feeding tube. Repeat this step at least one time and until you cannot see any of the LENVIMA mixture left in the syringe to make sure all of the medicine is taken. o If 6 capsules are required for your daily dose, follow the above instructions using 3 capsules at a time. • LENVIMA mixture may be stored in a covered container in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC) for a maximum of 24 hours. Throw away the LENVIMA mixture if not used within 24 hours of mixing. What are the possible side effects of LENVIMA? LENVIMA may cause serious side effects, including: • High blood pressure (hypertension). High blood pressure is a common side effect of LENVIMA and can be serious. Your blood pressure should be well controlled before you start taking LENVIMA. Your healthcare provider should check your blood pressure regularly during treatment with LENVIMA. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. • Heart problems. LENVIMA can cause serious heart problems that may lead to death. Call your healthcare provider right away if you get symptoms of heart problems, such as shortness of breath or swelling of your ankles. • Problem with blood clots in your blood vessels (arteries). Get emergency medical help right away if you get any of the following symptoms: Reference ID: 5482835 o severe chest pain or pressure o pain in your arms, back, neck or jaw o shortness of breath o numbness or weakness on one side of your body o trouble talking o sudden severe headache o sudden vision changes • Liver problems. LENVIMA may cause liver problems that may lead to liver failure and death. Your healthcare provider will check your liver function before and during treatment with LENVIMA. Tell your healthcare provider right away if you develop any of the following symptoms: o your skin or the white part of your eyes turns yellow (jaundice) o dark “tea colored” urine o light-colored bowel movements (stools) o feeling drowsy, confused or loss of consciousness • Kidney problems. Kidney failure, which can lead to death, has happened with LENVIMA treatment. Your healthcare provider should do regular blood tests to check your kidneys. • Increased protein in your urine (proteinuria). Proteinuria is a common side effect of LENVIMA and can be serious. Your healthcare provider should check your urine for protein before and during your treatment with LENVIMA. • Diarrhea. Diarrhea is a common side effect of LENVIMA and can be serious. If you get diarrhea, ask your healthcare provider about what medicines you can take to treat your diarrhea. It is important to drink more water when you get diarrhea. Tell your healthcare provider or go to the emergency room if you are unable to drink enough liquids and your diarrhea is not able to be controlled. • An opening in the wall of your stomach or intestines (perforation) or an abnormal connection between two or more body parts (fistula). Get emergency medical help right away if you develop severe stomach (abdomen) pain. • Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider will do blood tests before and during your treatment with LENVIMA to check the levels of potassium, magnesium, and calcium in your blood, and may check the electrical activity of your heart with an electrocardiogram (ECG). • Low levels of blood calcium (hypocalcemia). Your healthcare provider will check your blood calcium levels during treatment with LENVIMA and may tell you to take a calcium supplement if your calcium levels are low. • A condition called Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Call your healthcare provider right away if you get severe headache, seizures, weakness, confusion, or blindness or change in vision. • Bleeding. LENVIMA may cause serious bleeding problems that may lead to death. Tell your healthcare provider if you develop any signs or symptoms of bleeding during treatment with LENVIMA, including: o severe and persistent nose bleeds o vomiting blood o red or black (looks like tar) stools o blood in your urine o coughing up blood or blood clots o heavy or new onset vaginal bleeding • Change in thyroid hormone levels. Your healthcare provider should check your thyroid hormone levels before starting and every month during treatment with LENVIMA. • Wound healing problems. Wound healing problems have happened in some people who take LENVIMA. Tell your healthcare provider if you plan to have any surgery before or during treatment with LENVIMA. o You should stop taking LENVIMA at least 1 week before planned surgery. o Your healthcare provider should tell you when you may start taking LENVIMA again after surgery. • Severe jawbone problems (osteonecrosis). Severe jawbone problems have happened in some people who take LENVIMA. Certain risk factors such as taking a bisphosphonate medicine or the medicine denosumab, having dental disease, or an invasive dental procedure may increase your risk of getting jawbone problems. Your healthcare provider should examine your mouth before you start and during treatment with LENVIMA. Tell your dentist that you are taking LENVIMA. It is important for you to practice good mouth care during treatment with LENVIMA. Tell your healthcare provider right away if you get signs or symptoms of jawbone problems during treatment with LENVIMA, including jaw pain, toothache, or sores on your gums. Tell your healthcare provider if you plan to have any dental procedures before or during treatment with LENVIMA. You should avoid having Reference ID: 5482835 invasive dental procedures if possible, during treatment with LENVIMA. Stopping your bisphosphonate medicine before an invasive dental procedure may help decrease your risk of getting these jaw problems. o You should stop taking LENVIMA at least 1 week before planned dental surgery or invasive dental procedures. o Your healthcare provider should tell you when you may start taking LENVIMA again after dental procedures. The most common side effects of LENVIMA in people treated for thyroid cancer include: • tiredness • joint and muscle pain • decreased appetite • weight loss • nausea • mouth sores • headache • vomiting • rash, redness, itching, or peeling of your skin on your hands and feet • stomach (abdomen) pain • hoarseness The most common side effects of LENVIMA in people treated for kidney cancer in combination with everolimus include: • tiredness • joint and muscle pain • decreased appetite • vomiting • nausea • mouth sores • swelling in your arms and legs • cough • stomach (abdomen) pain • trouble breathing • rash • weight loss • bleeding The most common side effects of LENVIMA in people treated for liver cancer include: • tiredness • decreased appetite • joint and muscle pain • weight loss • stomach (abdomen) pain • rash, redness, itching, or peeling of your skin on your hands and feet • hoarseness • bleeding • decrease in thyroid hormone levels • nausea The most common side effects of LENVIMA when given in combination with pembrolizumab include: • decrease in thyroid hormone levels • tiredness • joint and muscle pain • nausea • decreased appetite • vomiting • mouth sores • weight loss • stomach-area (abdomen) pain • urinary tract infection • constipation • headache • bleeding • rash, redness, itching, or peeling of your skin on your hands and feet • hoarseness • rash LENVIMA may cause fertility problems in males and females. Talk to your healthcare provider if this is a concern for you. Your healthcare provider may need to reduce your dose of LENVIMA, or delay or completely stop treatment, if you have certain side effects. Reference ID: 5482835 These are not all the possible side effects of LENVIMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store LENVIMA? • Store LENVIMA at room temperature, between 68°F to 77°F (20°C to 25°C). • Keep LENVIMA and all medicines out of the reach of children. General information about the safe and effective use of LENVIMA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LENVIMA for a condition for which it was not prescribed. Do not give LENVIMA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LENVIMA that is written for health professionals. What are the ingredients in LENVIMA? Active ingredient: lenvatinib Inactive ingredients: calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropylcellulose, mannitol, microcrystalline cellulose, and talc. The capsule shell contains: ferric oxide red, ferric oxide yellow, hypromellose, and titanium dioxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol and shellac. Distributed by: Eisai Inc., Nutley, NJ 07110 LENVIMA® is a registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. For more information, call 1-877-873-4724 or go to www.LENVIMA.com. © 2015-2024 Eisai Inc. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 04/2024 Reference ID: 5482835	custom-source	2025-02-12T15:46:52.211645	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206947s032lbl.pdf', 'application_number': 206947, 'submission_type': 'SUPPL ', 'submission_number': 32}
80,262	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use REPATHA® safely and effectively. See full prescribing information for REPATHA. REPATHA (evolocumab) injection, for subcutaneous use Initial U.S. Approval: 2015 -------------------RECENT MAJOR CHANGES---------------------------------- Indications and Usage (1) 11/2024 Dosage and Administration (2.3) 11/2024 Warnings and Precautions (5.1) 11/2024 ---------------------------INDICATIONS AND USAGE--------------------------- REPATHA is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor indicated: • To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease (1) • as an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C (1) • as an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with HeFH, to reduce LDL-C (1) • as an adjunct to other LDL-C-lowering therapies in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH), to reduce LDL-C (1) -----------------------DOSAGE AND ADMINISTRATION---------------------- In adults with established CVD or with primary hyperlipidemia: o The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. (2.1) o If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. (2.1) In pediatric patients aged 10 years and older with HeFH: o The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. (2.1) o If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. (2.1) In adults and pediatric patients aged 10 years and older with HoFH: o The initial recommended dosage of REPATHA is 420 mg once monthly administered subcutaneously. (2.1) o The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. (2.1) o Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer REPATHA after the apheresis session is complete. (2.1) • Assess LDL-C when clinically appropriate. The LDL-lowering effect of REPATHA may be measured as early as 4 weeks after initiation. (2.1) • REPATHA is available as prefilled single-dose SureClick® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex. Consider prescribing a presentation of REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex. (2.3, 16) • Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm. Rotate injection sites for each administration. (2.3) • See Full Prescribing Information for important administration instructions. (2.3) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- • Injection: 140 mg/mL solution prefilled single-dose SureClick® autoinjector (3) • Injection: 140 mg/mL solution prefilled single-dose syringe (3) • Injection: 420 mg/3.5 mL solution single-dose Pushtronex® system (on-body infusor with prefilled cartridge) (3) -------------------------------CONTRAINDICATIONS----------------------------- Patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in REPATHA. (4) ---------------------------WARNINGS AND PRECAUTIONS------------------- Hypersensitivity Reactions: Angioedema has occurred. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. (5.1) ------------------------------ADVERSE REACTIONS------------------------------ Common (> 5% of patients treated with REPATHA and more frequently than placebo) adverse reactions in adults with: Primary hyperlipidemia: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. (6) Established CVD: diabetes mellitus, nasopharyngitis and upper respiratory tract infection. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Missed Doses 2.3 Important Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 1 of 24 Reference ID: 5482664 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE REPATHA is indicated: • To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease • As an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C • As an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with HeFH, to reduce LDL-C • As an adjunct to other LDL-C-lowering therapies in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH), to reduce LDL-C 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage • In adults with established cardiovascular disease or with primary hyperlipidemia: • The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously [see Dosage and Administration (2.3)]. • If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. • In pediatric patients aged 10 years and older with HeFH: • The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously [see Dosage and Administration (2.3)]. • If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. • In adults and pediatric patients aged 10 years and older with HoFH: • The initial recommended dosage of REPATHA is 420 mg once monthly administered subcutaneously [see Dosage and Administration (2.3)]. • The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. • Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer REPATHA after the apheresis session is complete. • Assess LDL-C when clinically appropriate. The LDL-lowering effect of REPATHA may be measured as early as 4 weeks after initiation. • When monitoring LDL-C for patients receiving REPATHA 420 mg once monthly, note that LDL-C can vary during the dosing interval in some patients; recommend measuring LDL-C just prior to the next scheduled dose [see Clinical Studies (14)]. 2 of 24 Reference ID: 5482664 2.2 Missed Doses If a dose is missed: • Within 7 days from the missed dose, instruct the patient to administer REPATHA and resume the patient’s original schedule. • More than 7 days after the missed dose: • For an every 2-week dose, instruct the patient to wait until the next dose on the original schedule. • For a once-monthly dose, instruct the patient to administer the dose and start a new schedule based on this date. 2.3 Important Administration Instructions • REPATHA is available as prefilled single-dose SureClick® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex [see How Supplied/Storage and Handling (16)]. Consider prescribing a presentation of REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex [see Warnings and Precautions (5.1)]. • Train patients and/or caregivers on how to prepare and administer REPATHA, according to the Instructions for Use and instruct them to read and follow the Instructions for Use each time they use REPATHA. • Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes for the prefilled single-dose SureClick® autoinjector or prefilled single-dose syringe and for at least 45 minutes for the on-body infusor with prefilled cartridge if REPATHA has been refrigerated [see How Supplied/Storage and Handling (16)]. • Visually inspect REPATHA prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy, discolored, or contains particles. • Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. Avoid injecting into areas with scars or stretch marks. Rotate injection sites for each administration. • The 420 mg dose of REPATHA can be administered: • over 5 minutes by using the single-dose on-body infusor with prefilled cartridge, or • by giving 3 injections consecutively within 30 minutes using the prefilled single-dose SureClick® autoinjector or prefilled single-dose syringe. 3 DOSAGE FORMS AND STRENGTHS REPATHA is a clear to opalescent, colorless to pale yellow solution available as follows: • Injection: 140 mg/mL solution in a prefilled single-dose SureClick® autoinjector • Injection: 140 mg/mL solution in a prefilled single-dose syringe • Injection: 420 mg/3.5 mL solution in a single-dose Pushtronex® system (on-body infusor with prefilled cartridge) 3 of 24 Reference ID: 5482664 4 CONTRAINDICATIONS REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in REPATHA. Serious hypersensitivity reactions including angioedema have occurred in patients treated with REPATHA [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema, have been reported in patients treated with REPATHA. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. REPATHA is contraindicated in patients with a history of serious hypersensitivity reactions to evolocumab or any excipient in REPATHA [see Contraindications (4)]. The prefilled single-dose SureClick® autoinjector and prefilled single-dose syringe presentations of REPATHA that contain dry natural rubber (a derivative of latex) in the needle cover may cause an allergic reaction in individuals sensitive to latex. Instruct patients to inform their healthcare provider if they are sensitive to latex. Consider prescribing a presentation of REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex [see How Supplied/Storage and Handling (16)]. 6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the label: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults with Primary Hyperlipidemia The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races. Adverse Reactions in a 52-Week Controlled Trial In a 52-week, double-blind, randomized, placebo-controlled trial, 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14)]. The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian; 6% identified as Hispanic ethnicity. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively). 4 of 24 Reference ID: 5482664 Table 1. Adverse Reactions Occurring in ≥ 3% of REPATHA-treated Patients and More Frequently than with Placebo in a 52-Week Trial Placebo (N = 302) % REPATHA (N = 599) % Nasopharyngitis 9.6 10.5 Upper respiratory tract infection 6.3 9.3 Influenza 6.3 7.5 Back pain 5.6 6.2 Injection site reactions† 5.0 5.7 Cough 3.6 4.5 Urinary tract infection 3.6 4.5 Sinusitis 3.0 4.2 Headache 3.6 4.0 Myalgia 3.0 4.0 Dizziness 2.6 3.7 Musculoskeletal pain 3.0 3.3 Hypertension 2.3 3.2 Diarrhea 2.6 3.0 Gastroenteritis 2.0 3.0 † includes erythema, pain, bruising Adverse Reactions in Seven Pooled 12-Week Controlled Trials In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian; 5% identified as Hispanic ethnicity. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2. Table 2. Adverse Reactions Occurring in ≥ 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Trials Placebo (N = 1224) % REPATHA† (N = 2052) % Nasopharyngitis 3.9 4.0 Back pain 2.2 2.3 Upper respiratory tract infection 2.0 2.1 Arthralgia 1.6 1.8 Nausea 1.2 1.8 Fatigue 1.0 1.6 Muscle spasms 1.2 1.3 Urinary tract infection 1.2 1.3 5 of 24 Reference ID: 5482664 Placebo (N = 1224) % REPATHA† (N = 2052) % Cough 0.7 1.2 Influenza 1.1 1.2 Contusion 0.5 1.0 † 140 mg every 2 weeks and 420 mg once monthly combined Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial) The adverse reactions described below are from a pool of the 52-week trial and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively. Local Injection Site Reactions Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHA-treated patients and placebo-treated patients were 0.1% and 0%, respectively. Hypersensitivity Reactions Hypersensitivity reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common hypersensitivity reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%). Adverse Reactions in the Cardiovascular Outcomes Trial In a double-blind, randomized, placebo-controlled cardiovascular outcomes trial, 27,525 patients received at least one dose of REPATHA or placebo [see Clinical Studies (14)]. The mean age was 62.5 years (range: 40 to 86 years), 45% were 65 years or older, 9% were 75 years or older, 25% women, 85% White, 2% Black and 10% Asian; 8% identified as Hispanic ethnicity. Patients were exposed to REPATHA or placebo for a median of 24.8 months; 91% of patients were exposed for ≥ 12 months, 54% were exposed for ≥ 24 months and 5% were exposed for ≥ 36 months. The safety profile of REPATHA in this trial was generally consistent with the safety profile described above in the 12- and 52-week controlled trials involving patients with primary hyperlipidemia. Common adverse reactions (> 5% of patients treated with REPATHA and occurring more frequently than placebo) included diabetes mellitus (8.8% REPATHA, 8.2% placebo), nasopharyngitis (7.8% REPATHA, 7.4% placebo), and upper respiratory tract infection (5.1% REPATHA, 4.8% placebo). Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients treated with REPATHA compared with 7.7% in patients that received placebo. Adverse Reactions in Pediatric Patients with HeFH In a 24-week, randomized, placebo-controlled, double-blind trial of 157 pediatric patients with HeFH, 104 patients received 420 mg REPATHA subcutaneously once monthly [see Clinical Studies (14)]. The mean age was 13.7 years (range: 10 to 17 years), 56% were female, 85% White, 1% Black, 1% Asian, and 13% other; 8% identified as Hispanic ethnicity. Common adverse reactions (> 5% of patients treated with REPATHA and occurring more frequently than placebo) included: • Nasopharyngitis (12% versus 11%) 6 of 24 Reference ID: 5482664 • Headache (11% versus 2%) • Oropharyngeal pain (7% versus 0%) • Influenza (6% versus 4%) • Upper respiratory tract infection (6% versus 2%) Adverse Reactions in Adults and Pediatric Patients with HoFH In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH, 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14)]. The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, included: • Upper respiratory tract infection (9.1% versus 6.3%) • Influenza (9.1% versus 0%) • Gastroenteritis (6.1% versus 0%) • Nasopharyngitis (6.1% versus 0%) In a multicenter, open-label 5-year extension study, 106 patients with HoFH, including 14 pediatric patients, received 420 mg of REPATHA subcutaneously once monthly or every 2 weeks [see Clinical Studies (14)]. The mean age was 34 years (range: 13 to 68 years), 51% were women, 80% White, 12% Asian, 1% Native American, and 7% other; 5% identified as Hispanic ethnicity. No new adverse reactions were observed during the open-label extension study. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to REPATHA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In a pool of placebo- and active-controlled clinical trials, 0.3% (48 out of 17,992) of adult patients treated with at least one dose of REPATHA tested positive for the development of binding antibodies. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies. The development of anti-evolocumab antibodies was not detected in clinical trials of pediatric patients treated with REPATHA. There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA. 7 of 24 Reference ID: 5482664 6.3 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of REPATHA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hypersensitivity reactions: Angioedema • Influenza-like illness 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from clinical trials and postmarketing reports on REPATHA use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month. In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses. The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier. Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, evolocumab has the potential to be transmitted from the mother to the developing fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. There is a pregnancy safety study for REPATHA. If REPATHA is administered during pregnancy, healthcare providers should report REPATHA exposure by contacting Amgen at 1-800-77-AMGEN (1-800-772-6436) or https://wwwext.amgen.com/products/global-patient-safety/adverse-event-reporting. Data Animal Data In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. No test of humoral immunity in infant monkeys was conducted with evolocumab. 8 of 24 Reference ID: 5482664 8.2 Lactation Risk Summary There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies for the treatment of HoFH have been established in pediatric patients aged 10 years and older. Use of REPATHA for this indication is supported by evidence from an adequate and well-controlled trial in adults and pediatric patients aged 13 years and older with HoFH (including 7 pediatric patients treated with REPATHA) and from open-label studies which included an additional 19 pediatric patients aged 11 years and older with HoFH not previously treated with REPATHA [see Adverse Reactions (6.1) and Clinical Studies (14)]. The safety and effectiveness of REPATHA as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 10 years and older. Use of REPATHA for this indication is based on data from a 24-week, randomized, placebo-controlled, double-blind trial in pediatric patients with HeFH. In the trial, 104 patients received REPATHA 420 mg subcutaneously once monthly and 53 patients received placebo; 39 patients (25%) were 10 to 11 years of age [see Adverse Reactions (6.1) and Clinical Studies (14)]. The safety and effectiveness of REPATHA have not been established in pediatric patients with HeFH or HoFH who are younger than 10 years old or in pediatric patients with other types of hyperlipidemia. 8.5 Geriatric Use In controlled trials, 7656 (41%) patients treated with REPATHA were ≥ 65 years old and 1500 (8%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dose adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. 9 of 24 Reference ID: 5482664 11 DESCRIPTION Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin type 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous use. Each 1 mL prefilled single-dose SureClick® autoinjector and prefilled single-dose syringe contains 140 mg evolocumab, acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0. Each single-dose Pushtronex® system (on-body infusor with prefilled cartridge) delivers a 3.5 mL solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels. 12.2 Pharmacodynamics Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation. Maximum LDL-C reduction occurred by 2 weeks after a single-dose of 140 mg of evolocumab and by 3 weeks after a single-dose of 420 mg of evolocumab. 12.3 Pharmacokinetics Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean of 18.6 µg/mL and AUClast mean of 188 day•µg/mL. Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean of 59.0 µg/mL and AUClast mean of 924 day•µg/mL. Following a single 420 mg intravenous dose, the mean systemic clearance was estimated to be 12 mL/hr. An approximate 2- to 3-fold accumulation was observed in trough serum concentrations (Cmin 7.21) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin 11.2), and serum trough concentrations approached steady-state by 12 weeks of dosing. Absorption Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%. 10 of 24 Reference ID: 5482664 Distribution Following a single 420 mg intravenous dose, the mean steady-state volume of distribution was estimated to be 3.3 L. Elimination Two elimination phases were observed for REPATHA. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of REPATHA is largely through a non-saturable proteolytic pathway. REPATHA was estimated to have an effective half-life of 11 to 17 days. Specific Populations The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance across all approved populations [see Use in Specific Populations (8.5)]. The exposure of evolocumab decreased with increasing body weight. These differences are not clinically meaningful. Pediatric Patients The pharmacokinetics of REPATHA were evaluated in 103 pediatric patients aged 10 to 17 years with HeFH (Study 6) [see Use in Specific Populations (8.4), and Clinical Studies (14)]. Following subcutaneous administration of 420 mg REPATHA once monthly, mean trough serum concentrations were 22.4 mcg/mL and 25.8 mcg/mL over the Week 12 and Week 24 time points, respectively. The pharmacokinetics of REPATHA were evaluated in 12 pediatric patients aged 11 to 17 years with HoFH (Study 9) [see Use in Specific Populations (8.4), and Clinical Studies (14)]. Following subcutaneous administration of 420 mg REPATHA once monthly, mean serum trough concentrations were 20.3 mcg/mL and 17.6 mcg/mL at Week 12 and Week 80, respectively. Renal Impairment Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab. In a clinical trial of 18 patients with either normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2, n = 6), severe renal impairment (eGFR < 30 mL/min/1.73 m2, n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6), exposure to evolocumab after a single 140 mg subcutaneous dose was decreased in patients with severe renal impairment or ESRD receiving hemodialysis. Reductions in PCSK9 levels in patients with severe renal impairment or ESRD receiving hemodialysis was similar to those with normal renal function [see Use in Specific Populations (8.6)]. Hepatic Impairment Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients [see Use in Specific Populations (8.7)]. Drug Interaction Studies An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in adult patients co-administered with a high-intensity statin regimen. This difference is not clinically meaningful. 11 of 24 Reference ID: 5482664 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks. There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. The mutagenic potential of evolocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes. There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embryonic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks. The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. In addition, there were no adverse evolocumab-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly. The highest dose tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. 13.2 Animal Toxicology and/or Pharmacology During a 3-month toxicology study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin in adult monkeys, there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after 1 to 2 months exposure. The highest dose tested corresponds to exposures 54- and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. Similarly, there were no effects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. 14 CLINICAL STUDIES Adult Patients with Established Cardiovascular Disease Study 1 (FOURIER, NCT01764633) was a double-blind, randomized, placebo-controlled, event-driven trial in 27,564 (13,784 REPATHA, 13,780 placebo) adult patients with established cardiovascular disease and with LDL-C ≥ 70 mg/dL and/or non-HDL-C ≥ 100 mg/dL despite high- or moderate-intensity statin therapy. Patients were randomly assigned 1:1 to receive either subcutaneous injections of REPATHA (140 mg every 2 weeks or 420 mg once monthly) or placebo; 86% used the every-2-week regimen throughout the trial. The median follow-up duration was 26 months. Overall, 99.2% of patients were followed until the end of the trial or death. The mean (SD) age at baseline was 63 (9) years, with 45% being at least 65 years old; 25% were women. The trial population was 85% White, 2% Black, and 10% Asian; 8% identified as Hispanic ethnicity. Regarding prior diagnoses of cardiovascular disease, 81% had prior myocardial infarction, 19% prior non-hemorrhagic stroke, and 13% had symptomatic peripheral arterial disease. Selected additional 12 of 24 Reference ID: 5482664 baseline risk factors included hypertension (80%), diabetes mellitus (1% type 1; 36% type 2), current daily cigarette smoking (28%), New York Heart Association class I or II congestive heart failure (23%), and eGFR < 60 mL/min per 1.73 m2 (6%). Most patients were on a high- (69%) or moderate-intensity (30%) statin therapy at baseline, and 5% were also taking ezetimibe. Most patients were taking at least one other cardiovascular medication including anti-platelet agents (93%), beta blockers (76%), angiotensin converting enzyme (ACE) inhibitors (56%), or angiotensin receptor blockers (23%). On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 92 [80, 109] mg/dL; the mean (SD) was 98 (28) mg/dL. REPATHA significantly reduced the risk for the primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p < 0.0001) and the key secondary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p < 0.0001). The Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 below. The results of primary and secondary efficacy endpoints are shown in Table 3 below. Table 3. Effect of REPATHA on Cardiovascular Events in Patients with Established Cardiovascular Disease in FOURIER Placebo REPATHA REPATHA vs. Placebo N = 13780 Incidence N = 13784 Incidence Hazard n (%) Rate (per n (%) Rate (per Ratio 100 100 (95% CI) patient patient years) years) Primary composite endpoint Time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina 1563 (11.3) 5.2 1344 (9.8) 4.5 0.85 (0.79, 0.92) Key secondary composite endpoint Time to first occurrence of cardiovascular death, myocardial infarction, stroke 1013 (7.4) 3.4 816 (5.9) 2.7 0.80 (0.73, 0.88) Other secondary endpoints Time to cardiovascular death 240 (1.7) 0.8 251 (1.8) 0.8 1.05 (0.88, 1.25) Time to death by any causea 426 (3.1) 1.4 444 (3.2) 1.5 1.04 (0.91, 1.19) Time to first fatal or non-fatal myocardial infarction 639 (4.6) 2.1 468 (3.4) 1.6 0.73 (0.65, 0.82) Time to first fatal or non-fatal stroke 262 (1.9) 0.9 207 (1.5) 0.7 0.79 (0.66, 0.95) 13 of 24 Reference ID: 5482664 18 16 14 ~ ~ 12 " ~ ·g 10 ., > ~ 8 :, E :, 6 u 4 2 0 Placebo REPATHA 0 No. at Risk 13780 13784 6 13276 13349 12 12822 12937 18 Months 11837 12034 24 7589 7743 30 3589 3652 14.6 Placebo 36 672 681 Placebo REPATHA REPATHA vs. Placebo N = 13780 n (%) Incidence Rate (per 100 patient years) N = 13784 n (%) Incidence Rate (per 100 patient years) Hazard Ratio (95% CI) Time to first coronary revascularization 965 (7.0) 3.2 759 (5.5) 2.5 0.78 (0.71, 0.86) Time to first hospitalization for unstable anginab 239 (1.7) 0.8 236 (1.7) 0.8 0.99 (0.82, 1.18) a Time to death by any cause is not a component of either the primary composite endpoint or key secondary composite endpoint. b Not a prespecified endpoint; an ad hoc analysis was performed to ensure results are provided for each individual component of the primary endpoint. Figure 1. Estimated Cumulative Incidence of Primary Composite Endpoint Over 3 Years in FOURIER 14 of 24 Reference ID: 5482664 16 14 l 12 ~ 10 C: Q) ~ '-' = 8 Q) > :;::; ~ 6 :, E :, t.) 4 0 0 6 No. at Risk Placebo 13780 13447 REPATHA 13784 13499 3.1 12 13140 13240 18 Months 12257 12422 24 7923 8066 30 3785 3837 9.9 Placebo 36 717 713 Figure 2. Estimated Cumulative Incidence of Key Secondary Composite Endpoint Over 3 Years in FOURIER The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −63% (95% CI: −63%, −62%) and from baseline to Week 72 was −57% (95% CI: −58%, −56%). At Week 48, the median [Q1, Q3] LDL-C was 26 [15, 46] mg/dL in the REPATHA group, with 47% of patients having LDL-C < 25 mg/dL. In EBBINGHAUS (NCT02207634), a substudy of 1974 patients enrolled in the FOURIER trial, REPATHA was non-inferior to placebo on selected cognitive function domains as assessed with the use of neuropsychological function tests over a median follow-up of 19 months. Primary Hyperlipidemia Study 2 (LAPLACE-2, NCT01763866) was a multicenter, double-blind, randomized controlled 12-week trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. The trial included 1896 patients with hyperlipidemia who received REPATHA, placebo, or ezetimibe as add-on therapy to daily doses of statins (atorvastatin, rosuvastatin, or simvastatin). Ezetimibe was also included as an active control only among those assigned to background atorvastatin. Overall, the mean age at baseline was 60 years (range: 20 to 80 years), 35% were ≥ 65 years old, 46% women, 94% White, 4% were Black, and 1% Asian; 5% identified as Hispanic or Latino ethnicity. After 4 weeks of background statin therapy, the mean baseline LDL-C ranged between 77 and 127 mg/dL across the five background therapy arms. The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −71% (95% CI: −74%, −67%; p < 0.0001) and −63% (95% CI: −68%, −57%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The difference between REPATHA and ezetimibe in mean percent change in LDL-C from baseline to Week 12 was −45% (95% CI: −52%, −39%; p < 0.0001) and −41% (95% CI: −47%, −35%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results, see Table 4 and Figure 3. 15 of 24 Reference ID: 5482664 Table 4. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia on Background Statin Regimens (Mean % Change from Baseline to Week 12 in LAPLACE-2) Treatment Group LDL-C Non-HDL-C Apo B Total Cholesterol REPATHA every 2 weeks vs. Placebo every 2 weeks (Background statin: atorvastatin 10 mg or 80 mg; rosuvastatin 5 mg or 40 mg; simvastatin 40 mg) Placebo every 2 weeks (n = 281) 8 6 5 4 REPATHA 140 mg every 2 weeks† (n = 555) -63 -53 -49 -36 Mean difference from placebo (95% CI) -71 (-74, -67) -59 (-62, -55) -55 (-58, -52) -40 (-43, -38) REPATHA once monthly vs. Placebo once monthly (Background statin: atorvastatin 10 mg or 80 mg; rosuvastatin 5 mg or 40 mg; simvastatin 40 mg) Placebo once monthly (n = 277) 4 5 3 2 REPATHA 420 mg once monthly (n = 562) -59 -50 -46 -34 Mean difference from placebo (95% CI) -63 (-68, -57) -54 (-58, -50) -50 (-53, -47) -36 (-39, -33) REPATHA every 2 weeks vs. Ezetimibe 10 mg daily (Background statin: atorvastatin 10 mg or 80 mg) Ezetimibe 10 mg daily (n = 112) -17 -16 -14 -12 REPATHA 140 mg every 2 weeks† (n = 219) -63 -52 -49 -36 Mean difference from Ezetimibe (95% CI) -45 (-52, -39) -36 (-41, -31) -35 (-40, -31) -24 (-28, -20) REPATHA once monthly vs. Ezetimibe 10 mg daily (Background statin: atorvastatin 10 mg or 80 mg) Ezetimibe 10 mg daily (n = 109) -19 -16 -11 -12 REPATHA 420 mg once monthly (n = 220) -59 -50 -46 -34 Mean difference from Ezetimibe (95% CI) -41 (-47, -35) -35 (-40, -29) -34 (-39, -30) -22 (-26, -19) Estimates based on a multiple imputation model that accounts for treatment adherence † 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C 16 of 24 Reference ID: 5482664 0 -10 (.) I -' 0 -20 -' .s <1) .s - 30 .; "' ~ E _g - 40 <1) O'> c:: "' -50 .c: (.) ~ -60 ,E <1) u -70 c:: ~ £1 i5 - 80 "E <1) E 1ii <1) i= - 90 - 100 REPATHA versus Placebo REPATHA versus Ezelimibe . . . . . . ... . ...... . ... . ................ . ..... . ........ . . . .......... . ... 1 ....... .. ......... . .. . I ... . . . ........ . ..... . . . ............ . . . .......... . ..... . ...... . ....... J ............ • ......... Pooled Stalins Atorvastatin 10 mg OD Atorvastatin 80 mg OD Rosuvastatin 5 mg OD Rosuvastati n 40 mg OD Simvastatin 40 mg OD Atorvastatin 10 mg OD - REPATHA 140 mg every 2 weeks _...,_ REPATHA 420 mg once monthly Atorvastatin 80 mg OD Figure 3. Effect of REPATHA on LDL-C in Patients with Hyperlipidemia when Combined with Statins (Mean % Change from Baseline to Week 12 in LAPLACE-2) Estimates based on a multiple imputation model that accounts for treatment adherence Error bars indicate 95% confidence intervals Study 3 (DESCARTES, NCT01516879) was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 901 patients with hyperlipidemia who received protocol-determined background lipid-lowering therapy of a cholesterol-lowering diet either alone or in addition to atorvastatin (10 mg or 80 mg daily) or the combination of atorvastatin 80 mg daily with ezetimibe. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or REPATHA 420 mg administered subcutaneously once monthly. Overall, the mean age at baseline was 56 years (range: 25 to 75 years), 23% were ≥ 65 years, 52% women, 80% White, 8% Black, and 6% Asian; 6% identified as Hispanic or Latino ethnicity. After stabilization on the assigned background therapy, the mean baseline LDL-C ranged between 90 and 117 mg/dL across the four background therapy groups. In these patients with hyperlipidemia on a protocol-determined background therapy, the difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was −55% (95% CI: −60%, −50%; p ˂ 0.0001) (Table 5 and Figure 4). For additional results, see Table 5. 17 of 24 Reference ID: 5482664 0 N 0 0 ~ "' \ .5 0 ffl ' a, \ \ E \ _g 0 N \ "' I C> ] '-' 0 1': "' "' I le 8: 0 \ \ \ \ \ ..,. I \ 0 "' I 15 \ I +------ - --"'f J-------i------ - I Baseline Week 12 Week 24 Week 36 Week 52 • Placebo once montllly Observed n: 302 267 279 246 258 _..,..__ REPATHA 420 mg once monthly Observed n: 599 530 555 481 509 GRH0434v1 Table 5. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia* (Mean % Change from Baseline to Week 52 in DESCARTES) Treatment Group LDL-C Non-HDL-C Apo B Total Cholesterol Placebo once monthly (n = 302) 8 8 2 5 REPATHA 420 mg once monthly (n = 599) -47 -39 -38 -26 Mean difference from placebo -55 -46 -40 -31 (95% CI) (-60, -50) (-50, -42) (-44, -37) (-34, -28) Estimates based on a multiple imputation model that accounts for treatment adherence * Prior to randomization, patients were stabilized on background therapy consisting of a cholesterol-lowering diet either alone or in addition to atorvastatin (10 mg or 80 mg daily) or the combination of atorvastatin 80 mg daily with ezetimibe. Figure 4. Effect of REPATHA 420 mg Once Monthly on LDL-C in Patients with Hyperlipidemia in DESCARTES Estimates based on a multiple imputation model that accounts for treatment adherence Error bars indicate 95% confidence intervals Study 4 (MENDEL-2, NCT01763827) was a multicenter, double-blind, randomized, placebo- and active-controlled, 12-week trial that included 614 patients with hyperlipidemia who were not taking lipid-lowering therapy at baseline. Patients were randomly assigned to receive subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. Blinded administration of ezetimibe was also included as an active control. Overall, the mean age at baseline was 53 years (range: 20 to 80 years), 18% were ≥ 65 years old, 66% were women, 83% White, 7% Black, and 9% Asian; 11% identified as Hispanic or Latino ethnicity. The mean baseline LDL-C was 143 mg/dL. 18 of 24 Reference ID: 5482664 The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −55% (95% CI: −60%, −50%; p < 0.0001) and −57% (95% CI: −61%, −52%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The difference between REPATHA and ezetimibe in mean percent change in LDL-C from baseline to Week 12 was −37% (95% CI: −42%, −32%; p < 0.0001) and −38% (95% CI: −42%, −34%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results, see Table 6. Table 6. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia (Mean % Change from Baseline to Week 12 in MENDEL-2) Total Treatment Group LDL-C Non-HDL-C Apo B Cholesterol Placebo every 2 weeks (n = 76) 1 0 1 0 Ezetimibe 10 mg daily (n = 77) -17 -14 -13 -10 REPATHA 140 mg every 2 weeks† -54 -47 -44 -34 (n = 153) Mean difference from placebo -55 -47 -45 -34 (95% CI) (-60, -50) (-52, -43) (-50, -41) (-37, -30) Mean difference from Ezetimibe -37 -33 -32 -23 (95% CI) (-42, -32) (-37, -29) (-36, -27) (-27, -20) Placebo once monthly (n = 78) 1 2 2 0 Ezetimibe 10 mg daily (n = 77) -18 -16 -13 -12 REPATHA 420 mg once monthly -56 -49 -46 -35 (n = 153) Mean difference from placebo -57 -51 -48 -35 (95% CI) (-61, -52) (-54, -47) (-52, -44) (-38, -32) Mean difference from Ezetimibe -38 -32 -33 -23 (95% CI) (-42, -34) (-36, -29) (-36, -29) (-26, -20) Estimates based on a multiple imputation model that accounts for treatment adherence †140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C Study 5 (RUTHERFORD-2, NCT01763918) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with HeFH on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 5, 38% of patients had clinical atherosclerotic cardiovascular disease. The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy. The differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −61% (95% CI: −67%, −55%; p < 0.0001) and −60% (95% CI: −68%, −52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results, see Table 7 and Figure 5. 19 of 24 Reference ID: 5482664 40 30 20 "' 10 cc ~ "' "' E -10 ~ -20 "' g' -30 ~ u -40 cc "' -50 " "' 0- -60 -70 -80 -90 Placebo every 2 weeks REPATHA 140mg every 2 weeks Placebo once monthly REPATHA 420 mg once monthly Observed n ~ 54 110 55 110 Baseline \ -+t \,, """, ""1 1 53 106 53 105 Week 2 51 50 50 102 106 102 54 47 45 \\ 103 103 103 Week 8 Week 10 Week12 1-e- Placebo every 2 weeks - + - REPATHA 140mg every 2 weeks -~ - Placebo once monthly ---t. - REPATHA 420 mg once monthly I Table 7. Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2) Total Treatment Group LDL-C Non-HDL-C Apo B Cholesterol Placebo every 2 weeks (n = 54) -1 -1 -1 -2 REPATHA 140 mg every 2 weeks† (n = -62 -56 -49 -42 110) Mean difference from placebo -61 -54 -49 -40 (95% CI) (-67, -55) (-60, -49) (-54, -43) (-45, -36) Placebo once monthly (n = 55) 4 4 4 2 REPATHA 420 mg once monthly (n = 110) -56 -49 -44 -37 Mean difference from placebo -60 -53 -48 -39 (95% CI) (-68, -52) (-60, -46) (-55, -41) (-45, -33) Estimates based on a multiple imputation model that accounts for treatment adherence † 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C Figure 5. Effect of REPATHA on LDL-C in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2) N = number of patients randomized and dosed in the full analysis set Estimates based on a multiple imputation model that accounts for treatment adherence Error bars indicate 95% confidence intervals Pediatric Patients with HeFH Study 6 (HAUSER-RCT, NCT02392559) was a randomized, multicenter, placebo-controlled, double-blind, 24-week trial in 157 pediatric patients aged 10 to 17 years with HeFH [see Use in Specific Populations (8.4)]. HeFH was diagnosed by diagnostic criteria for HeFH [Simon Broome Register Group (1991), the Dutch Lipid Clinic Network (1999), MEDPED (1993)] or by genetic testing. Patients were required to be on a low-fat diet and optimized background lipid-lowering therapy. Patients were randomly assigned 2:1 to receive 24 weeks of subcutaneous once monthly 420 mg REPATHA or placebo; 104 patients received REPATHA and 53 patients received placebo. The mean age was 14 years (range: 10 to 20 of 24 Reference ID: 5482664 Number of subjects: 1 53 53 44 2 104 101 96 .__ _________________________________ ___. Baseline Week 12 Week 24 Study Week --te-- 1: Placebo QM (N=53) - + - 2: EvoMab 420 mg QM (N=104) I 17 years), 56% were female, 85% White, 1% Black, 1% Asian, 13% Other, and 8% Hispanic. The mean LDL-C at baseline was 184 mg/dL; 17% of patients were on high-intensity statin, 62% on moderate-intensity statin, and 13% on ezetimibe. The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 24 was −38% (95% CI: −45%, −31%; p < 0.0001). For additional results, see Table 8 and Figure 6. Figure 6. Effect of REPATHA on LDL-C in Pediatric Patients with HeFH (Mean % Change from Baseline in HAUSER-RCT) EvoMab = evolocumab; LDL-C = low density lipoprotein cholesterol; QM = monthly (subcutaneous) N = number of patients randomized and dosed in the full analysis set. Vertical lines represent the standard error around the mean. Plot is based on observed data and no imputation is used for missing values. Table 8. Effect of REPATHA on Lipid Parameters in Pediatric Patients with HeFH (Mean % Change from Baseline to Week 24 in HAUSER-RCT) Treatment Group LDL-C Non- HDL-C Apo B Total Cholesterol Placebo once monthly (n = 53) -6 -6 -2 -5 REPATHA 420 mg once monthly (n = 104) -44 -41 -35 -32 Mean difference from placebo (95% CI) -38 (-45, -31) -35 (-42, -28) -32 (-39, -26) -27 (-32, -21) All adjusted p-values < 0.0001. n = number of patients randomized and dosed in the full analysis set. Adults and Pediatric Patients with HoFH Study 7 (TESLA, NCT01588496) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with HoFH. In this trial, 33 patients received 21 of 24 Reference ID: 5482664 subcutaneous injections of 420 mg of REPATHA once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other. The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received REPATHA. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents. The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −31% (95% CI: −44%, −18%; p < 0.0001). For additional results, see Table 9. Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA. Table 9. Effect of REPATHA on Lipid Parameters in Patients with HoFH (Mean % Change from Baseline to Week 12 in TESLA) Treatment Group LDL-C Non-HDL-C Apo B Total Cholesterol Placebo once monthly (n = 16) 9 8 4 8 REPATHA 420 mg once monthly (n = 33) -22 -20 -17 -17 Mean difference from placebo -31 -28 -21 -25 (95% CI) (-44, -18) (-41, -16) (-33, -9) (-36, -14) Estimates based on a multiple imputation model that accounts for treatment adherence Study 8 (TAUSSIG, NCT01624142) was a multicenter, open-label 5-year extension study with REPATHA in 106 patients with HoFH, who were treated with REPATHA as an adjunct to other lipid-lowering therapies. The study included 14 pediatric patients (ages 13 to 17 years). All patients in the study were initially treated with REPATHA 420 mg once monthly except for those receiving lipid apheresis at enrollment, who began with REPATHA 420 mg every 2 weeks. Dose frequency in non-apheresis patients could be titrated up to 420 mg once every 2 weeks based on LDL-C response and PCSK9 levels. A total of 48 patients with HoFH received REPATHA 420 mg once monthly for at least 12 weeks in Study 8 followed by REPATHA 420 mg every 2 weeks for at least 12 weeks. Mean percent change from baseline in LDL-C were −20% at Week 12 of 420 mg once monthly treatment and −30% at Week 12 of 420 mg every 2 weeks treatment, based on available data. Study 9 (HAUSER-OLE, NCT02624869) was an open-label, single-arm, multicenter, 80-week study to evaluate the safety, tolerability, and efficacy of REPATHA for LDL-C reduction in pediatric patients aged 10 to 17 years with HoFH [see Use in Specific Populations (8.4)]. Patients were on a low-fat diet and receiving background lipid-lowering therapy. Overall, 12 patients with HoFH received 420 mg REPATHA subcutaneously once monthly. The mean age was 12 years (range 11 to 17 years), 17% were female, 75% White, 17% Asian, and 8% Other. Median (Q1, Q3) LDL-C at baseline was 398 (343, 475) mg/dL, and all patients were on statins (atorvastatin or rosuvastatin) and ezetimibe. No patients were receiving lipid apheresis. The diagnosis of HoFH was made by genetic confirmation in all patients but enrollment by a clinical diagnosis was permitted. The median (Q1, Q3) percent change in LDL-C from baseline to Week 80 was −14% (−41, 4). Two of the 3 subjects with < 5% LDLR activity responded to evolocumab treatment. 22 of 24 Reference ID: 5482664 16 HOW SUPPLIED/STORAGE AND HANDLING REPATHA is a clear to opalescent, colorless to pale yellow solution supplied as follows: Not Made with Natural Rubber Latex – 140 mg/mL prefilled single-dose SureClick® autoinjector 2 pack NDC 72511-393-02 140 mg/mL prefilled single-dose SureClick® autoinjector 1 pack NDC 72511-393-01 140 mg/mL prefilled single-dose Syringe 1 pack NDC 72511-501-01 420 mg/3.5 mL single-dose Pushtronex® system (on-body infusor with prefilled cartridge) 1 pack NDC 72511-770-01 Contains Dry Natural Rubber – 140 mg/mL prefilled single-dose SureClick® autoinjector* 2 pack NDC 72511-760-02 140 mg/mL prefilled single-dose Syringe* 1 pack NDC 72511-750-01 * The needle cover of the glass prefilled single-dose SureClick® autoinjector and prefilled single-dose syringe contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex [see Warnings and Precautions (5.1)]. Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. For convenience, REPATHA may be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton for 30 days. If not used within the 30 days, discard REPATHA. 17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use). Hypersensitivity Inform patients that serious hypersensitivity reactions (e.g., angioedema) have been reported in patients treated with REPATHA. Advise patients on the symptoms of hypersensitivity reactions and instruct them to discontinue REPATHA and seek medical attention promptly, if such symptoms occur. Latex-Sensitivity Instruct patients to inform their healthcare provider if they are sensitive to latex. Inform patients that REPATHA is available as prefilled single-dose SureClick® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex, and the carton and Instructions for Use state if the product contains dry natural rubber. Advise latex-sensitive patients that the needle cover of the glass prefilled single-dose SureClick® autoinjector and prefilled single-dose syringe that contain dry natural rubber (a derivative of latex) may cause allergic reactions in individuals sensitive to latex. [see How Supplied/Storage and Handling (16)]. Pregnancy Advise women who are exposed to REPATHA during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Amgen at 1-800-77-AMGEN (1-800-772-6436) or https://wwwext.amgen.com/products/global-patient safety/adverse-event-reporting [see Use in Specific Populations (8.1)]. 23 of 24 Reference ID: 5482664 AMGEN Administration Provide guidance to patients and caregivers on proper subcutaneous administration technique and how to use the prefilled single-dose SureClick® autoinjector, prefilled single-dose syringe, or single-dose on-body infusor with prefilled cartridge correctly. Inform patients that it may take up to 15 seconds to administer REPATHA using the prefilled single-dose SureClick® autoinjector or prefilled single-dose syringe and about 5 minutes to administer REPATHA using the single-dose on-body infusor with prefilled cartridge. The single-dose on-body infusor with prefilled cartridge is not made with natural rubber latex. For more information about REPATHA, go to www.REPATHA.com or call 1-844-REPATHA (1-844-737-2842). REPATHA® (evolocumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License Number 1080 Patent: http://pat.amgen.com/repatha/ © 2015-2021, 2024 Amgen Inc. All rights reserved. v11 24 of 24 Reference ID: 5482664 Patient Information REPATHA® (ri-PAth-a) (evolocumab) injection, for subcutaneous use What is REPATHA? REPATHA is an injectable prescription medicine used: • To reduce the risk of major adverse cardiovascular (CV) events, such as death from cardiovascular disease, heart attack, stroke, certain types of chest pain conditions (unstable angina) requiring hospitalization, or certain types of heart surgery, in adults with cardiovascular disease. • along with diet alone or together with other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia [HeFH]) to reduce low density lipoprotein (LDL) or bad cholesterol. • along with diet and other LDL-lowering medicines in children aged 10 years and older with HeFH to reduce LDL cholesterol. • along with other LDL-lowering medicines in adults and children aged 10 years and older with a type of high cholesterol called homozygous familial hypercholesterolemia (HoFH), to reduce LDL cholesterol. It is not known if REPATHA is safe and effective in children with HeFH or HoFH who are younger than 10 years of age or in children with other types of hyperlipidemia. Who should not use REPATHA? Do not use REPATHA if you or your child are allergic to evolocumab or to any of the ingredients in REPATHA. See the end of this leaflet for a complete list of ingredients in REPATHA. What should I tell my healthcare provider before using REPATHA? Before you or your child start using REPATHA, tell your healthcare provider about all your medical conditions, including if you or your child: • are allergic to rubber or latex. REPATHA is available as prefilled single-dose SureClick® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex. The carton and “Instructions for Use” will state if your prefilled single-dose SureClick autoinjector or prefilled single-dose syringe contains dry natural rubber. o The single-dose Pushtronex® system (on-body infusor with prefilled cartridge) is not made with natural rubber latex. • are pregnant or plan to become pregnant. It is not known if REPATHA will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking REPATHA. • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take REPATHA or breastfeed. If you or your child are pregnant or breastfeed during REPATHA treatment, you are encouraged to call Amgen at 1-800-772-6436 (1-800-77-AMGEN) or visit https://wwwext.amgen.com/products/global-patient-safety/adverse-event-reporting to share information about the health of you and your baby or your child and your child’s baby. Tell your healthcare provider or pharmacist about any prescription and over-the-counter medicines, vitamins, or herbal supplements you or your child take. How should I use REPATHA? • See the detailed “Instructions for Use” that comes with this Patient Information about the right way to prepare and give REPATHA. • Use REPATHA exactly as your healthcare provider tells you or your child to use it. • REPATHA is given under the skin (subcutaneously), every 2 weeks or 1 time each month. o If you or your child have HoFH, the recommended starting dose is 420 mg one time each month. After 12 weeks, your healthcare provider may decide to increase the dose to 420 mg every two weeks. If you or your child receive lipid apheresis, your healthcare provider may decide to start you or your child on a dose of 420 mg every two weeks to match with the apheresis treatment and you or your child should take the dose after the apheresis treatment. • REPATHA comes as a prefilled single-dose (1 time) autoinjector (SureClick autoinjector), as a prefilled single-dose syringe or as a single-dose Pushtronex system (on-body infusor with prefilled cartridge). Your healthcare provider will prescribe the type and dose that is best for you or your child. Reference ID: 5482664 • If your healthcare provider prescribes you or your child the 420 mg dose, you or your child may use: o a single-dose on-body infusor with prefilled cartridge to give the injection over 5 minutes, or o 3 separate injections in a row, using a different prefilled single-dose SureClick autoinjector or prefilled single-dose syringe for each injection. Give all of these injections within 30 minutes. • If your healthcare provider decides that you or your child or a caregiver can give REPATHA, you or your child or your caregiver should receive training on the right way to prepare and inject REPATHA. Do not try to inject REPATHA until you or your child have been shown the right way by your healthcare provider or nurse. o If you or your child are using the prefilled single-dose SureClick autoinjector, put the yellow safety guard (needle inside) of the prefilled single-dose SureClick autoinjector on the skin before injecting. • You or your child can inject into the thigh, upper arm, or stomach (abdomen), except for a two-inch area around the belly button. • Do not choose an area where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. • Always check the label of your prefilled single-dose SureClick autoinjector, prefilled single-dose syringe, or single-dose on-body infusor with prefilled cartridge to make sure you have the correct medicine and the correct dose of REPATHA before each injection. • If you or your child forget to use REPATHA or are not able to take the dose at the regular time, inject your or your child’s missed dose as soon as you remember, as long as it is within 7 days of the missed dose. o If it is more than 7 days from the missed dose and you or your child are using the every-2-week dose, inject the next dose based on the original schedule. This will put you or your child back on the original schedule. o If it is more than 7 days from the missed dose and you or your child are using the 1 time each-month dose, inject the dose and start a new schedule using this date. If you or your child are not sure when to take REPATHA after a missed dose, ask your healthcare provider or pharmacist. • If your healthcare provider has prescribed REPATHA along with other cholesterol-lowering medicines for you or your child, follow instructions from your healthcare provider. Read the Patient Information for those medicines. • If you or your child use more REPATHA than you should, talk to your healthcare provider or pharmacist. • Do not stop using REPATHA without talking with your healthcare provider. If you or your child stop using REPATHA, the cholesterol levels can increase. What are the possible side effects of REPATHA? REPATHA can cause serious side effects including: • Serious Allergic Reactions. Some people taking REPATHA have had serious allergic reactions. Stop taking REPATHA and call your healthcare provider or seek emergency medical help right away if you or your child have any of these symptoms: o trouble breathing or swallowing o raised bumps (hives) o rash, or itching o swelling of the face, lips, tongue, throat or arms The most common side effects of REPATHA include: runny nose, sore throat, symptoms of the common cold, flu or flu-like symptoms, back pain, high blood sugar levels (diabetes) and redness, pain, or bruising at the injection site. Tell your healthcare provider if you or your child have any side effect that bothers you or that does not go away. These are not all the possible side effects of REPATHA. Ask your healthcare provider or pharmacist for more information. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store REPATHA? • Store REPATHA in the refrigerator between 36°F to 46°F (2°C to 8°C). Store REPATHA in the original carton until use to protect it from light. • If needed, REPATHA can be stored at room temperature between 68°F to 77°F (20°C to 25°C) in the original carton for up to 30 days. Throw away REPATHA that has been stored at room temperature for more than 30 days. • Do not freeze REPATHA. • Do not shake REPATHA. Keep REPATHA and all medicines out of the reach of children. Reference ID: 5482664 AMGEN General information about the safe and effective use of REPATHA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REPATHA for a condition for which it was not prescribed. Do not give REPATHA to other people, even if they have the same symptoms that you or your child have. It may harm them. You can ask your pharmacist or healthcare provider for information about REPATHA that is written for healthcare professionals. What are the ingredients in REPATHA? • Active Ingredient: evolocumab • Inactive Ingredients: proline; acetate; polysorbate 80; water for injection, USP; and sodium hydroxide. Manufactured by: Amgen Inc. One Amgen Center Drive, Thousand Oaks, California 91320-1799. U.S. License Number 1080 Patent: http://pat.amgen.com/repatha/ © 2017-2021, 2024 Amgen Inc. All rights reserved. For more information about REPATHA, go to www.REPATHA.com or call 1-844-REPATHA (1-844-737-2842). This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 v9 Reference ID: 5482664 INSTRUCTIONS FOR USE REPATHA® (ri-PAth-a) (evolocumab) injection, for subcutaneous use 140 mg/mL single-dose prefilled SureClick® autoinjector (contains dry natural rubber) This Instructions for Use contains information on how to inject REPATHA with a SureClick autoinjector. If your healthcare provider decides that you or a caregiver may be able to give your injections of REPATHA at home, you should receive training on the right way to prepare and inject REPATHA. Do not try to inject yourself until you have been shown the right way to give the injections by your healthcare provider or nurse. The medicine in the REPATHA autoinjector is for injection under the skin (subcutaneous injection). See the REPATHA Patient Information for information about REPATHA. Getting to know your prefilled autoinjector Gray start button Expiration date Window Medicine Yellow safety guard (needle inside) Orange cap (contains dry natural rubber) 140 mg/mL Reference ID: 5482664 - Refrigerate in carton until ready to use 1. Important Information You Need to Know Before Injecting REPATHA • It is important that you do not try to give the injection until you have fully read and understood this Instructions for Use. • The orange cap on the REPATHA SureClick autoinjector contains a needle cover (located inside the cap) that contains dry natural rubber, which is made from latex. Tell your healthcare provider if you are allergic to latex. • Do not use the autoinjector if the carton is damaged or the seal is broken. • Do not use the autoinjector after the expiration date on the label. • Do not shake the autoinjector. • Do not remove the orange cap from the autoinjector until you are ready to inject. • Do not use the autoinjector if it has been frozen. • Do not use the autoinjector if it has been dropped on a hard surface. Part of the autoinjector may be broken even if you cannot see the break. Use a new autoinjector and call 1-844-REPATHA (1-844-737-2842). Frequently asked questions: For additional information and answers to frequently asked questions, visit www.repatha.com. Where to get help: If you want more information or help using REPATHA: • Contact your healthcare provider, • Visit www.repatha.com, or • Call 1-844-REPATHA (1-844-737-2842) 2. Storing and Preparing to Inject REPATHA 2a Refrigerate the autoinjector carton until you are ready to use it. • Keep the autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C). • Keep the autoinjector in the original carton to protect it from light or physical damage. • Do not freeze the autoinjector. • Do not store the autoinjector in extreme heat or cold. For example, avoid storing in your vehicle’s glove box or trunk. Important: Keep the autoinjector and all medicines out of the sight and reach of children. Reference ID: 5482664 - - 0 0 30 days WAIT minutes 2b Wait 30 minutes for the autoinjector to reach room temperature. • Remove the number of autoinjectors you need for your injection and put any unused autoinjectors back into the refrigerator. • Let the autoinjector warm up naturally. • Do not heat the autoinjector with hot water, a microwave, or direct sunlight. • Do not shake the autoinjector at any time. • Using the autoinjector at room temperature makes sure the full dose is delivered and allows for a more comfortable injection. 2c You may keep REPATHA at room temperature for up to 30 days, if needed. • For example, when you are traveling, you may keep REPATHA at room temperature. o Keep it at room temperature between 68°F to 77°F (20°C to 25°C) in the original carton. o Record the date you removed it from the refrigerator and use it within 30 days. Important: Place the autoinjector in a sharps disposal container if it has reached room temperature and has not been used within 30 days. Reference ID: 5482664 • - []-- Medicine Inspect the medicine. It should be clear and colorless to slightly yellow. 2d • It is okay to see air bubbles in the autoinjector. • Do not use REPATHA if the medicine is cloudy, discolored, or has flakes or particles. Important: If the medicine is cloudy, discolored, or has flakes or particles, or if the autoinjector is damaged or expired, call 1-844-REPATHA (1-844-737-2842). Expiration date 2e Check the expiration date (Exp.) and inspect the autoinjector for damage. • Do not use the autoinjector if the expiration date has passed. • Do not use the autoinjector if: o the orange cap is missing or loose. o it has cracks or broken parts. o it has been dropped on a hard surface. • Make sure you have the right medicine and dose. 3. Getting Ready for Your Injection Sharps disposal container Alcohol wipe Adhesive bandage Cotton ball or gauze pad Reference ID: 5482664 - - I - 3a Gather and place the following items for your injection on a clean, flat, and well-lit surface: • REPATHA autoinjector (room temperature) • Sharps disposal container [see Disposing of REPATHA and Checking the Injection Site] • Alcohol wipe • Adhesive bandage • Cotton ball or gauze pad 3b Inject into 1 of these sites. • Inject into the front of your thigh or stomach (except for 2 inches around your belly button). • Someone else can inject in your thigh, stomach, or back of your upper arm. • Choose a different site for each injection. Important: Avoid areas with scars or stretch marks, or where the skin is tender, bruised, red, hard, raised, thick or scaly skin patch or lesion. 3c Wash hands thoroughly with soap and water. Reference ID: 5482664 - 3d Clean the injection site with an alcohol wipe. • Let the skin dry on its own. • Do not touch this area again before injecting. 4. Injecting REPATHA Important: Only remove the orange cap when you can inject right away (within 5 minutes) because the medicine can dry out. Do not recap. Window should be visible Grasp the autoinjector so you can see the window. Pull the orange cap straight off. You may need to pull 4a hard. • Do not twist, bend or wiggle the orange cap to pull it off. • Never put the orange cap back on. It may damage the needle. • Do not put your finger inside the yellow safety guard. • It is normal to see a drop of medicine at the end of the needle or yellow safety guard. Reference ID: 5482664 ----- ------------------------------------ > -• STRETCH PINCH Stretch or pinch the skin to create a firm surface at the injection site. Place the yellow safety guard straight 4b against the skin. • Keep the skin stretched or pinched until the injection is finished. • Make sure you can see the window. • Make sure the autoinjector is positioned straight on the injection site (at a 90-degree angle). PUSH and hold against skin Firmly push the autoinjector down until the yellow safety guard stops moving. Hold the autoinjector down, 4c do not lift. • The yellow safety guard pushes in and unlocks the gray start button. Reference ID: 5482664 1111 > - PRESS gray start button 4d Keep pushing the autoinjector down and press the gray start button to start the injection. • You may hear or feel a click. • The window starts to turn yellow. • It is okay to let go of the gray start button. WATCH and CONFIRM that the window turns fully yellow 4e Keep pushing the autoinjector down. When the window is fully yellow, the injection is complete. • The injection may take up to 15 seconds to complete. • You may hear or feel a click. • Lift the autoinjector away from your skin. • The yellow safety guard locks around the needle. Important: If the window has not turned fully yellow, or it looks like the medicine is still coming out, you have not received a full dose. Call your healthcare provider right away. Reference ID: 5482664 - 5. Disposing of REPATHA and Checking the Injection Site Place the used autoinjector and orange cap in an FDA-cleared sharps disposal container right away after 5a use. Important: Do not throw away the autoinjector in your household trash. • Do not reuse the autoinjector. • Do not touch the yellow safety guard. 5b Check the injection site. • Do not rub the injection site. • If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if necessary. Additional information about your sharps disposal container If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: • made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, • upright and stable during use, • leak-resistant, and • properly labeled to warn of hazardous waste inside the container. Disposing of sharps disposal containers: When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Reference ID: 5482664 AMGEN For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Important: Keep the autoinjector and sharps disposal container out of the sight and reach of children. For more information or help call 1-844-REPATHA (1-844-737-2842). REPATHA (evolocumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License Number 1080 © 2015-2022, 2024 Amgen Inc. All rights reserved. <Part number> This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 v11 Reference ID: 5482664 INSTRUCTIONS FOR USE REPATHA® (ri-PAth-a) (evolocumab) injection, for subcutaneous use 140 mg/mL single-dose prefilled SureClick® autoinjector This Instructions for Use contains information on how to inject REPATHA with a SureClick autoinjector. If your healthcare provider decides that you or a caregiver may be able to give your injections of REPATHA at home, you should receive training on the right way to prepare and inject REPATHA. Do not try to inject yourself until you have been shown the right way to give the injections by your healthcare provider or nurse. The medicine in the REPATHA autoinjector is for injection under the skin (subcutaneous injection). See the REPATHA Patient Information for information about REPATHA. Getting to know your prefilled autoinjector Gray start button Expiration date Window Medicine Yellow safety guard (needle inside) Orange cap 140 mg/mL 1. Important Information You Need to Know Before Injecting REPATHA • It is important that you do not try to give the injection until you have fully read and understood this Instructions for Use. • Do not use the autoinjector if the carton is damaged or the seal is broken. • Do not use the autoinjector after the expiration date on the label. • Do not shake the autoinjector. • Do not remove the orange cap from the autoinjector until you are ready to inject. • Do not use the autoinjector if it has been frozen. • Do not use the autoinjector if it has been dropped on a hard surface. Part of the autoinjector may be broken even if you cannot see the break. Use a new autoinjector and call 1-844-REPATHA (1-844-737-2842). • The autoinjector is not made with natural rubber latex. Reference ID: 5482664 - - Refrigerate in carton until ready to use Frequently asked questions: For additional information and answers to frequently asked questions, visit www.repatha.com. Where to get help: If you want more information or help using REPATHA: • Contact your healthcare provider, • Visit www.repatha.com, or • Call 1-844-REPATHA (1-844-737-2842) 2. Storing and Preparing to Inject REPATHA 2a Refrigerate the autoinjector carton until you are ready to use it. • Keep the autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C). • Keep the autoinjector in the original carton to protect it from light or physical damage. • Do not freeze the autoinjector. • Do not store the autoinjector in extreme heat or cold. For example, avoid storing in your vehicle’s glove box or trunk. Important: Keep the autoinjector and all medicines out of the sight and reach of children. WAIT minutes 2b Wait 30 minutes for the autoinjector to reach room temperature. • Remove the number of autoinjectors you need for your injection and put any unused autoinjectors back into the refrigerator. • Let the autoinjector warm up naturally. • Do not heat the autoinjector with hot water, a microwave, or direct sunlight. • Do not shake the autoinjector at any time. • Using the autoinjector at room temperature makes sure the full dose is delivered and allows for a more comfortable injection. Reference ID: 5482664 - - - 0-0 30 days 2c You may keep REPATHA at room temperature for up to 30 days, if needed. • For example, when you are traveling, you may keep REPATHA at room temperature. o Keep it at room temperature between 68°F to 77°F (20°C to 25°C) in the original carton. o Record the date you removed it from the refrigerator and use it within 30 days. Important: Place the autoinjector in a sharps disposal container if it has reached room temperature and has not been used within 30 days. Medicine Inspect the medicine. It should be clear and colorless to slightly yellow. 2d • It is okay to see air bubbles in the autoinjector. • Do not use REPATHA if the medicine is cloudy, discolored, or has flakes or particles. Important: If the medicine is cloudy, discolored, or has flakes or particles, or if the autoinjector is damaged or expired, call 1-844-REPATHA (1-844-737-2842). Expiration date 2e Check the expiration date (Exp.) and inspect the autoinjector for damage. • Do not use the autoinjector if the expiration date has passed. • Do not use the autoinjector if: o the orange cap is missing or loose. o it has cracks or broken parts. Reference ID: 5482664 [3--- - - o it has been dropped on a hard surface. • Make sure you have the right medicine and dose. 3. Getting Ready for Your Injection Sharps disposal container Alcohol wipe Adhesive bandage Cotton ball or gauze pad 3a Gather and place the following items for your injection on a clean, flat, and well-lit surface: • REPATHA autoinjector (room temperature) • Sharps disposal container [see Disposing of REPATHA and Checking the Injection Site] • Alcohol wipe • Adhesive bandage • Cotton ball or gauze pad 3b Inject into 1 of these sites. • Inject into the front of your thigh or stomach (except for 2 inches around your belly button). • Someone else can inject in your thigh, stomach, or back of your upper arm. • Choose a different site for each injection. Important: Avoid areas with scars or stretch marks, or where the skin is tender, bruised, red, hard, raised, thick or scaly skin patch or lesion. Reference ID: 5482664 - - 3c Wash hands thoroughly with soap and water. 3d Clean the injection site with an alcohol wipe. • Let the skin dry on its own. • Do not touch this area again before injecting. 4. Injecting REPATHA Important: Only remove the orange cap when you can inject right away (within 5 minutes) because the medicine can dry out. Do not recap. Window should be visible Grasp the autoinjector so you can see the window. Pull the orange cap straight off. You may need to pull 4a hard. • Do not twist, bend or wiggle the orange cap to pull it off. • Never put the orange cap back on. It may damage the needle. • Do not put your finger inside the yellow safety guard. • It is normal to see a drop of medicine at the end of the needle or yellow safety guard. Reference ID: 5482664 ----- ------------------------------------ > STRETCH PINCH Stretch or pinch the skin to create a firm surface at the injection site. Place the yellow safety guard straight 4b against the skin. • Keep the skin stretched or pinched until the injection is finished. • Make sure you can see the window. • Make sure the autoinjector is positioned straight on the injection site (at a 90-degree angle). PUSH and hold against skin Firmly push the autoinjector down until the yellow safety guard stops moving. Hold the autoinjector down, 4c do not lift. • The yellow safety guard pushes in and unlocks the gray start button. Reference ID: 5482664 1111 > - PRESS gray start button 4d Keep pushing the autoinjector down and press the gray start button to start the injection. • You may hear or feel a click. • The window starts to turn yellow. • It is okay to let go of the gray start button. WATCH and CONFIRM that the window turns fully yellow 4e Keep pushing the autoinjector down. When the window is fully yellow, the injection is complete. • The injection may take up to 15 seconds to complete. • You may hear or feel a click. • Lift the autoinjector away from your skin. • The yellow safety guard locks around the needle. Important: If the window has not turned fully yellow, or it looks like the medicine is still coming out, you have not received a full dose. Call your healthcare provider right away. Reference ID: 5482664 - 5. Disposing of REPATHA and Checking the Injection Site Place the used autoinjector and orange cap in an FDA-cleared sharps disposal container right away after 5a use. Important: Do not throw away the autoinjector in your household trash. • Do not reuse the autoinjector. • Do not touch the yellow safety guard. 5b Check the injection site. • Do not rub the injection site. • If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if necessary. Additional information about your sharps disposal container If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: • made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, • upright and stable during use, • leak-resistant, and • properly labeled to warn of hazardous waste inside the container. Disposing of sharps disposal containers: When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Reference ID: 5482664 AMGEN For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Important: Keep the autoinjector and sharps disposal container out of the sight and reach of children. For more information or help call 1-844-REPATHA (1-844-737-2842). REPATHA (evolocumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License Number 1080 © 2024 Amgen Inc. All rights reserved. <Part number> This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 v1 Reference ID: 5482664 Instructions for Use Repatha® (ri-PAth-a) (evolocumab) prefilled single-dose syringe (contains dry natural rubber) Getting to know the prefilled syringe Before use After use Plunger rod Used plunger Used syringe barrel Medicine Syringe barrel Used Needle Gray needle cap on (contains dry natural rubber) Gray needle cap off (contains dry natural rubber) Needle is inside Reference ID: 5482664 Important Before you use a prefilled single-dose syringe, read this important information: • It is important that you do not try to give the injection until you have fully read and understood this Instructions for Use. • Check the carton, prefilled syringe label, and prescription to make sure you have the correct medicine and dose. • Check the expiration date on the REPATHA prefilled syringe carton: do not use if this date has passed. • It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. • The gray needle cap on the prefilled syringe contains dry natural rubber, which is made from latex. Tell your healthcare provider if you are allergic to latex. Storage of REPATHA: • Keep the prefilled syringe in the original carton to protect from light during storage. • Keep the prefilled syringe in the refrigerator between 36°F to 46°F (2°C to 8°C). • If removed from the refrigerator, the prefilled syringe should be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton and must be used within 30 days. Place the prefilled syringe in a sharps disposal container if it has reached room temperature and has not been used within 30 days. • Do not freeze the prefilled syringe or use a prefilled syringe that has been frozen. • Do not store the prefilled syringe in extreme heat or cold. For example, avoid storing in your vehicle’s glove box or trunk. Do not: • Do not use the prefilled syringe if the packaging is open or damaged. • Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. • Do not use the prefilled syringe if it has been dropped onto a hard surface. Part of the prefilled syringe may be broken even if you cannot see the break. Use a new prefilled syringe and call 1-844-REPATHA (1-844-737-2842). • Do not use the prefilled syringe after the expiration date. A healthcare provider who knows how to use the prefilled syringe should be able to answer your questions. For more information, call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com. Keep the prefilled syringe and all medicines out of the sight and reach of children. Step 1: Prepare 1 A Remove the prefilled syringe carton from the refrigerator and wait 30 minutes. Wait at least 30 minutes for the prefilled syringe in the carton to reach room temperature before injecting. 30 minutes Using the prefilled syringe at room temperature makes sure the full dose is delivered and allows for a more comfortable injection. Do not heat the syringe. Let it warm up on its own naturally. Do not try to warm the prefilled syringe by using a heat source such as hot water or microwave. Do not leave the prefilled syringe in direct sunlight. Do not shake the prefilled syringe. Reference ID: 5482664 I 1 B Gather all materials needed for your injection. Wash your hands thoroughly with soap and water. On a clean, well-lit, flat work surface, place: ● 1 REPATHA prefilled syringe in carton ● Alcohol wipes ● Cotton ball or gauze pad ● Adhesive bandage ● Sharps disposal container (see Step 4: Finish) 1 C Choose your injection site. Upper arm Stomach Front of thigh You can use the: ● front of your thigh ● stomach (abdomen), except for a 2 inch area around your belly button If someone else is giving you the injection, they can also use the outer area of the upper arm. Do not choose an area where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Choose a different site each time you give yourself an injection. Reference ID: 5482664 1 D Clean your injection site. Clean your injection site with an alcohol wipe. Let your skin dry before injecting. Do not touch this area of skin again before injecting. 1 E Remove prefilled syringe from tray. Turn tray Gently Press over To remove: ● Peel paper off of tray. ● Place the tray on your hand. ● Turn the tray over and gently press the middle of the tray’s back to release the prefilled syringe into your palm. ● If the prefilled syringe does not release from the tray, gently press on the back of the tray. Do not pick up or pull the prefilled syringe by the plunger rod or gray needle cap. This could damage the syringe. Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. Always hold the prefilled syringe by the syringe barrel. Reference ID: 5482664 1 F Check the medicine and syringe. Syringe label with Plunger rod Syringe barrel expiration date Gray needle cap on Medicine Always hold the prefilled syringe by the syringe barrel. Check that: ● the name REPATHA appears on the prefilled syringe label. ● the medicine in the prefilled syringe is clear and colorless to slightly yellow. ● the expiration date on the prefilled syringe has not passed. If the expiration date has passed, do not use the prefilled syringe. Do not use the prefilled syringe if any part of the prefilled syringe appears cracked or broken. Do not use the prefilled syringe if the gray needle cap is missing or not securely attached. Do not use the prefilled syringe if the medicine is cloudy or discolored or contains particles. In any above cases, use a new prefilled syringe and call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com. Step 2: Get ready 2 A Carefully pull the gray needle cap straight out and away from your body. Do not leave the gray needle cap off for more than 5 minutes. This can dry out the medicine. It is normal to see a drop of Place the gray needle cap in the sharps medicine at the end of the needle. disposal container right away. Do not twist or bend the gray needle cap. This can damage the needle. Do not put the gray needle cap back onto the prefilled syringe. Do not try to remove any air bubbles in the syringe before the injection. Reference ID: 5482664 2 B Pinch your injection site to create a firm surface. Pinch the skin firmly between your thumb and fingers, creating an area about 2 inches wide. It is important to keep the skin pinched while injecting. Step 3: Inject 3 A Hold the pinch. Insert the needle into the skin using a 45 to 90 degree angle. Do not place your finger on the plunger rod while inserting the needle. 3 B Using slow and constant pressure, push the plunger rod all the way down until the prefilled syringe is empty. You may have to push harder on the plunger rod than for other injectable medicines. Reference ID: 5482664 3 C When the prefilled syringe is empty, release your thumb, and gently lift the syringe out of the skin. Do not put the gray needle cap back onto the used prefilled syringe. Step 4: Finish 4 A Place the used prefilled syringe in a sharps disposal container right away. Do not reuse the used prefilled syringe. Do not use any medicine that is left in the used prefilled syringe. • Put the used prefilled syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the syringe in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: • made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, • upright and stable during use, • leak-resistant, and • properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Keep the used syringe and sharps container out of the sight and reach of children. Reference ID: 5482664 I AMGEN 4 B Check the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if needed. Do not rub the injection site. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Amgen Inc. Thousand Oaks, CA 91320-1799 U.S. License Number 1080 © 2015-2016, 2021, 2024 Amgen Inc. All rights reserved. <part number> Revised: 11/2024 v4 Reference ID: 5482664 Instructions for Use Repatha® (ri-PAth-a) (evolocumab) prefilled single-dose syringe Getting to know the prefilled syringe Before use After use Plunger rod Used plunger Medicine Syringe barrel Used syringe barrel Used Needle Gray needle cap on Gray needle cap off Needle is inside Reference ID: 5482664 Important Before you use a prefilled single-dose syringe, read this important information: • It is important that you do not try to give the injection until you have fully read and understood this Instructions for Use. • Check the carton, prefilled syringe label, and prescription to make sure you have the correct medicine and dose. • Check the expiration date on the REPATHA prefilled syringe carton: do not use if this date has passed. • It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. • The prefilled syringe is not made with natural rubber latex. Storage of REPATHA: • Keep the prefilled syringe in the original carton to protect from light during storage. • Keep the prefilled syringe in the refrigerator between 36°F to 46°F (2°C to 8°C). • If removed from the refrigerator, the prefilled syringe should be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton and must be used within 30 days. Place the prefilled syringe in a sharps disposal container if it has reached room temperature and has not been used within 30 days. • Do not freeze the prefilled syringe or use a prefilled syringe that has been frozen. • Do not store the prefilled syringe in extreme heat or cold. For example, avoid storing in your vehicle’s glove box or trunk. Do not: • Do not use the prefilled syringe if the packaging is open or damaged. • Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. • Do not use the prefilled syringe if it has been dropped onto a hard surface. Part of the prefilled syringe may be broken even if you cannot see the break. Use a new prefilled syringe and call 1-844-REPATHA (1-844-737-2842). • Do not use the prefilled syringe after the expiration date. A healthcare provider who knows how to use the prefilled syringe should be able to answer your questions. For more information, call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com. Keep the prefilled syringe and all medicines out of the sight and reach of children. Step 1: Prepare 1 A Remove the prefilled syringe carton from the refrigerator and wait 30 minutes. Wait at least 30 minutes for the prefilled syringe in the carton to reach room temperature before injecting. 30 minutes Using the prefilled syringe at room temperature makes sure the full dose is delivered and allows for a more comfortable injection. Do not heat the syringe. Let it warm up on its own naturally. Do not try to warm the prefilled syringe by using a heat source such as hot water or microwave. Do not leave the prefilled syringe in direct sunlight. Do not shake the prefilled syringe. Reference ID: 5482664 1 B Gather all materials needed for your injection. Wash your hands thoroughly with soap and water. On a clean, well-lit, flat work surface, place: ● 1 REPATHA prefilled syringe in carton ● Alcohol wipes ● Cotton ball or gauze pad ● Adhesive bandage ● Sharps disposal container (see Step 4: Finish) 1 C Choose your injection site. Upper arm Stomach Front of thigh You can use the: ● front of your thigh ● stomach (abdomen), except for a 2 inch area around your belly button If someone else is giving you the injection, they can also use the outer area of the upper arm. Do not choose an area where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Choose a different site each time you give yourself an injection. Reference ID: 5482664 1 D Clean your injection site. Clean your injection site with an alcohol wipe. Let your skin dry before injecting. Do not touch this area of skin again before injecting. 1 E Remove prefilled syringe from tray. Turn tray Gently Press over To remove: ● Peel paper off of tray. ● Place the tray on your hand. ● Turn the tray over and gently press the middle of the tray’s back to release the prefilled syringe into your palm. ● If the prefilled syringe does not release from the tray, gently press on the back of the tray. Do not pick up or pull the prefilled syringe by the plunger rod or gray needle cap. This could damage the syringe. Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. Always hold the prefilled syringe by the syringe barrel. Reference ID: 5482664 1 F Check the medicine and syringe. Syringe label with Plunger rod Syringe barrel expiration date Gray needle cap on Medicine Always hold the prefilled syringe by the syringe barrel. Check that: ● the name REPATHA appears on the prefilled syringe label. ● the medicine in the prefilled syringe is clear and colorless to slightly yellow. ● the expiration date on the prefilled syringe has not passed. If the expiration date has passed, do not use the prefilled syringe. Do not use the prefilled syringe if any part of the prefilled syringe appears cracked or broken. Do not use the prefilled syringe if the gray needle cap is missing or not securely attached. Do not use the prefilled syringe if the medicine is cloudy or discolored or contains particles. In any above cases, use a new prefilled syringe and call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com. Step 2: Get ready 2 A Carefully pull the gray needle cap straight out and away from your body. Do not leave the gray needle cap off for more than 5 minutes. This can dry out the medicine. It is normal to see a drop of Place the gray needle cap in the sharps medicine at the end of the needle. disposal container right away. Do not twist or bend the gray needle cap. This can damage the needle. Do not put the gray needle cap back onto the prefilled syringe. Do not try to remove any air bubbles in the syringe before the injection. Reference ID: 5482664 2 B Pinch your injection site to create a firm surface. Pinch the skin firmly between your thumb and fingers, creating an area about 2 inches wide. It is important to keep the skin pinched while injecting. Step 3: Inject 3 A Hold the pinch. Insert the needle into the skin using a 45 to 90 degree angle. Do not place your finger on the plunger rod while inserting the needle. 3 B Using slow and constant pressure, push the plunger rod all the way down until the prefilled syringe is empty. You may have to push harder on the plunger rod than for other injectable medicines. Reference ID: 5482664 3 C When the prefilled syringe is empty, release your thumb, and gently lift the syringe out of the skin. Do not put the gray needle cap back onto the used prefilled syringe. Step 4: Finish 4 A Place the used prefilled syringe in a sharps disposal container right away. Do not reuse the used prefilled syringe. Do not use any medicine that is left in the used prefilled syringe. • Put the used prefilled syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the syringe in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: • made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, • upright and stable during use, • leak-resistant, and • properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Keep the used syringe and sharps container out of the sight and reach of children. Reference ID: 5482664 I AMGEN 4 B Check the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if needed. Do not rub the injection site. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Amgen Inc. Thousand Oaks, CA 91320-1799 U.S. License Number 1080 © 2024 Amgen Inc. All rights reserved. <part number> Issued: 11/2024 v1 Reference ID: 5482664	custom-source	2025-02-12T15:46:52.383950	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125522s044lbl.pdf', 'application_number': 125522, 'submission_type': 'SUPPL ', 'submission_number': 44}
80,274	Reference ID: 5483060 Reference ID: 5483060 Reference ID: 5483060 Reference ID: 5483060 Reference ID: 5483060 Reference ID: 5483060 Reference ID: 5483060 Reference ID: 5483060 212153 Reference ID: 5483060	custom-source	2025-02-12T15:46:53.988079	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022360Orig1s018lbl.pdf', 'application_number': 22360, 'submission_type': 'SUPPL ', 'submission_number': 18}
80,281	PERCODAN® (Oxycodone and Aspirin Tablets, USP) CII WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF PERCODAN Addiction, Abuse, and Misuse Because the use of PERCODAN exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see WARNINGS]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of PERCODAN, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of PERCODAN are essential [see WARNINGS]. Accidental Ingestion Accidental ingestion of even one dose of PERCODAN, especially by [or in] children, can result in a fatal overdose of oxycodone [see WARNINGS]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of PERCODAN and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see WARNINGS]. Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see WARNINGS] Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see WARNINGS]. Cytochrome P450 3A4 Interaction The concomitant use of PERCODAN with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving PERCODAN and any CYP3A4 inhibitor or inducer frequently [see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions]. 1 Reference ID: 5482781 • HCI DESCRIPTION PERCODAN (oxycodone HCl USP and aspirin USP) tablets are an immediate-release opioid agonist intended for oral administration only. Each PERCODAN Tablet contains: Oxycodone Hydrochloride, USP 4.8355 mg* Aspirin, USP 325 mg *4.8355 mg oxycodone HCl is equivalent to 4.3346 mg of oxycodone as the free base. PERCODAN Tablets also contain the following inactive ingredients: D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose and corn starch. The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17 methyl-, hydrochloride, (5α)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol and is represented by the following structural formula: C18H21NO4●HCl MW 351.82 The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle-like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula: C9H8O 4 MW 180.16 2 Reference ID: 5482781 CLINICAL PHARMACOLOGY Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action of oxycodone is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in both carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Use caution in hypovolemic patients, such as those suffering acute myocardial infarction, because oxycodone may cause or further aggravate their hypotension. Caution must also be used in patients with cor pulmonale who have received therapeutic doses of opioids. 3 Reference ID: 5482781 Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION]. Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION]. The dose of PERCODAN must be individualized because the effective analgesic dose for some patients will be too high to be tolerated by other patients [see DOSAGE AND ADMINISTRATION]. Platelet Aggregation Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Pharmacokinetics Absorption The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. This high oral bioavailability is due to low pre-systemic elimination and/or first-pass metabolism. Distribution The volume of distribution after intravenous administration is 211.9 ± 186.6 L. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. Oxycodone has been found in breast milk [see PRECAUTIONS]. 4 Reference ID: 5482781 Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin. Elimination Metabolism Oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated. Noroxycodone and noroxymorphone are the major circulating metabolites. CYP3A mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs (see Drug-Drug Interactions). Noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone, however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors. Although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent. Oxymorphone, is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone. Oxymorphone has been shown to be active and possessing analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant, based on the amount formed. Other metabolites (α- and ß-oxycodol, noroxycodol and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone. The enzymes responsible for keto-reduction and glucuronidation pathways in oxycodone metabolism have not been established. The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours. Excretion Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours. Drug-Drug Interactions [see PRECAUTIONS] Inhibitors of CYP3A4 Since the CYP3A4 isoenzyme plays a major role in the metabolism of PERCODAN, drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. A published study showed that the co-administration of the antifungal drug, voriconazole, increased oxycodone AUC and Cmax by 3.6- and 1.7-fold, respectively. The expected clinical results would be increased or prolonged opioid effects. 5 Reference ID: 5482781 Inducers of CYP450 CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations. A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone (oral) AUC and Cmax by 86% and 63% respectively. The expected clinical results would be lack of efficacy or, possibly, development of abstinence syndrome in a patient who had developed physical dependence to oxycodone. Induction of CYP3A4 may be of greatest importance given oxycodone’s metabolic pathways. INDICATIONS AND USAGE PERCODAN is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see WARNINGS], reserve PERCODAN for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia PERCODAN should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. CONTRAINDICATIONS PERCODAN is contraindicated in patients with: • Significant respiratory depression [see WARNINGS] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS] • Hypersensitivity to oxycodone or aspirin (e.g., angioedema) [see WARNINGS] • Patients with hemophilia • Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome [see WARNINGS] WARNINGS Addiction, Abuse, and Misuse PERCODAN contain Oxycodone, a Schedule II controlled substance. As an opioid, PERCODAN exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE]. 6 Reference ID: 5482781 Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed PERCODAN. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing PERCODAN, and reassess all patients receiving PERCODAN for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as PERCODAN but use in such patients necessitates intensive counseling about the risks and proper use of PERCODAN along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, DOSAGE AND ADMINISTRATION]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing PERCODAN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug [see PRECAUTIONS; Information for Patients/Caregivers]. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of PERCODAN, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of PERCODAN are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the PERCODAN dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of PERCODAN, especially by children can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS; Information for Patients/Caregivers]. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with PERCODAN. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by 7 Reference ID: 5482781 prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see PRECAUTIONS; Information for Patients/Caregivers]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see WARNINGS, PRECAUTIONS; Information for Patients/Caregivers, OVERDOSAGE]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of PERCODAN with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, DOSAGE AND ADMINISTRATION]. Advise both patients and caregivers about the risks of respiratory depression and sedation when PERCODAN is used with benzodiazepine or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS; Drug Interactions]. Neonatal Opioid Withdrawal Syndrome Use of PERCODAN for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients/Caregivers, Pregnancy]. 8 Reference ID: 5482781 Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of PERCODAN with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see WARNINGS], particularly when an inhibitor is added after a stable dose of PERCODAN is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in PERCODAN-treated patients may increase PERCODAN plasma concentrations and prolong opioid adverse reactions. When using PERCODAN with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in PERCODAN-treated patients, evaluate patients at frequent intervals and consider dosage reduction of PERCODAN until stable drug effects are achieved [see PRECAUTIONS; Drug Interactions]. Concomitant use of PERCODAN with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using PERCODAN with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see PRECAUTIONS; Drug Interactions]. Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see DRUG ABUSE AND DEPENDENCE]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful 9 Reference ID: 5482781 stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see WARNINGS, DOSAGE AND ADMINISTRATION]. Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of PERCODAN in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: PERCODAN-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of PERCODAN [see WARNINGS]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS]. Regularly evaluate patients, particularly when initiating and titrating PERCODAN and when PERCODAN is given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension PERCODAN may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of PERCODAN. In patients with circulatory shock, PERCODAN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of PERCODAN in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), PERCODAN may reduce respiratory drive, and the 10 Reference ID: 5482781 resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with PERCODAN. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of PERCODAN in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions PERCODAN is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The oxycodone in PERCODAN may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in PERCODAN may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during PERCODAN therapy. Withdrawal Do not abruptly discontinue PERCODAN in a patient physically dependent on opioids. When discontinuing PERCODAN, in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxycodone and aspirin in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION, DRUG ABUSE AND DEPENDENCE]. Additionally, avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including PERCODAN. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see PRECAUTIONS; Drug Interactions]. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including PERCODAN, in pregnant women at about 30 weeks gestation and later. NSAIDs including PERCODAN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including PERCODAN, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit PERCODAN use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic 11 Reference ID: 5482781 fluid if PERCODAN treatment extends beyond 48 hours. Discontinue PERCODAN if oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS; Pregnancy]. Risks of Driving and Operating Machinery PERCODAN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of PERCODAN and know how they will react to the medication [see PRECAUTIONS; Information for Patients/Caregivers]. Hypersensitivity to Oxycodone or Aspirin (e.g., angioedema) PERCODAN tablets are contraindicated in patients with known hypersensitivity to oxycodone or aspirin, and in any situation where opioids or aspirin are contraindicated. Reye Syndrome Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Serious Skin Reactions NSAIDs, including aspirin, a component of Percodan, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Percodan at the first appearance of skin rash or any other sign of hypersensitivity. Percodan is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS ]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients taking NSAIDs such as PERCODAN. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue PERCODAN and evaluate the patient immediately. Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. 12 Reference ID: 5482781 PRECAUTIONS General Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Hemorrhage Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities. Ambulatory Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Information for Patients/Caregivers Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store PERCODAN securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving PERCODAN unsecured can pose a deadly risk to others in the home [see WARNINGS, DRUG ABUSE AND DEPENDENCE]. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused PERCODAN should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of PERCODAN, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS]. Instruct patients not to share PERCODAN with others and to take steps to protect PERCODAN from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting PERCODAN or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see WARNINGS]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS]. 13 Reference ID: 5482781 Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if PERCODAN is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see WARNINGS, PRECAUTIONS; Drug Interactions]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with PERCODAN. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see WARNINGS, DOSAGE AND ADMINISTRATION]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see OVERDOSAGE]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS; ADVERSE REACTIONS]. Serotonin Syndrome Inform patients that PERCODAN could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. MAOI Interaction Inform patients to avoid taking PERCODAN while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking PERCODAN [see PRECAUTIONS; Drug Interactions]. Important Administration Instructions Instruct patients how to properly take PERCODAN. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams [see DOSAGE AND ADMINISTRATION, PRECAUTIONS]. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue PERCODAN without first discussing a tapering plan with the prescriber [see DOSAGE AND ADMINISTRATION]. 14 Reference ID: 5482781 Driving or Operating Heavy Machinery Inform patients that PERCODAN may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY]. Adrenal Insufficiency Inform patients that PERCODAN could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS]. Hypotension Inform patients that PERCODAN may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Anaphylaxis Inform patients that anaphylaxis have been reported with ingredients contained in PERCODAN. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of PERCODAN for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy] Embryo-Fetal Toxicity Inform female patients of reproductive potential that PERCODAN can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy. Inform pregnant women to avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with PERCODAN is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy]. Lactation Advise breastfeeding women using PERCODAN to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs. Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS]. 15 Reference ID: 5482781 Serious Skin Reactions, including DRESS Advise patients to stop taking PERCODAN immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS]. Laboratory Tests Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime-trimethylsilyl (MO-TMS) derivative. Table 1: Clinically Significant Drug Interactions with PERCODAN Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of PERCODAN and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of PERCODAN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of PERCODAN is achieved [see WARNINGS]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of PERCODAN until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the PERCODAN dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of PERCODAN and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see WARNINGS]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the PERCODAN dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal and sedation. If a CYP3A4 inducer is discontinued, consider PERCODAN dose reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin 16 Reference ID: 5482781 Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue PERCODAN if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS]. Intervention: The use of PERCODAN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of PERCODAN and/or precipitate withdrawal symptoms Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of PERCODAN and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs 17 Reference ID: 5482781 Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when PERCODAN is used concomitantly with anticholinergic drugs. Analgesics Clinical Impact: Analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms Intervention: Should be administered with caution to a patient who has received or is receiving a full opioid agonist such as oxycodone. Examples: Pentazocine, nalbuphine, naltrexone, and butorphanol Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance. Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance. Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone. Drug/Laboratory Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of PERCODAN tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical 18 Reference ID: 5482781 considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone and aspirin have not been conducted. Mutagenesis The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Impairment of Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been conducted. Aspirin has been shown to inhibit ovulation in rats. Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS]. Available data with PERCODAN are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus. Use of NSAIDs, including aspirin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of PERCODAN use between about 20 and 30 weeks of gestation, and avoid PERCODAN use at about 30 weeks of gestation and later in pregnancy [see WARNINGS; Fetal Toxicity]. Premature Closure of Fetal Ductus Arteriosus: Use of NSAIDs, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of 19 Reference ID: 5482781 prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, and manage accordingly [see WARNINGS]. Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including PERCODAN, can cause premature closure of the fetal ductus arteriosus [see WARNINGS; Fetal Toxicity]. Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If PERCODAN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue PERCODAN and follow up according to clinical practice [see WARNINGS; Fetal Toxicity]. Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and pyscho-physiologic effects in neonates. An opioid antagonist, such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. PERCODAN is not recommended for use in women during and immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics, including PERCODAN, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, 20 Reference ID: 5482781 neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data: Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m2 basis). Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose (see Data). In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression (see Clinical Considerations). There are no data on the effects of the oxycodone on milk production. Salicylic acid has been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspiring in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome cause by salicylate in breast milk is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PERCODAN and any potential adverse effects on the breastfed child from PERCODAN or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to PERCODAN through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breastfeeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that 21 Reference ID: 5482781 following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20- 200 ng/mL). Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use PERCODAN tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co- administered with other agents that depress respiration. Titrate the dosage of PERCODAN slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. Hepatic Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. Avoid aspirin in patients with severe hepatic impairment. Renal Impairment In a study of patients with end stage renal impairment, mean elimination half-life of oxycodone was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. Avoid aspirin in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute). 22 Reference ID: 5482781 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see WARNINGS] • Life-Threatening Respiratory Depression [see WARNINGS] • Neonatal Opioid Withdrawal Syndrome [see WARNINGS] • Opioid-Induced Hyperalgesia and Allodynia [see WARNINGS] • Interactions with Benzodiazepines and Other CNS Depressants [see WARNINGS] • Adrenal Insufficiency [see WARNINGS] • Severe Hypotension [see WARNINGS] • Gastrointestinal Adverse Reactions [see WARNINGS] • Seizures [see WARNINGS] • Withdrawal [see WARNINGS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Serious adverse reactions that may be associated with PERCODAN tablet use include, apnea, circulatory depression, hypotension, respiratory arrest, respiratory depression, and shock [see OVERDOSAGE]. The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation and pruritus. Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function. Furthermore, aspirin has the potential to cause anaphylaxis in hypersensitive patients as well as angioedema especially in patients with chronic urticaria. Other adverse reactions due to aspirin use include anorexia, reversible hepatotoxicity, leukopenia, thrombocytopenia, purpura, decreased plasma iron concentration, and shortened erythrocyte survival time. Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The adverse reactions obtained from postmarketing experiences with PERCODAN tablets are listed by organ system and in decreasing order of severity and/or frequency as follows: Body as a Whole allergic reaction, malaise, asthenia, headache, anaphylaxis, fever, hypothermia, thirst, increased sweating, accident, accidental overdose, non-accidental overdose 23 Reference ID: 5482781 Cardiovascular tachycardia, dysrhythmias, hypotension, orthostatic hypotension, bradycardia, palpitations Central and Peripheral Nervous System stupor, paresthesia, agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures, anxiety, mental impairment Fluid and Electrolyte dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis Gastrointestinal hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye syndrome, pancreatitis, intestinal obstruction, ileus Hearing and Vestibular hearing loss, tinnitus. Patients with high frequency loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Hematologic unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia Hypersensitivity acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction Metabolic and Nutritional hypoglycemia, hyperglycemia, acidosis, alkalosis Musculoskeletal rhabdomyolysis Ocular miosis, visual disturbances, red eye Psychiatric drug dependence, drug abuse, somnolence, depression, nervousness, hallucination Reproductive prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding, closure of patent ductus arteriosis Respiratory System bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema 24 Reference ID: 5482781 Skin and Appendages Urticaria, rash, flushing, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention Serotonin syndrome Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis Anaphylaxis has been reported with ingredients contained in PERCODAN. Androgen deficiency Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY]. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see WARNINGS] Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY]. Early signs of acute aspirin (salicylate) overdose including tinnitus occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. 25 Reference ID: 5482781 Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in PERCODAN, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions PERCODAN should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see WARNINGS]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of PERCODAN for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see WARNINGS]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with PERCODAN. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS]. 26 Reference ID: 5482781 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with PERCODAN [see WARNINGS, PRECAUTIONS; Information for Patients/Caregivers]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see WARNINGS; Addiction, Abuse, and Misuse; Life-Threatening Respiratory Depression; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants]. Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. Initial Dosage Initiating Treatment with PERCODAN Initiate treatment with one tablet every 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of PERCODAN. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets. Titration and Maintenance of Therapy Individually titrate PERCODAN to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving PERCODAN to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see WARNINGS]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the PERCODAN dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see WARNINGS]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Safe Reduction or Discontinuation of PERCODAN Tablets Do not abruptly discontinue PERCODAN in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug- seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking PERCODAN, there are a variety of factors that should be considered, including the total daily dose of opioid (including PERCODAN) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so 27 Reference ID: 5482781 that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on PERCODAN who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see WARNINGS; Withdrawal, DRUG ABUSE AND DEPENDENCE]. DRUG ABUSE AND DEPENDENCE Controlled Substance PERCODAN contain oxycodone, a Schedule II controlled substance. Abuse PERCODAN contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see WARNINGS]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of PERCODAN increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of PERCODAN with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some 28 Reference ID: 5482781 individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of PERCODAN abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use PERCODAN in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. PERCODAN, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of PERCODAN PERCODAN is for oral use only. Abuse of PERCODAN poses a risk of overdose and death. The risk is increased with concurrent use of PERCODAN with alcohol and/or other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue PERCODAN in a patient physically dependent on opioids. Rapid tapering of PERCODAN in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing PERCODAN, gradually taper the dosage using a patient specific plan that considers the following: the dose of PERCODAN the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and 29 Reference ID: 5482781 minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see DOSAGE AND ADMINISTRATION and WARNINGS] Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs. HOW SUPPLIED PERCODAN (Oxycodone and Aspirin Tablets, USP), tablets are supplied as a yellow round tablet, scored and debossed with “PERCODAN” on one side and plain on the other side. Available in: Bottles of 100 NDC 63481-121-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). DEA Order Form Required. Store PERCODAN securely and dispose of properly [see PRECAUTIONS; Information for Patients/Caregivers]. Manufactured for: Endo USA Malvern, PA 19355 © 2024 Endo, Inc. or one of its affiliates. Revised: November 2024 30 Reference ID: 5482781 MEDICATION GUIDE PERCODAN® (ˈpər-kə-ˌdan) (oxycodone hydrochloride and aspirin) tablets, for oral use, CII PERCODAN is: • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about PERCODAN: • Get emergency help or call 911 right away if you take too much PERCODAN (overdose). When you first start taking PERCODAN, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. • Taking PERCODAN with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Never give anyone else your PERCODAN. They could die from taking it. Selling or giving away PERCODAN is against the law. • Store PERCODAN securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take PERCODAN if you have: • severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. Before taking PERCODAN, tell your healthcare provider if you have a history of: • head injury, seizures ● liver, kidney, thyroid problems • problems urinating ● pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you: • notice your pain getting worse. If your pain gets worse after you take PERCODAN, do not take more of PERCODAN without first talking to your healthcare provider. Talk to your healthcare provider if the pain you have increases, if you feel more sensitive to pain, or if you have new pain after taking PERCODAN. • Are pregnant or planning to become pregnant. Use of PERCODAN for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. Taking NSAID-containing products like PERCODAN at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding. PERCODAN passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. • develop any type of rash or fever. Contact your healthcare provider as soon as possible and stop taking PERCODAN. • are living in a household where there are small children or someone who has abused street or prescription drugs. 31 Reference ID: 5482781 • are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking PERCODAN with certain other medicines can cause serious side effects that could lead to death. When taking PERCODAN: • Do not change your dose. Take PERCODAN exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose at the same time every day. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. • For acute (short-term) pain, you may only need to take PERCODAN for a few days. You may have some PERCODAN left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused PERCODAN. • Take your prescribed dose [one tablet every six hours] as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. • Call your healthcare provider if the dose you are taking does not control your pain. • If you have been taking PERCODAN regularly, do not stop taking PERCODAN without talking to your healthcare provider. • Dispose of expired, unwanted, or unused PERCODAN by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking PERCODAN DO NOT: • Drive or operate heavy machinery, until you know how PERCODAN affects you. PERCODAN can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with PERCODAN may cause you to overdose and die. The possible side effects of PERCODAN: • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, rash, or fever. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of PERCODAN. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Distributed by: Endo Pharmaceuticals Inc., Malvern, PA 19355, www.endo.com or call 1-800-462-3636 PERCODAN® is a registered trademark of Endo International plc or one of its affiliates. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: April 2024 32 Reference ID: 5482781	custom-source	2025-02-12T15:46:56.093374	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/007337s057lbl.pdf', 'application_number': 7337, 'submission_type': 'SUPPL ', 'submission_number': 57}
80,288	Mefenamic Acid Capsules, USP 250 mg Rx only WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS). • Mefenamic acid is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS, WARNINGS). Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see WARNINGS). DESCRIPTION Mefenamic Acid Capsules are a member of the fenamate group of nonsteroidal anti- inflammatory drugs (NSAIDs). Each blue-banded, ivory capsule contains 250 mg of mefenamic acid for oral administration. Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230°-231°C and water solubility of 0.004% at pH 7.1. The chemical name is N-2,3 xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C15H15N02 and the structural formula of mefenamic acid is: Each capsule also contains lactose, NF. The capsule shell and/or band contains citric acid, USP; D&C yellow No. 10; FD&C blue No. 1; FD&C red No. 3; FD&C yellow No. 6; gelatin, NF; glycerol monooleate; silicon dioxide, NF; sodium benzoate, NF; sodium lauryl sulfate, NF; titanium dioxide, USP. CLINICAL PHARMACOLOGY Mechanism of Action Mefenamic acid has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of mefenamic acid, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Mefenamic acid is a potent inhibitor of prostaglandin synthesis in vitro. Mefenamic acid Reference ID: 5482790 concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because mefenamic acid is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Pharmacokinetics Absorption Mefenamic acid is rapidly absorbed after oral administration. In two 500-mg single oral dose studies, the mean extent of absorption was 30.5 mcg/hr/mL (17%CV). The bioavailability of the capsule relative to an IV dose or an oral solution has not been studied. Following a single 1-gram oral dose, mean peak plasma levels ranging from 10-20 mcg/mL have been reported. Peak plasma levels are attained in 2 to 4 hours and the elimination half-life approximates 2 hours. Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. In a multiple dose trial of normal adult subjects (n= 6) receiving 1 gram doses of mefenamic acid four times daily, steady-state concentrations of 20 mcg/mL were reached on the second day of administration, consistent with the short half-life. The effect of food on the rate and extent of absorption of mefenamic acid has not been studied. Concomitant ingestion of antacids containing magnesium hydroxide has been shown to significantly increase the rate and extent of mefenamic acid absorption (see PRECAUTIONS; Drug Interactions). Distribution Mefenamic acid has been reported as being greater than 90% bound to albumin. The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vzss/F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg. Based on its physical and chemical properties, mefenamic acid is expected to be excreted in human breast milk (see PRECAUTIONS; Nursing Mothers). Elimination Metabolism Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite I). Further oxidation to a 3-carboxymefenamic acid (Metabolite II) may occur. The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. A peak plasma level approximating 20 mcg/mL was observed at 3 hours for the hydroxy metabolite and its glucuronide (n= 6) after a single 1-gram dose. Similarly, a peak plasma level of 8 mcg/mL was observed at 6-8 hours for the carboxy metabolite and its glucuronide. Reference ID: 5482790 Excretion Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3- carboxymefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid. The elimination half-life of mefenamic acid is approximately two hours. Half-lives of metabolites I and II have not been precisely reported, but appear to be longer than the parent compound. The metabolites may accumulate in patients with renal or hepatic failure. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. Because both renal and hepatic excretions are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). TABLE 1. Pharmacokinetic Parameter Estimates for Mefenamic Acid PK Parameters Normal Healthy Adults (18-45 yr) Tmax (hr) Oral clearance (L/hr) Apparent volume of distribution; Vz/F (L/kg) Half-life; t ½ (hrs) Value 2 21.13 1.06 2 to 4 CV 66 38 60 N/A Special Populations Pediatric: Mefenamic acid has not been adequately investigated in pediatric patients less than 14 years of age. A study in 17 preterm infants administered 2 mg/kg indicated that the half-life was about five times as long as adults, consistent with the low activity of metabolic enzymes in newborn infants. The mean Cmax in this study was 4 mcg/mL (range 2.9-6.1). The mean time to maximum concentration (Tmax) was 8 hours (range 2-18 hours). Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction. As hepatic metabolism is a significant pathway of mefenamic acid elimination, patients with acute and chronic hepatic disease may require reduced doses of mefenamic acid compared to patients with normal hepatic function (see WARNINGS; Hepatotoxicity). Renal Impairment: Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency. Given that mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys, the potential exists for mefenamic acid metabolites to accumulate. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS; Drug Interactions). Reference ID: 5482790 Clinical Studies In controlled, double-blind, clinical trials, mefenamic acid was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either mefenamic acid, 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Mefenamic acid was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Mefenamic acid is indicated: • For relief of mild to moderate pain in patients ≥ 14 years of age, when therapy will not exceed one week (7 days). • For treatment of primary dysmenorrhea. CONTRAINDICATIONS Mefenamic acid is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to mefenamic acid or any components of the drug product (see WARNINGS;Anaphylactic Reactions, Serious Skin Reactions). • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic Reaction, Exacerbation of Asthma Related to Aspirin Sensitivity). • In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events). WARNINGS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest Reference ID: 5482790 effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as mefenamic acid, increases the risk of serious gastrointestinal (GI) events (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of mefenamic acid in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including mefenamic acid, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. Reference ID: 5482790 • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue mefenamic acid until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions). Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including mefenamic acid. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately, and perform a clinical evaluation of the patient. Hypertension NSAIDs, including mefenamic acid, can lead to new onset of hypertension or worsening of pre existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions). Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of mefenamic acid may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (see PRECAUTIONS; Drug Interactions). Avoid the use of mefenamic acid in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If mefenamic acid is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Reference ID: 5482790 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of mefenamic acid in patients with advanced renal disease. The renal effects of mefenamic acid may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid (see PRECAUTIONS; Drug Interactions). Avoid the use of mefenamic acid in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions Mefenamic acid has been associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity). Seek emergency help if anaphylactic reaction occurs. Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, mefenamic acid is contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS). When mefenamic acid is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions NSAIDs, including mefenamic acid, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of mefenamic acid at the first appearance of skin rash or any other sign of hypersensitivity. Mefenamic acid is contraindicated in patients with previous serious Reference ID: 5482790 skin reactions to NSAIDs (see CONTRAINDICATIONS). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as mefenamic acid. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue mefenamic acid and evaluate the patient immediately. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including mefenamic acid, in pregnant women at about 30 weeks gestation and later. NSAIDs including mefenamic acid, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including mefenamic acid, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit mefenamic acid use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if mefenamic acid treatment extends beyond 48 hours. Discontinue mefenamic acid if oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS; Pregnancy]. Hematological Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with mefenamic acid has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including mefenamic acid, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS; Drug Interactions). PRECAUTIONS General Mefenamic acid cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. Reference ID: 5482790 Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families and their caregivers of the following information before initiating therapy with mefenamic acid and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS; Cardiovascular Thrombotic Events). Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop mefenamic acid and seek immediate medical therapy (see WARNINGS; Hepatotoxicity). Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS; Heart Failure and Edema). Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see CONTRAINDICATIONS, WARNINGS; Anaphylactic Reactions). Serious Skin Reactions, including DRESS Advise patients to stop mefenamic acid immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see WARNINGS). Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including mefenamic acid, may be associated with a reversible delay in ovulation. (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility). Fetal Toxicity Inform pregnant women to avoid use of mefenamic acid and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with mefenamic acid is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, PRECAUTIONS; Drug Interactions). Alert patients that NSAIDs may be present in Reference ID: 5482790 “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with mefenamic acid until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions). Masking of Inflammation and Fever The pharmacological activity of mefenamic acid in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile checked periodically (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity). Drug Interactions See Table 2 for clinically significant drug interactions with mefenamic acid. Reference ID: 5482790 Table 2: Clinically Significant Drug Interactions with Mefenamic Acid Drugs That Interfere with Hemostasis Clinical Impact: • Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity). Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation). Intervention: Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (includingpropranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Reference ID: 5482790 Intervention: During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia). Digoxin Clinical Impact: The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation). Intervention: The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Reference ID: 5482790 Intervention: During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacid Clinical Impact: In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. Intervention: Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. Drug/Laboratory Test Interactions Mefenamic acid may prolong prothrombin time. Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary. A false-positive reaction for urinary bile, using the diazo tablet test, may result after mefenamic acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of mefenamic acid have not been conducted. Mutagenesis Studies to evaluate the mutagenic potential of mefenamic acid have not been completed. Impairment of Fertility Dietary administration of mefenamic acid to male rats 61 days- and to female rats 15 days- prior to mating through to Gestation Day (GD) 21 at a dose of 155 mg/kg/day (equivalent to the Maximum Recommended Human Dose [MRHD] of 1500 mg/day on a mg/m2 basis) resulted in decreased corpora lutea. In another study, rats administered up to 10-times a human dose of 250 mg showed decreased fertility. Pregnancy Risk Summary Use of NSAIDs, including mefenamic acid, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of mefenamic acid use between about 20 and 30 weeks of gestation, and avoid mefenamic acid use at about 30 weeks of gestation and later in pregnancy [see WARNINGS; Fetal Toxicity]. Reference ID: 5482790 --- Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including mefenamic acid, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as mefenamic acid, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Pregnant rats administered 249 mg/kg of mefenamic acid (1.6-times the MRHD of 1500 mg/day on a mg/m2 basis) from GD 6 to GD 15 did not result in any clear adverse developmental effects. Pregnant rabbits given 50 mg/kg of mefenamic acid (0.6-times the MRHD on a mg/m2 basis) from GD 6 to GD 18 did not result in any clear treatment-related adverse developmental effects. However, incidences of resorption were greater in treated compared to control animals. This dose was associated with some evidence of maternal toxicity with 4 of 18 rabbits exhibiting diarrhea and weight loss. Dietary administration of mefenamic acid at a dose of 181 mg/kg (1.2-times the MRHD on a mg/m2 basis) to pregnant rats from GD 15 to weaning resulted in an increased incidence of perinatal death. Treated dams were associated with decreased weight gain and delayed parturition. In another study, dietary administration of mefenamic acid at a dose of 155 mg/kg (equivalent to the MRHD of 1500 mg/day on a mg/m2 basis) to females 15 days prior to mating through to weaning resulted in smaller average litter sizes and higher incidence of perinatal death. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including mefenamic acid, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the Reference ID: 5482790 lowest effective dose and shortest duration possible. If mefenamic acid treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue mefenamic acid and follow up according to clinical practice (see WARNINGS; Fetal Toxicity). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, decreased pup survival occurred and increased the incidence of stillbirth. The effects of mefenamic acid on labor and delivery in pregnant women are unknown. Nursing Mothers Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from mefenamic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including mefenamic acid may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin in mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including mefenamic acid, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 5482790 Pediatric Use Safety and effectiveness in pediatric patients below the age of 14 have not been established. Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS; Laboratory Monitoring). Clinical studies of mefenamic acid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any NSAID, caution should be exercised in treating the elderly (65 years and older). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (See CLINICAL PHARMACOLOGY, ADVERSE REACTIONS). ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events (see WARNINGS) • GI Bleeding, Ulceration and Perforation (see WARNINGS) • Hepatotoxicity (see WARNINGS) • Hypertension (see WARNINGS) • Heart Failure and Edema (see WARNINGS)) • Renal Toxicity and Hyperkalemia (see WARNINGS) • Anaphylactic Reactions (see WARNINGS) • Serious Skin Reactions (see WARNINGS) • Hematologic Toxicity (see WARNINGS) Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In patients taking mefenamic acid or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% of patients are: Gastrointestinal experiences including - abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting, abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, tinnitus Additional adverse experiences reported occasionally and listed here by body system include: Body as a whole - fever, infection, sepsis Reference ID: 5482790 Cardiovascular system - congestive heart failure, hypertension, tachycardia, syncope Digestive system - dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and lymphatic system - ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and nutritional - weight changes Nervous system - anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness; insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory system - asthma, dyspnea Skin and appendages - alopecia, photosensitivity, pruritus, sweat Special senses - blurred vision Urogenital system - cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a whole - anaphylactoid reactions, appetite changes, death Cardiovascular system - arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive system - eructation, liver failure, pancreatitis Hemic and lymphatic system - agranulocytosis, hemolytic anemia, aplastic anemia, lymph adenopathy, pancytopenia Metabolic and nutritional - hyperglycemia Nervous system - convulsions, coma, hallucinations, meningitis Respiratory - respiratory depression, pneumonia Skin and appendages - angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, fixed drug eruption (FDE), urticaria Special senses - conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia). Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, contact a poison control center (1-800-222 1222). DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of mefenamic acid and other treatment options Reference ID: 5482790 before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). After observing the response to initial therapy with mefenamic acid, the dose and frequency should be adjusted to suit an individual patient's needs. For the relief of acute pain in adults and adolescents ≥14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week. For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, given orally, starting with the onset of bleeding and associated symptoms. Clinical studies indicate that effective treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days. HOW SUPPLIED Mefenamic acid is available as 250 mg blue-banded, ivory capsules, imprinted with “ FHPC 400" and "PONSTEL®". Bottles of 30 count NDC 42192-620-30 Bottles of 100 count NDC 42192-620-01 Dispense in a tight container as defined in the USP. Storage Store at room temperature 20° to 25°C (68°to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Distributed by: Avion Pharmaceuticals Alpharetta, GA 30005 Rev. 11/2024 For inquiries call 1-888-612-8466 Reference ID: 5482790 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDS) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAID can cause serious side effects, including: • Increase risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)". Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increase risk of bleeding, ulcers and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAID should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o or the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. Reference ID: 5482790 • right before or after heart bypass surgery. Before taking NSAIDs, tell our healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy • are breastfeeding or plan to breastfeed Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482790 What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problem including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects if NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble • slurred speech breathing • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in the bowel movement or it is black and sticky like tar • diarrhea • unusual weight gain • itching • skin rash or blisters with fever • your skin or eyes look yellow • swelling of the arms, legs, hands, and feet • indigestion or stomach pain • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at Reference ID: 5482790 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAID for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Avion Pharmaceuticals Alpharetta, GA 30005 For more information, call 1-888-612-8466 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 Reference ID: 5482790	custom-source	2025-02-12T15:46:56.543549	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/015034s046lbl.pdf', 'application_number': 15034, 'submission_type': 'SUPPL ', 'submission_number': 46}
80,286	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SYNALGOS®-DC safely and effectively. See full prescribing information for SYNALGOS®-DC. SYNALGOS®-DC (aspirin, caffeine, and dihydrocodeine bitartrate) capsules, for oral use, CIII Initial U.S. Approval: 1958 -------------------------RECENT MAJOR CHANGES-------------------- Boxed Warning 12/2023 Indications and Usage (1) 12/2023 Dosage and Administration (2.1, 2.3, 2.4) 12/2023 Warnings and Precautions (5.8) 12/2023 Warnings and Precautions (5.21) 07/2024 ------------------------INDICATIONS AND USAGE------------------------ SYNALGOS-DC is a combination of dihydrocodeine, an opioid agonist, aspirin, a nonsteroidal anti-inflammatory drug, and caffeine, a methylxanthine, and is indicated for the management of pain severe WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SYNALGOS-DC See full prescribing information for complete boxed warning. • SYNALGOS-DC exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of SYNALGOS-DC are essential. (5.2) • Accidental ingestion of SYNALGOS-DC, especially by children, can result in a fatal overdose of dihydrocodeine. (5.2) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.3, 7) • If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4) • Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra- rapid metabolizer of codeine due to a CYP2D6 polymorphism. (5.6) SYNALGOS-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine. • The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with dihydrocodeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SYNALGOS DC requires careful consideration of the effects on the parent drug, dihydrocodeine, and the active metabolite, dihydromorphine. (5.7), (7) enough to require an opioid analgesic and for which alternative treatments are inadequate. (1) Limitations of Use (1) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration (5.1), reserve SYNALGOS-DC for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia. SYNALGOS-DC should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. -----------------------DOSAGE AND ADMINISTRATION---------------- • SYNALGOS-DC should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1) • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of SYNALGOS-DC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5) • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1) • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with SYNALGOSDC. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2) • Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with SYNALGOS-DC. Consider prescribing naloxone based on the patient’s risk factors for overdose (2.2, 5.1, 5.3, 5.7). • Initiate treatment with two capsules every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of SYNALGOS-DC. (2.1, 5) • Administer SYNALGOS-DC with food or a full glass of water to minimize gastrointestinal (GI) distress. (2.1) • Do not abruptly discontinue SYNALGOS-DC in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5, 5.16) -------------------------DOSAGE FORMS AND STRENGTHS----------- Capsules: 356.4 mg aspirin, 30 mg caffeine, and 16 mg dihydrocodeine bitartrate (3) Reference ID: 5482786 ---------------------------------CONTRAINDICATIONS---------------------- ------------------------------DRUG INTERACTIONS------------------------ • Children younger than 12 years of age (4) • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. • Post-operative management in children younger than 18 years of age Discontinue SYNALGOS-DC if serotonin syndrome is suspected. (7) following tonsillectomy and/or adenoidectomy (4) • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid • Significant respiratory depression (4) use with SYNALGOS-DC because they may reduce analgesic effect of • Acute or severe bronchial asthma in an unmonitored setting or in absence SYNALGOS-DC or precipitate withdrawal symptoms. (7) of resuscitative equipment (4) • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of ------------------------USE IN SPECIFIC POPULATIONS----------------- MAOIs within the last 14 days (4) • Known or suspected gastrointestinal obstruction, including paralytic ileus • Lactation: Breastfeeding not recommended. (8.2) (4) • • • • Hypersensitivity to dihydrocodeine, codeine, or aspirin (4) Hemophilia (4) Reye’s Syndrome (4) Known allergy to NSAIDs (4) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 • Syndrome of asthma, rhinitis, and nasal polyps (4) ------------------WARNINGS AND PRECAUTIONS---------------------- • Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.8) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.9) • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.11) • Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of SYNALGOS-DC in patients with circulatory shock. (5.12) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of SYNALGOS-DC in patients with impaired consciousness or coma. (5.13) • Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease: Aspirin can cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.14) • Fetal Toxicity: Limit use of NSAIDs, including SYNALGOS-DC, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.17, 8.1). • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.22) -----------------------------ADVERSE REACTIONS------------------------- Most common adverse reactions were lightheadedness, dizziness, drowsiness, sedation, nausea, vomiting, constipation, pruritus, and skin reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800 FDA-1088 or www.fda.gov/medwatch. Reference ID: 5482786 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SYNALGOS-DC 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose 2.3 Initial Dosage 2.4 Titration and Maintenance of Therapy 2.5 Safe Reduction or Discontinuation of SYNALGOS-DC 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse 5.2 Life-Threatening Respiratory Depression 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants 5.4 Neonatal Opioid Withdrawal Syndrome 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) 5.6 Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children 5.7 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 5.8 Opioid-Induced Hyperalgesia and Allodynia 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients 5.10 Interaction with Monoamine Oxidase Inhibitors 5.11 Adrenal Insufficiency 5.12 Severe Hypotension 5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness 5.14 Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease 5.15 Increased Risk of Seizures in Patients with Seizure Disorders 5.16 Withdrawal 5.17 Fetal Toxicity 5.18 Risks of Driving and Operating Machinery 5.19 Coagulation Abnormalities and Bleeding Risks 5.20 Reye’s Syndrome 5.21 Serious Skin Reactions 5.22 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.23 Allergy 5.24 Renal Toxicity and Hyperkalemia 5.25 Premature Closure of Fetal Ductus Arteriosus 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482786 I ______ _ FULL PRESCRIBING INFORMATION WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SYNALGOS-DC Addiction, Abuse, and Misuse Because the use of SYNALGOS-DC exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of SYNALGOS-DC, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of SYNALGOS-DC are essential [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of SYNALGOS-DC, especially by children, can result in a fatal overdose of dihydrocodeine [see Warnings and Precautions (5.2)]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of SYNALGOS-DC and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3), Drug Interactions (7)] Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS): Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)]. Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening: Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions (5.4)]. SYNALGOS-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy Reference ID: 5482786 and/or adenoidectomy [see Contraindications (4)]. Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with dihydrocodeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SYNALGOS-DC requires careful consideration of the effects on dihydrocodeine, and the active metabolite, dihydromorphine [see Warnings and Precautions (5.7), Drug Interactions (7)]. Reference ID: 5482786 1. INDICATIONS AND USAGE SYNALGOS-DC is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1)], reserve SYNALGOS-DC for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia SYNALGOS-DC should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions SYNALGOS-DC should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of SYNALGOS-DC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with SYNALGOS-DC. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2)]. Reference ID: 5482786 Administer SYNALGOS-DC with food or a full glass of water to minimize GI distress. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SYNALGOS-DC [see Warnings and Precautions (5.2)] Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.3)]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Initiating Treatment with SYNALGOS-DC Initiate treatment in adults with two capsules of SYNALGOS-DC orally every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of SYNALGOS-DC. Conversion from Other Opioids to SYNALGOS-DC There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of SYNALGOS-DC. It is safer to underestimate a patient’s 24-hour SYNALGOS-DC dosage than to overestimate the 24-hour SYNALGOS-DC dosage and manage an adverse reaction due to overdose. 2.4 Titration and Maintenance of Therapy Individually titrate SYNALGOS-DC to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving SYNALGOS-DC to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as Reference ID: 5482786 reassessing for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.16)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the SYNALGOS-DC dosage. If after increasing the dosage, unacceptable opioid- related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of SYNALGOS-DC Do not abruptly discontinue SYNALGOS-DC in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking SYNALGOS-DC, there are a variety of factors that should be considered, including the total daily dose of opioid (including SYNALGOS-DC) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on SYNALGOS DC who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful Reference ID: 5482786 taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.3)]. 3 DOSAGE FORMS AND STRENGTHS Capsules: 356.4 mg aspirin, 30 mg caffeine, and 16 mg dihydrocodeine bitartrate (blue and gray, marked “CP” and “419”) 4 CONTRAINDICATIONS SYNALGOS-DC is contraindicated for: • All children younger than 12 years of age [see Warnings and Precautions (5.6)] • Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6)] SYNALGOS-DC is also contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10), Drug Interactions (7)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)] • Hypersensitivity to dihydrocodeine, codeine, or aspirin, or NSAIDs [see Adverse Reactions (6)] • Hemophilia [see Warnings and Precautions (5.19)] • Reye’s Syndrome [see Warnings and Precautions (5.20)] • Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions Reference ID: 5482786 (5.23)] • Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions (5.23)] 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse SYNALGOS-DC contains dihydrocodeine bitartrate, a Schedule III controlled substance. As an opioid, SYNALGOS-DC exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SYNALGOS-DC. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing SYNALGOS-DC, and reassess all patients receiving SYNALGOS-DC for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as SYNALGOS-DC, but use in such patients necessitates intensive counseling about the risks and proper use of SYNALGOS-DC along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing SYNALGOS-DC. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Reference ID: 5482786 SYNALGOS-DC, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of SYNALGOS-DC are essential [see Dosage and Administration (2)]. Overestimating the SYNALGOS-DC dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of SYNALGOS-DC, especially by children, can result in respiratory depression and death due to an overdose of dihydrocodeine. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SYNALGOS-DC. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.1, 5.3), Overdosage (10)]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SYNALGOS-DC with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, Reference ID: 5482786 antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug- related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Advise both patients and caregivers about the risks of respiratory depression and sedation when SYNALGOS-DC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)]. 5.4 Neonatal Opioid Withdrawal Syndrome Use of SYNALGOS-DC for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)]. 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) Reference ID: 5482786 for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 5.6 Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Because of comparable metabolic pathways for codeine and dihydrocodeine and similar potencies for codeine and dihydrocodeine and morphine and dihydromorphine, the risks associated with ultra-rapid metabolism of codeine are present for dihydrocodeine. Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon postmarketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with opioids for post- tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death: • SYNALGOS-DC is contraindicated for all children younger than 12 years of age [see Contraindications (4)]. • SYNALGOS-DC is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. • Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine unless the Reference ID: 5482786 benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. • As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [see Use in Specific Populations (8.4), Overdosage (10)]. Nursing Mothers At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with SYNALGOS-DC [see Use in Specific Populations (8.2)]. CYP2D6 Genetic Variability: Ultra-rapid metabolizer Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as 1/1xN or 1/2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). Data are not available for other ethnic groups. These individuals convert dihydrocodeine into its active metabolite, dihydromorphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum dihydromorphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10)]. Therefore, individuals who are ultra-rapid metabolizers should not use SYNALGOS-DC. 5.7 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with dihydrocodeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SYNALGOS-DC requires careful consideration of the effects on dihydrocodeine and the active metabolite, dihydromorphine. • Cytochrome P450 3A4 Interaction The concomitant use of SYNALGOS-DC with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in dihydrocodeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater dihydromorphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Reference ID: 5482786 The concomitant use of SYNALGOS-DC with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower dihydrocodeine levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihydromorphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Evaluate patients receiving SYNALGOS-DC and any CYP3A4 inhibitor or inducer at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when SYNALGOS-DC is used in conjunction with inhibitors and inducers of CYP3A4. If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of SYNALGOS-DC until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the SYNALGOS-DC dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for signs of opioid withdrawal [see Drug Interactions (7)]. • Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of SYNALGOS-DC with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in dihydrocodeine plasma concentrations and a decrease in active metabolite dihydromorphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in dihydrocodeine plasma concentration and an increase in active metabolite dihydromorphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Evaluate patients receiving SYNALGOS-DC and any CYP2D6 inhibitor at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when SYNALGOS-DC is used in conjunction with inhibitors of CYP2D6. If concomitant use with a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for signs of reduced efficacy or opioid withdrawal and consider increasing the SYNALGOS-DC dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the SYNALGOS-DC dosage and evaluate the patients at frequent intervals for signs and symptoms of respiratory depression or sedation [see Drug Interactions (7)]. Reference ID: 5482786 5.8 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2), Warnings and Precautions (5)]. 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of SYNALGOS-DC in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: SYNALGOS-DC-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of SYNALGOS-DC [see Warnings and Precautions (5.2)]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)]. Monitor patients, particularly when initiating and titrating SYNALGOS-DC and when SYNALGOS-DC is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3)]. Alternatively, consider the use of non- opioid analgesics in these patients. 5.10 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of dihydromorphine, dihydrocodeine’s active metabolite, including respiratory depression, coma, and confusion. Reference ID: 5482786 SYNALGOS-DC should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 5.11 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.12 Severe Hypotension SYNALGOS-DC may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of SYNALGOS-DC. In patients with circulatory shock, SYNALGOS-DC may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of SYNALGOS-DC in patients with circulatory shock. 5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), SYNALGOS-DC may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with SYNALGOS-DC. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SYNALGOS-DC in patients with impaired consciousness or coma. 5.14 Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease SYNALGOS-DC is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The dihydrocodeine in SYNALGOS-DC may cause spasm of the sphincter of Oddi. Opioids may Reference ID: 5482786 cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. Gastrointestinal Bleeding, Ulceration, and Perforation: The aspirin in SYNALGOS-DC can cause GI side effects including stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such high-risk patients, as well as those with active GI bleeding, consider alternate therapies other than SYNALGOS-DC. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SYNALGOS-DC until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.15 Increased Risk of Seizures in Patients with Seizure Disorders The dihydrocodeine in SYNALGOS-DC may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure Reference ID: 5482786 control during SYNALGOS-DC therapy. 5.16 Withdrawal Do not abruptly discontinue SYNALGOS-DC in a patient physically dependent on opioids. When discontinuing SYNALGOS-DC in a physically dependent patient, gradually taper the dosage. Rapid tapering of SYNALGOS-DC in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including SYNALGOS-DC. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. 5.17 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including SYNALGOS-DC, in pregnant women at about 30 weeks gestation and later. NSAIDs, including SYNALGOS-DC, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including SYNALGOS-DC, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit SYNALGOS-DC use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if SYNALGOS-DC treatment extends beyond 48 hours. Discontinue SYNALGOS-DC if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.18 Risks of Driving and Operating Machinery SYNALGOS-DC may impair the mental or physical abilities needed to perform potentially Reference ID: 5482786 5.19 5.20 5.21 5.22 hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of SYNALGOS-DC and know how they will react to the medication. Coagulation Abnormalities and Bleeding Risks Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (i.e. hemophilia) or acquired (i.e. liver disease or vitamin K deficiency) bleeding disorders. Aspirin is contraindicated in patients with hemophilia. Aspirin administered pre-operatively may prolong the bleeding time. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Reye’s Syndrome Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. Serious Skin Reactions NSAIDs, including aspirin, a component of SYNALGOS-DC, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of SYNALGOS-DC at the first appearance of skin rash or any other sign of hypersensitivity. SYNALGOS-DC is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as SYNALGOS-DC. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue SYNALGOS-DC and evaluate the patient immediately. Reference ID: 5482786 5.23 Allergy Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). 5.24 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of SYNALGOS-DC in patients with advanced renal disease. The renal effects of SYNALGOS-DC may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating SYNALGOS-DC. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of SYNALGOS-DC [see Drug Interactions (7)]. Avoid the use of SYNALGOS-DC in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If SYNALGOS-DC is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic- hypoaldosteronism state. 6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] Reference ID: 5482786 • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)] • Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)] • Adrenal Insufficiency [see Warnings and Precautions (5.11)] • Severe Hypotension [see Warnings and Precautions (5.12)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)] • Seizures [see Warnings and Precautions (5.15)] • Withdrawal [see Warnings and Precautions (5.16)] • Coagulation Abnormalities and Bleeding [see Warnings and Precautions (5.19)] • Reye’s Syndrome [see Warnings and Precautions (5.20)] • Serious Skin Reactions [see Warnings and Precautions (5.21)] • Allergy [see Warnings and Precautions (5.23)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.24)] The following adverse reactions associated with the use of SYNALGOS-DC were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature [see Warnings and Precautions (5)]. Body as a Whole: Fever, hypothermia, thirst. Cardiovascular: Dysrhythmias, hypotension, tachycardia. Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures. Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis. Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye's syndrome, pancreatitis. Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia. Reference ID: 5482786 Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria. Musculoskeletal: Rhabdomyolysis. Metabolism: Hypoglycemia (in children), hyperglycemia. Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding. Respiratory: Hyperpnea, pulmonary edema, tachypnea. Special Senses: Hearing loss, tinnitus. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SYNALGOS-DC. Androgen Deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8)] Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Reference ID: 5482786 7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with SYNALGOS-DC. Table 1: Clinically Significant Drug Interactions with SYNALGOS-DC Inhibitors of CYP3A4 Clinical The concomitant use of SYNALGOS-DC with CYP3A4 inhibitors may result in an Impact: increase in dihydrocodeine plasma concentration with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater dihydromorphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of SYNALGOS DC is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower dihydrocodeine plasma levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihydromorphine levels [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to dihydrocodeine. Intervention: If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of SYNALGOS-DC until stable drug effects are achieved. Evaluate at frequent time intervals patients for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the SYNALGOS-DC dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical The concomitant use of SYNALGOS-DC and CYP3A4 inducers can result in lower Impact: dihydrocodeine levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihydromorphine levels [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to dihydrocodeine [see Warnings and Precautions (5.16)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the dihydrocodeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater dihydromorphine levels [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. Reference ID: 5482786 Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate patients at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the SYNALGOS-DC dosage as needed. If a CYP3A4 inducer is discontinued, consider SYNALGOS-DC dosage reduction, and evaluate for signs of respiratory depression and sedation at frequent intervals. Examples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical The dihydrocodeine in SYNALGOS-DC is metabolized by CYP2D6 to form Impact: dihydromorphine. The concomitant use of SYNALGOS-DC and CYP2D6 inhibitors can increase the plasma concentration of dihydrocodeine, and decrease the plasma concentration of the active metabolite dihydromorphine. This could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of SYNALGOS-DC is achieved [see Clinical Pharmacology (12.3)]. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the dihydrocodeine plasma concentration will decrease but the active metabolite dihydromorphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)]. Intervention: If concomitant use with a CYP2D6 inhibitor is necessary or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of SYNALGOS-DC and evaluate patients at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, evaluate patients at frequent intervals for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the SYNALGOS-DC as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the SYNALGOS-DC and follow the patient for signs and symptoms of respiratory depression or sedation. Examples: Quinidine, fluoxetine, paroxetine, bupropion Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is Reference ID: 5482786 warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2, 2.5), Warnings and Precautions (5.1, 5.2, 5.3)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue SYNALGOS-DC if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)] Intervention: Do not use SYNALGOS-DC in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydromorphone, or buprenorphine) to treat pain while closely following blood pressure and signs and symptoms of CNS and respiratory depression. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of SYNALGOS-DC and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Dihydrocodeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Reference ID: 5482786 Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of SYNALGOS-DC and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3)]. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when SYNALGOS-DC is used concomitantly with anticholinergic drugs. Anticoagulants Clinical Impact: Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sides, leading to prolongation of both the prothrombin time and the bleeding time. Intervention: Inform patients of this interaction and frequently evaluate for signs of bleeding. Examples: Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban Uricosuric Agents Clinical Impact: Aspirin inhibits the uricosuric effects of uricosuric agents. Intervention: Avoid concomitant use. Examples: Probenecid Carbonic Anhydrase Inhibitors Clinical Impact: Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion. Intervention: Consider reducing the dose of the carbonic anhydrase inhibitor and assess the patient for any adverse effects from the carbonic anhydrase inhibitor. Examples: Acetazolamide, methazolamide Methotrexate Clinical Impact: Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Reference ID: 5482786 Intervention: Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Reevaluate patients for methotrexate toxicity. Nephrotoxic Agents Clinical Impact: Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion. Intervention: Use SYNALGOS-DC with caution if used concomitantly with nephrotoxic agents. Frequently reevaluate the renal function of patients. Examples: Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin Angiotensin Converting Enzyme (ACE) Inhibitors Clinical Impact: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Intervention: Use caution if using concomitantly. Reevaluate the blood pressure and renal function of patients. Examples: Ramipril, captopril Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Intervention: Use caution if using concomitantly. Follow the blood pressure and renal function of patients. Examples: Metoprolol, propranolol Hypoglycemic Agents Clinical Impact: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Intervention: Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur. Examples: Insulin, glimepiride, glipizide Anticonvulsants Clinical Impact: Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Intervention: Use caution if using concomitantly. Examples: Phenytoin, valproic acid Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Clinical Impact: Concurrent use with aspirin may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketoralac by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Reference ID: 5482786 Intervention: Avoid concomitant use. Examples: Ketorolac, ibuprofen, naproxen, diclofenac Corticosteroids Clinical Impact: In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance. Intervention: Avoid concomitant use. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Use of NSAIDs, including aspirin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SYNALGOSDC use between about 20 and 30 weeks of gestation, and avoid SYNALGOS DC use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Reference ID: 5482786 Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)]. Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SYNALGOS-DC, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If SYNALGOS-DC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SYNALGOS-DC and follow up according to clinical practice (see Data). Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. SYNALGOS-DC is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including SYNALGOS-DC, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Reference ID: 5482786 Data Human Data Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Animal reproduction studies have not been conducted with the combination of aspirin, caffeine, and dihydrocodeine capsules or with dihydrocodeine alone. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (0.7 times the human daily dose of 360 mg caffeine on a mg/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. 8.2 Lactation Risk Summary SYNALGOS-DC is not recommended for use in nursing women. Dihydrocodeine and its active metabolite, dihydromorphine, are present in human milk. There are Reference ID: 5482786 published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants; this would be expected to occur with dihydrocodeine as well. In women with normal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent. There is no information on the effects of the dihydrocodeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SYNALGOS-DC [see Warnings and Precautions (5.6)]. Aspirin and caffeine are also excreted in breast milk in small amounts. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Use of high doses of aspirin may lead to rashes, platelet abnormalities, and bleeding in nursing infants. Nursing women are advised against aspirin use because of the possible development of Reye’s Syndrome in their babies. The risk of Reye’s Syndrome caused by salicylate in breast milk is unknown [see Warnings and Precautions (5.20)]. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression, rashes, platelet abnormalities, bleeding, and the possibility of Reye Syndrome in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SYNALGOS-DC. Clinical Considerations If infants are exposed to SYNALGOS-DC through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. Aspirin and caffeine are also excreted in breast milk in small amounts. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2)], Nonclinical Toxicology (13.1)]. Reference ID: 5482786 Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including aspirin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including aspirin, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Preparations containing aspirin should be kept out of the reach of children. Reye’s Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. The safety and effectiveness of SYNALGOS-DC in pediatric patients below 12 years of age have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions (5.6)]. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of opioids. Because of the risk of life-threatening respiratory depression and death: • SYNALGOS-DC is contraindicated for all children younger than 12 years of age [see Contraindications (4)]. • SYNALGOS-DC is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. • Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions (5.6)]. 8.5 Geriatric Use Clinical studies of SYNALGOS-DC did not include sufficient numbers of subjects 65 years of age and older to determine whether elderly subjects respond differently from younger subjects. Elderly patients (aged 65 years or older) may have increased sensitivity to dihydrocodeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of Reference ID: 5482786 concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co- administered with other agents that depress respiration. Titrate the dosage of SYNALGOS-DC slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)]. Component of this drug product are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and regularly evaluate patients for adverse effects [see Warnings and Precautions (5.9)]. 8.6 Hepatic Impairment SYNALGOS-DC contains aspirin, which should be avoided in patients with severe hepatic impairment. No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of dihydrocodeine in this patient population is unknown. Start these patients cautiously with lower doses of SYNALGOS-DC or with longer dosing intervals and titrate slowly while carefully following for side effects. In patients with severe hepatic disease, follow effects of therapy with serial liver function tests. 8.7 Renal Impairment SYNALGOS-DC contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Dihydrocodeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of SYNALGOS-DC or with longer dosing intervals and titrate slowly while carefully following for side effects. In patients with renal disease, follow effects of therapy with serial renal function tests. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance SYNALGOS-DC contains dihydrocodeine, a Schedule III controlled substance. Reference ID: 5482786 9.2 Abuse SYNALGOS-DC contains dihydrocodeine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of SYNALGOS-DC increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of SYNALGOS-DC with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of SYNALGOS-DC abuse include those with a history of prolonged use of any opioid, including products containing dihydrocodeine, those with a history of drug or alcohol abuse, or those who use SYNALGOS-DC in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. SYNALGOS-DC, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Reference ID: 5482786 Risks Specific to Abuse of SYNALGOS-DC Abuse of SYNALGOS-DC poses a risk of overdose and death. The risk is increased with concurrent use of SYNALGOS-DC with alcohol and/or other CNS depressants. SYNALGOS-DC is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue SYNALGOS-DC in a patient physically dependent on opioids. Rapid tapering of SYNALGOS-DC in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing SYNALGOS-DC, gradually taper the dosage using a patient-specific plan that considers the following: the dose of SYNALGOS-DC the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), and Warnings and Precautions (5.17)]. Reference ID: 5482786 10 OVERDOSAGE Clinical Presentation Serious overdose with SYNALGOS-DC is characterized by signs and symptoms of opioid and salicylate overdose. Acute overdose with dihydrocodeine can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Early signs of acute aspirin (salicylate) overdose including tinnitus occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. In acute salicylate overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration, and coma. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Serious symptoms such as depression, coma, and respiratory failure progress rapidly. Salicylism (chronic salicylate toxicity) may be noted by symptoms such as dizziness, tinnitus, difficulty hearing, nausea, vomiting, diarrhea, and mental confusion. More severe salicylism may result in respiratory alkalosis. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Treatment of acid- base disturbances and electrolyte disorders is also important. Because of the concern over salicylate toxicity, acid-base status should be followed closely with serial blood gas and serum pH determinations. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to dihydrocodeine overdose, administer an opioid antagonist. Reference ID: 5482786 Because the duration of opioid reversal is expected to be less than the duration of action of dihydrocodeine in SYNALGOS-DC, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. In severe cases of salicylate overdose, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. With more severe acute toxicity respiratory alkalosis may occur. Hemodialysis and peritoneal dialysis can be performed to reduce the body content of aspirin. In patients with renal insufficiency or in cases of life-threatening salicylate intoxication dialysis is usually required. Exchange transfusion may be indicated in infants and young children. In case of real or suspected overdose, a poison control center should be consulted for the treatment of salicylism. 11 DESCRIPTION SYNALGOS-DC (aspirin, caffeine, and dihydrocodeine bitartrate) capsules are a three-drug combination of dihydrocodeine, an opioid agonist, aspirin, a nonsteroidal anti-inflammatory drug, and caffeine, a methylxanthine. SYNALGOS-DC capsules are available as, 356.4 mg aspirin, 30 mg caffeine, and 16 mg dihydrocodeine bitartrate for oral administration. The chemical name for dihydrocodeine bitartrate is morphinan-6-ol, 4,5-epoxy-3-methoxy-17-methyl , (5α,6α)-2,3- dihydroxybutanedioate (1:1) (salt). It is also known as 4,5α-epoxy-3-methoxy-17 methylmorphinan-6α-ol (+)-tartrate (salt). The molecular weight for dihydrocodeine bitartrate is 451.48. Its molecular formula is C18H23NO3•C4H6O6, and it has the following chemical structure. Reference ID: 5482786 H OHO OH HO }I 0 Dihydrocodeine is a fine, white, odorless, crystalline powder that is synthesized from codeine. Dihydrocodeine bitartrate dissolves in water (1 g in 4.5 g) and turns into a clear, colorless solution. It has a dissociation constant of pKa 8.89 at 25°C and pKa 8.67 at 37°C. Dihydrocodeine bitartrate has partition coefficient of logP 1.16 and a pH of 3.2 to 4.2. The chemical name for aspirin is 2-(acetyloxy)benzoic acid. The molecular weight for aspirin is 180.16. Its molecular formula is C9H8O4, and it has the following chemical structure. Aspirin is a white, crystalline powder, or white crystals (usually needle-like). It is odorless or has a faint odor, and is stable in dry air. In moist air, it gradually hydrolyzes to salicylic and acetic acids. Aspirin is slightly soluble in water, freely soluble in alcohol, soluble in chloroform and ether, and sparingly soluble in absolute ether. Aspirin has a dissociation constant of 1.8×10-4 at 25°C. The chemical name for caffeine is 1,3,7-trimethylxanthine. The molecular weight for caffeine is 194.19. Its molecular formula is C8H10N4O2, and it has the following chemical structure. Reference ID: 5482786 Caffeine is a white, crystalline substance or granules. It is freely soluble in boiling water, sparingly soluble in water at 20°C, and slightly soluble in ethanol. It has a pH of 6.9 (1% solution) and a pKa of 14.0 at 25°C. Caffeine has a partition coefficient of Kp 0.96 (n-octanol/aqueous solution pH 7.41) and Kp 0.72 (n-octanol/0.1 M HCl). The inactive ingredients in SYNALGOS-DC include: alginic acid, cellulose, D&C Red 28, FD&C Blue 1, gelatin, iron oxides, stearic acid, and titanium dioxide. SYNALGOS-DC is available as blue and gray capsules that are marked “CP” and “419”. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SYNALGOS-DC contains dihydrocodeine, a full opioid agonist, aspirin, a nonsteroidal anti- inflammatory drug, and caffeine, a methylxanthine. Dihydrocodeine is an opioid agonist relatively selective for the µ-opioid receptor, but with a much weaker affinity than dihydromorphine. The analgesic properties of dihydrocodeine have been speculated to come from its conversion to dihydromorphine, although the exact mechanism of analgesic action remains unknown. Aspirin is a nonsteroidal anti-inflammatory drug and a non-selective irreversible inhibitor of cyclooxygenases. Caffeine is a methylxanthine and CNS stimulant. The exact mechanism with respect to the indication is not clear; however, the effects of caffeine may be due to antagonism of adenosine receptors. 12.2 Pharmacodynamics Effects on the Central Nervous System Dihydrocodeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Dihydrocodeine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Aspirin works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating Reference ID: 5482786 center to reduce fever, however, other mechanisms may be involved. Effects on the Gastrointestinal Tract and Other Smooth Muscle Dihydrocodeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Effects on the Cardiovascular System Dihydrocodeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclooxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor, thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date Reference ID: 5482786 [see Adverse Reactions (6)]. Effect on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationship The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists [see Dosage and Administration (2.1)]. The minimum effective analgesic concentration of dihydrocodeine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1)]. Concentration-Adverse Reaction Relationships There is a relationship between increasing dihydrocodeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1), (2.3), (2.4)]. 12.3 Pharmacokinetics Aspirin Absorption In general, immediate-release aspirin is well and completely absorbed from the gastrointestinal (GI) tract. Following absorption, aspirin is hydrolyzed to salicylic acid with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. The rate of absorption from the GI tract is dependent upon the dosage form, the presence or absence of food, gastric pH (the presence or absence of GI antacids or buffering agents), and other physiologic factors. Distribution Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, renal cortex, heart, and lungs. The protein binding of salicylate is concentration-dependent, i.e., nonlinear. At low concentrations (< 100 micrograms/milliliter (µg/mL)), approximately 90 percent of plasma salicylate is bound to albumin while at higher concentrations (> 400 µg/mL), only about 75 percent is bound. Reference ID: 5482786 Elimination Metabolism Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin are essentially undetectable 1 to 2 hours after dosing. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 grams (g)), the plasma half-life may be increased to over 20 hours. Excretion The elimination of salicylic acid follows zero order pharmacokinetics; (i.e., the rate of drug elimination is constant in relation to plasma concentration). Renal excretion of unchanged drug depends upon urine pH. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from < 5 percent to > 80 percent. Following therapeutic doses, approximately 10 percent is found excreted in the urine as salicylic acid, 75 percent as salicyluric acid, and 10 percent phenolic and 5 percent acyl glucuronides of salicylic acid. Dihydrocodeine Metabolism CYP3A4 and CYP2D6 are involved in the metabolism of dihydrocodeine. Dihydrocodeine is mainly metabolized by CYP2D6 to its active metabolite dihydromorphine. Caffeine Absorption Like most xanthines, caffeine is rapidly absorbed. Distribution Caffeine is distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. Elimination Caffeine is cleared rapidly through metabolism and excretion in the urine. Metabolism Reference ID: 5482786 Caffeine is mainly metabolized by CYP1A2. Other enzymes, including CYP2E1, CYP3A4, CYP2C8 and CYP2C9 may play a minor role in its metabolism. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1- methyluric acid. Excretion Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug. The plasma half-life is about 3 hours. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of the combination of aspirin, caffeine, and dihydrocodeine bitartrate or dihydrocodeine alone have not been conducted. Administration of aspirin for 68 weeks at 0.5 percent in the feed of rats was not carcinogenic. In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2.8 and 4.6 times, respectively, the daily dose of 360 mg caffeine on a mg/m2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (0.7 times the daily dose of 360 mg caffeine on a mg/m2 basis). Mutagenesis The combination of aspirin, caffeine, and dihydrocodeine or dihydrocodeine alone has not been evaluated for mutagenicity. Aspirin is not mutagenic in the Ames Salmonella assay; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine was negative in the in vitro bacterial reverse mutation assay (Ames test). Reference ID: 5482786 Impairment of Fertility Animal studies to evaluate the effects of the combination of aspirin, caffeine, and dihydrocodeine or dihydrocodeine alone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (0.7 times the daily dose of 360 mg caffeine on a mg/m2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration. 16 HOW SUPPLIED/STORAGE AND HANDLING SYNALGOS-DC (aspirin, caffeine, and dihydrocodeine bitartrate) are blue and gray capsules marked with “CP” and “419”, and are supplied as: NDC 49708-419-88 (356.4 mg aspirin/30 mg caffeine/16 mg dihydrocodeine bitartrate): 100 capsules per bottle Store at room temperature, approx. 25°C (77°F). Keep tightly closed. Dispense in tight container. Store SYNALGOS-DC securely and dispose of properly. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store SYNALGOS-DC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving SYNALGOS-DC unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or DEA-registered collectors are available, instruct patients to dispose of SYNALGOS-DC by following these four steps: • Mix SYNALGOS-DC (do not crush) with an unpalatable substance such as dirt, cat litter, or used Reference ID: 5482786 coffee grounds; • Place the mixture in a container such as a sealed plastic bag; • Throw the container in the household trash; • Remove all personal information on the prescription label of the empty bottle. Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of SYNALGOS-DC, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share SYNALGOS-DC with others and to take steps to protect SYNALGOS-DC from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting SYNALGOS-DC or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if SYNALGOS-DC is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3), Drug Interactions (7)]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SYNALGOS-DC. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Reference ID: 5482786 Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Advise caregivers that SYNALGOS-DC is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving SYNALGOS-DC to monitor for signs of respiratory depression [see Warnings and Precautions (5.6)]. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.8), Adverse Reactions (6.2)]. Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)]. MAOI Interaction Inform patients not to take SYNALGOS-DC while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking SYNALGOS-DC [see Drug Interactions (7)]. Important Administration Instructions Reference ID: 5482786 Instruct patients how to properly take SYNALGOS-DC. Administer SYNALGOS-DC with food or a full glass of water to minimize GI distress [see Dosage and Administration (2.1)]. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue SYNALGOS DC without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)] Driving or Operating Heavy Machinery Inform patients that SYNALGOS-DC may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.11)]. Hypotension Inform patients that SYNALGOS-DC may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12)]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in SYNALGOS-DC. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)]. Serious Skin Reactions, including DRESS Advise patients to stop taking SYNALGOS-DC immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.21, 5.22)]. Aspirin Allergy Reference ID: 5482786 Patients should be informed that SYNALGOS-DC contains aspirin and should not be taken by patients with an aspirin or NSAID allergy. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of SYNALGOS-DC for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life- threatening if not recognized and treated [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that SYNALGOS-DC can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Inform pregnant women to avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with SYNALGOS-DC is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.17) and Use in Specific Populations (8.1)]. Lactation Advise women that breastfeeding is not recommended during treatment with SYNALGOS-DC [see Use in Specific Populations (8.2)]. Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6)]. Advise females of reproductive potential who desire pregnancy that NSAIDs, including SYNALGOS- DC, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Risk of Bleeding Inform patients about the signs and symptoms of bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding. Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin [see Warnings and Precautions (5.18)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of SYNALGOS-DC with NSAIDs or other salicylates (e.g., Reference ID: 5482786 diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.14) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Manufactured by: Mikart, Inc. Atlanta, Georgia 30318 Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Rev. 11/2024 Reference ID: 5482786 Medication Guide SYNALGOS®-DC (sin-AAL-gus-dee-see) (aspirin, caffeine, and dihydrocodeine bitartrate) capsules, CIII SYNALGOS-DC is: • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about SYNALGOS-DC: • Get emergency help or call 911 right away if you take too much SYNALGOS-DC (overdose). When you first start taking SYNALGOS-DC, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. • Taking SYNALGOS-DC with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Increases risk of bleeding and ulcers. • Never give anyone else your SYNALGOS-DC. They could die from taking it. Selling or giving away SYNALGOS- DC is against the law. • Store SYNALGOS-DC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Important Information Guiding Use in Pediatric Patients: • Do not give SYNALGOS-DC to a child younger than 12 years of age. • Do not give SYNALGOS-DC to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. • Avoid giving SYNALGOS-DC to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems. Do not give SYNALGOS-DC to a child or teenager with a viral illness. Reye’s Syndrome, a life- threatening condition, can happen when aspirin (an ingredient in SYNALGOS-DC) is used in children and teenagers who have certain viral illnesses. Do not take SYNALGOS-DC if you have: • severe asthma, asthma in combination with runny nose and nasal polyps, trouble breathing, or other lung problems • a bowel blockage or have narrowing of the stomach or intestines • allergic to any of the ingredients in SYNALGOS-DC • known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) Reference ID: 5482786 • a rare disorder in which your blood doesn’t clot normally (hemophilia) Before taking SYNALGOS-DC, tell your healthcare provider if you have a history of: • head injury, seizures • liver, kidney, thyroid problems • problems urinating • pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems • have been told by your healthcare provider that you are a “rapid metabolizer” of certain medicines • stomach ulcers, or stomach or intestinal bleeding with use of acetylsalicylic acid (ASA) or NSAIDs Tell your healthcare provider if you are: • noticing your pain getting worse. If your pain gets worse after you take SYNALGOS-DC, do not take more of SYNALGOS-DC without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking SYNALGOS-DC. • pregnant or planning to become pregnant. Use of SYNALGOS-DC for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life- threatening if not recognized and treated. Taking NSAID-containing products like SYNALGOS DC at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • breastfeeding. Not recommended during treatment with SYNALGOS-DS; may harm your baby. • develop any type of rash or fever. Contact your healthcare provider as soon as possible and stop taking SYNALGOS-DC. • living in a household where there are small children or someone who has abused street or prescription drugs. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking SYNALGOS-DC with certain other medicines can cause serious side effects that could lead to death. Taking with corticosteroids or anticoagulants increases risk of ulcers and stomach/intestinal bleeding. When taking SYNALGOS-DC: • Do not change your dose. Take SYNALGOS-DC exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. • For acute (short-term) pain, you may only need to take SYNALGOS-DC for a few days. You may have some SYNALGOS-DC left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused SYNALGOS-DC. Reference ID: 5482786 • Take your prescribed dose every 4 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. • Call your healthcare provider if the dose you are taking does not control your pain. • If you have been taking SYNALGOS-DC regularly, do not stop taking SYNALGOS-DC without talking to your healthcare provider. • After you stop taking SYNALGOS-DC, dispose the unused SYNALGOS-DC in accordance with the local state guidelines and/or regulations. Dispose of expired, unwanted, or unused SYNALGOS-DC by taking your drug to an authorized DEA-registered collector or drug take-back program. If one is not available, you can dispose of SYNALGOS-DC by mixing the product with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag, and throwing the bag in your trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking SYNALGOS-DC DO NOT: • Drive or operate heavy machinery, until you know how SYNALGOS-DC affects you. SYNALGOS-DC can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with SYNALGOS-DC may cause you to overdose and die. The possible side effects of SYNALGOS-DC: • bleeding, constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, rash, or fever. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. • if you are a nursing mother taking SYNALGOS-DC and your breastfeeding baby has increased sleepiness, confusion, difficulty breathing, shallow breathing, limpness, or difficulty breastfeeding. These are not all the possible side effects of SYNALGOS-DC. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Manufactured by: Mikart, Inc., Atlanta, Georgia 30318 and Distributed by: Sun Pharmaceutical Industries, Inc., Cranbury, NJ 08512, www.SYNALGOSDC.com or call 1-800-406-7984 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 12/2023 Reference ID: 5482786	custom-source	2025-02-12T15:46:57.238872	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/011483s037lbl.pdf', 'application_number': 11483, 'submission_type': 'SUPPL ', 'submission_number': 37}
80,263	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KEYTRUDA safely and effectively. See full prescribing information for KEYTRUDA. KEYTRUDA® (pembrolizumab) injection, for intravenous use Initial U.S. Approval: 2014 --------------------------- RECENT MAJOR CHANGES --------------------------- Indications and Usage (1) 09/2024 Dosage and Administration (2) 09/2024 Warnings and Precautions (5) 03/2024 ----------------------------INDICATIONS AND USAGE ---------------------------- KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated: Melanoma • for the treatment of patients with unresectable or metastatic melanoma. (1.1) • for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. (1.1) Non-Small Cell Lung Cancer (NSCLC) • in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. (1.2) • in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. (1.2) • as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: o Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or o metastatic. (1.2, 2.1) • as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. (1.2, 2.1) • for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.2) • as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. (1.2) Malignant Pleural Mesothelioma (MPM) • in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with unresectable advanced or metastatic MPM. (1.3) Head and Neck Squamous Cell Cancer (HNSCC) • in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. (1.4) • as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. (1.4, 2.1) • as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. (1.4) Classical Hodgkin Lymphoma (cHL) • for the treatment of adult patients with relapsed or refractory cHL. (1.5) • for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (1.5) Primary Mediastinal Large B-Cell Lymphoma (PMBCL) • for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. (1.6) • Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer • in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. (1.7) • as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: o are not eligible for any platinum-containing chemotherapy, or o who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum- containing chemotherapy. (1.7) • as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. (1.7) Microsatellite Instability-High or Mismatch Repair Deficient Cancer • for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. (1.8, 2.1) Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC) • for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. (1.9, 2.1) Gastric Cancer • in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.1 (1.10) • in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. (1.10) Esophageal Cancer • for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: o in combination with platinum- and fluoropyrimidine-based chemotherapy, or o as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. (1.11, 2.1) Cervical Cancer • in combination with chemoradiotherapy, for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. (1.12) • in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (1.12, 2.1) • as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (1.12, 2.1) Hepatocellular Carcinoma (HCC) • for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD- 1/PD-L1-containing regimen. (1.13) Biliary Tract Cancer (BTC) • in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer. (1.14) Reference ID: 5482742 Merkel Cell Carcinoma (MCC) • for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. (1.15) Renal Cell Carcinoma (RCC) • in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. (1.16) • in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. (1.16) • for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (1.16) Endometrial Carcinoma • in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. (1.17) • in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA- approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.17, 2.1) • as a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.17, 2.1) Tumor Mutational Burden-High (TMB-H) Cancer • for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.1 (1.18, 2.1) • Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma (cSCC) • for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. (1.19) Triple-Negative Breast Cancer (TNBC) • for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.20) • in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA approved test. (1.20, 2.1) Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks • for use at an additional recommended dosage of 400 mg every 6 weeks for Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma in adults.2 (1.21, 2.2) 1 This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 2 This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials. ----------------------- DOSAGE AND ADMINISTRATION ----------------------- • Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • MPM: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • Urothelial Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • HCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • BTC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting, or in the advanced setting with either: o axitinib 5 mg orally twice daily or o lenvatinib 20 mg orally once daily. (2.2) • Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks o in combination with carboplatin and paclitaxel regardless of MMR or MSI status, or o in combination with lenvatinib 20 mg orally once daily for pMMR or not MSI-H tumors, or o as a single agent for MSI-H or dMMR tumors. (2.2) • TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Administer KEYTRUDA as an intravenous infusion over 30 minutes after dilution. (2.4) • See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. (2.3, 2.4) --------------------- DOSAGE FORMS AND STRENGTHS --------------------- • Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial (3) ------------------------------- CONTRAINDICATIONS ------------------------------- None. (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------- • Immune-Mediated Adverse Reactions (5.1) o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune- mediated colitis, immune-mediated hepatitis, immune- mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue based on severity and type of reaction. • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue KEYTRUDA based on the severity of reaction. (5.2) • Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3) • Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4) Reference ID: 5482742 • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception. (5.5, 8.1, 8.3) ------------------------------ ADVERSE REACTIONS ------------------------------ Most common adverse reactions (reported in ≥20% of patients) were: • KEYTRUDA as a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. (6.1) • KEYTRUDA in combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. (6.1) • KEYTRUDA in combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite. (6.1) • KEYTRUDA in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. (6.1) • KEYTRUDA in combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury. (6.1) • KEYTRUDA in combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Melanoma 1.2 Non-Small Cell Lung Cancer 1.3 Malignant Pleural Mesothelioma 1.4 Head and Neck Squamous Cell Cancer 1.5 Classical Hodgkin Lymphoma 1.6 Primary Mediastinal Large B-Cell Lymphoma 1.7 Urothelial Cancer 1.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer 1.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer 1.10 Gastric Cancer 1.11 Esophageal Cancer 1.12 Cervical Cancer 1.13 Hepatocellular Carcinoma 1.14 Biliary Tract Cancer 1.15 Merkel Cell Carcinoma 1.16 Renal Cell Carcinoma 1.17 Endometrial Carcinoma 1.18 Tumor Mutational Burden-High Cancer 1.19 Cutaneous Squamous Cell Carcinoma 1.20 Triple-Negative Breast Cancer 1.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Dose Modifications 2.4 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Severe and Fatal Immune-Mediated Adverse Reactions 5.2 Infusion-Related Reactions 5.3 Complications of Allogeneic HSCT 5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone 5.5 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Melanoma 14.2 Non-Small Cell Lung Cancer 14.3 Malignant Pleural Mesothelioma 14.4 Head and Neck Squamous Cell Cancer 14.5 Classical Hodgkin Lymphoma 14.6 Primary Mediastinal Large B-Cell Lymphoma 14.7 Urothelial Cancer 14.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer 14.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer 14.10 Gastric Cancer 14.11 Esophageal Cancer 14.12 Cervical Cancer 14.13 Hepatocellular Carcinoma 14.14 Biliary Tract Cancer 14.15 Merkel Cell Carcinoma 14.16 Renal Cell Carcinoma 14.17 Endometrial Carcinoma 14.18 Tumor Mutational Burden-High Cancer 14.19 Cutaneous Squamous Cell Carcinoma 14.20 Triple-Negative Breast Cancer 14.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482742 4 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Melanoma KEYTRUDA® is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. 1.2 Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations, and is: • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or • metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. 1.3 Malignant Pleural Mesothelioma KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). 1.4 Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. 1.5 Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). Reference ID: 5482742 5 KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. 1.6 Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. 1.7 Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: • who are not eligible for any platinum-containing chemotherapy, or • who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. 1.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options [see Dosage and Administration (2.1)]. 1.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.10 Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.10)]. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. 1.11 Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: • in combination with platinum- and fluoropyrimidine-based chemotherapy, or • as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. Reference ID: 5482742 6 1.12 Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.13 Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. 1.14 Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). 1.15 Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 1.16 Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC. KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [see Clinical Studies (14.16)]. 1.17 Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)]. 1.18 Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test [see Dosage and Administration (2.1)], that have progressed following prior treatment and who have no satisfactory alternative treatment options. Reference ID: 5482742 7 This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.18)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. 1.19 Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. 1.20 Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks KEYTRUDA is indicated for use at an additional recommended dosage of 400 mg every 6 weeks for classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma in adults [see Indications and Usage (1.5, 1.6), Dosage and Administration (2.2)]. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety [see Clinical Pharmacology (12.2), Clinical Studies (14.21)]. Continued approval for this dosage may be contingent upon verification and description of clinical benefit in the confirmatory trials. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics. Patient Selection for Single-Agent Treatment Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in: • Stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.2)]. • metastatic NSCLC [see Clinical Studies (14.2)]. • first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.4)]. • previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.11)]. • recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.12)]. For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.8, 14.9)]. For the TMB-H indication, select patients for treatment with KEYTRUDA as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.18)]. Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas. Reference ID: 5482742 8 Additional Patient Selection Information for MSI-H or dMMR in Patients with non-CRC Solid Tumors Due to discordance between local tests and FDA-approved tests, confirmation of MSI-H or dMMR status is recommended by an FDA-approved test in patients with MSI-H or dMMR solid tumors, if feasible. If unable to perform confirmatory MSI-H/dMMR testing, the presence of TMB ≥10 mut/Mb, as determined by an FDA-approved test, may be used to select patients for treatment [see Clinical Studies (14.8)]. Patient Selection for Combination Therapy For use of KEYTRUDA in combination with chemotherapy and trastuzumab, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma [see Clinical Studies (14.10)]. For use of KEYTRUDA in combination with chemotherapy, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.12)]. For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with KEYTRUDA in combination with lenvatinib based on MSI or MMR status in tumor specimens [see Clinical Studies (14.17)]. For use of KEYTRUDA in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC [see Clinical Studies (14.20)]. Additional Patient Selection Information  An FDA-approved test for the detection of not MSI-H is currently unavailable for the selection of patients with not MSI-H endometrial carcinoma for treatment with KEYTRUDA in combination with lenvatinib [see Clinical Studies (14.17)]. 2.2 Recommended Dosage Table 1: Recommended Dosage Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment Monotherapy Adult patients with unresectable or metastatic melanoma 200 mg every 3 weeks or 400 mg every 6 weeks* Until disease progression or unacceptable toxicity Adjuvant treatment of adult patients with melanoma, NSCLC, or RCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease recurrence, unacceptable toxicity, or up to 12 months Adult patients with NSCLC, HNSCC, cHL, PMBCL, locally advanced or metastatic Urothelial Carcinoma, MSI-H or dMMR Cancer, MSI-H or dMMR CRC, MSI-H or dMMR Endometrial Carcinoma, Esophageal Cancer, Cervical Cancer, HCC, MCC, TMB-H Cancer, or cSCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with high-risk BCG- unresponsive NMIBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until persistent or recurrent high-risk NMIBC, disease progression, unacceptable toxicity, or up to 24 months Pediatric patients with cHL, PMBCL, MSI-H or dMMR Cancer, MCC, or TMB- H Cancer 2 mg/kg every 3 weeks (up to a maximum of 200 mg)* Until disease progression, unacceptable toxicity, or up to 24 months Pediatric patients (12 years and older) for adjuvant treatment of melanoma 2 mg/kg every 3 weeks (up to a maximum of 200 mg)* Until disease recurrence, unacceptable toxicity, or up to 12 months Combination Therapy† Reference ID: 5482742 9 Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment Adult patients with resectable NSCLC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 12 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent after surgery for 39 weeks or until disease recurrence or unacceptable toxicity Adult patients with NSCLC, MPM, HNSCC, HER2-negative Gastric Cancer, Esophageal Cancer, or BTC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with locally advanced or metastatic urothelial cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA after enfortumab vedotin when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with HER2-positive Gastric Cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to trastuzumab and chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with Cervical Cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemoradiotherapy or prior to chemotherapy with or without bevacizumab when given on the same day. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months Adult patients with RCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA in combination with axitinib 5 mg orally twice daily‡ or Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months Adult patients with Endometrial Carcinoma 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to carboplatin and paclitaxel when given on the same day. or Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months Adult patients with high-risk early-stage TNBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent for up to Reference ID: 5482742 10 Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicity§ Adult patients with locally recurrent unresectable or metastatic TNBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months * 30-minute intravenous infusion † Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate. ‡ When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. § Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA. 2.3 Dose Modifications No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity* Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withhold† Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold† Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with axitinib, see Table 3. AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold† AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver‡ Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold† ALT or AST increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Reference ID: 5482742 11 Adverse Reaction Severity* Dosage Modification Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold† Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold† Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold† Grade 3 or 4 Permanently discontinue Hematologic toxicity in patients with cHL or PMBCL Grade 4 Withhold until resolution to Grades 0 or 1 Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue * Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 † Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. ‡ If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal The following table represents dosage modifications that are different from those described above for KEYTRUDA or in the Full Prescribing Information for the drug administered in combination. Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib Treatment Adverse Reaction Severity Dosage Modification KEYTRUDA in combination with axitinib Liver enzyme elevations* ALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both KEYTRUDA and axitinib until resolution to Grades 0 or 1† ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST ≥10 times ULN Permanently discontinue both KEYTRUDA and axitinib * Consider corticosteroid therapy † Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information. ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal Recommended Dose Modifications for Adverse Reactions for KEYTRUDA in Combination with Lenvatinib When administering KEYTRUDA in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information. 2.4 Preparation and Administration Preparation for Intravenous Infusion • Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed. Reference ID: 5482742 12 • Dilute KEYTRUDA injection (solution) prior to intravenous administration. • Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL. • Discard any unused portion left in the vial. Storage of Diluted Solution The product does not contain a preservative. Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion. • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake. Discard after 6 hours at room temperature or after 96 hours under refrigeration. Do not freeze. Administration • Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. • Do not co-administer other drugs through the same infusion line. 3 DOSAGE FORMS AND STRENGTHS • Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune- mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune- mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Reference ID: 5482742 13 Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune- mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients. In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received KEYTRUDA as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients. Reference ID: 5482742 14 KEYTRUDA with Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.3)]. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both KEYTRUDA and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). No patients discontinued KEYTRUDA due to thyroiditis. KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (2) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Reference ID: 5482742 15 The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy. Immune-Mediated Nephritis with Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence of immune- mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other PD- Reference ID: 5482742 16 1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada- like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica Endocrine: Hypoparathyroidism Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection 5.2 Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion- related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)]. 5.3 Complications of Allogeneic HSCT Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid- requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Reference ID: 5482742 17 Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)]. • Infusion-related reactions [see Warnings and Precautions (5.2)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE- 040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non- randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open- label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. Melanoma Ipilimumab-Naive Melanoma The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year. The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%). In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both Reference ID: 5482742 18 KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006. Table 4: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006 Adverse Reaction KEYTRUDA 10 mg/kg every 2 or 3 weeks n=555 Ipilimumab n=256 All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 28 0.9 28 3.1 Skin and Subcutaneous Tissue Rash‡ 24 0.2 23 1.2 Vitiligo§ 13 0 2 0 Musculoskeletal and Connective Tissue Arthralgia 18 0.4 10 1.2 Back pain 12 0.9 7 0.8 Respiratory, Thoracic and Mediastinal Cough 17 0 7 0.4 Dyspnea 11 0.9 7 0.8 Metabolism and Nutrition Decreased appetite 16 0.5 14 0.8 Nervous System Headache 14 0.2 14 0.8 * Adverse reactions occurring at same or higher incidence than in the ipilimumab arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo- papular, rash papular, rash pruritic, and exfoliative rash. § Includes skin hypopigmentation Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%). Table 5: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006 Laboratory Test† KEYTRUDA 10 mg/kg every 2 or 3 weeks Ipilimumab All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 45 4.2 45 3.8 Hypertriglyceridemia 43 2.6 31 1.1 Hyponatremia 28 4.6 26 7 Increased AST 27 2.6 25 2.5 Hypercholesterolemia 20 1.2 13 0 Hematology Anemia 35 3.8 33 4.0 Lymphopenia 33 7 25 6 * Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm † Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205. ‡ Graded per NCI CTCAE v4.0 Reference ID: 5482742 19 Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3- 4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4). Ipilimumab-Refractory Melanoma The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator’s choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months. The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis. In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002. Reference ID: 5482742 20 Table 6: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002 Adverse Reaction KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks n=357 Chemotherapy† n=171 All Grades‡ (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Pruritus 28 0 8 0 Rash§ 24 0.6 8 0 Gastrointestinal Constipation 22 0.3 20 2.3 Diarrhea 20 0.8 20 2.3 Abdominal pain 13 1.7 8 1.2 Respiratory, Thoracic and Mediastinal Cough 18 0 16 0 General Pyrexia 14 0.3 9 0.6 Asthenia 10 2.0 9 1.8 Musculoskeletal and Connective Tissue Arthralgia 14 0.6 10 1.2 * Adverse reactions occurring at same or higher incidence than in chemotherapy arm † Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin ‡ Graded per NCI CTCAE v4.0 § Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%). Table 7: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002 Laboratory Test† KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 49 6 44 6 Hypoalbuminemia 37 1.9 33 0.6 Hyponatremia 37 7 24 3.8 Hypertriglyceridemia 33 0 32 0.9 Increased alkaline phosphatase 26 3.1 18 1.9 Increased AST 24 2.2 16 0.6 Decreased bicarbonate 22 0.4 13 0 Hypocalcemia 21 0.3 18 1.9 Increased ALT 21 1.8 16 0.6 * Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123. ‡ Graded per NCI CTCAE v4.0 Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4). Adjuvant Treatment of Resected Stage IIB or IIC Melanoma Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required Reference ID: 5482742 21 immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Adjuvant Treatment of Stage III Resected Melanoma The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes). Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054. Table 8: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=509 Placebo n=502 All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Diarrhea 28 1.2 26 1.2 Nausea 17 0.2 15 0 Skin and Subcutaneous Tissue Pruritus 19 0 12 0 Rash 13 0.2 9 0 Musculoskeletal and Connective Tissue Arthralgia 16 1.2 14 0 Endocrine Hypothyroidism 15 0 2.8 0 Hyperthyroidism 10 0.2 1.2 0 Respiratory, Thoracic and Mediastinal Cough 14 0 11 0 General Asthenia 11 0.2 8 0 Influenza like illness 11 0 8 0 Investigations Weight loss 11 0 8 0 * Adverse reactions occurring at same or higher incidence than in placebo arm † Graded per NCI CTCAE v4.03 Reference ID: 5482742 22 Table 9: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054 Laboratory Test† KEYTRUDA 200 mg every 3 weeks Placebo All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Increased ALT 25 2.4 15 0.2 Increased AST 22 1.8 14 0.4 Hematology Lymphopenia 22 1 15 1.2 * Laboratory abnormalities occurring at same or higher incidence than placebo. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 502 to 505 patients) and placebo (range: 491 to 497 patients). ‡ Graded per NCI CTCAE v4.03 NSCLC First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE- 189. Reference ID: 5482742 23 Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189 Adverse Reaction KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 All Grades* (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Nausea 56 3.5 52 3.5 Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24 3.7 23 3.0 General Fatigue† 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition Decreased appetite 28 1.5 30 0.5 Skin and Subcutaneous Tissue Rash‡ 25 2.0 17 2.5 Respiratory, Thoracic and Mediastinal Cough 21 0 28 0 Dyspnea 21 3.7 26 5 * Graded per NCI CTCAE v4.03 † Includes asthenia and fatigue ‡ Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy All Grades† % Grades 3-4 % All Grades % Grades 3-4 % Hematology Anemia 85 17 81 18 Lymphopenia 65 22 64 25 Neutropenia 50 21 41 19 Thrombocytopenia 30 12 29 8 Chemistry Hyperglycemia 63 9 60 7 Increased ALT 47 3.8 42 2.6 Increased AST 47 2.8 40 1.0 Hypoalbuminemia 39 2.8 39 1.1 Increased creatinine 37 4.2 25 1.0 Hyponatremia 32 7 23 6 Hypophosphatemia 30 10 28 14 Increased alkaline phosphatase 26 1.8 29 2.1 Hypocalcemia 24 2.8 17 0.5 Hyperkalemia 24 2.8 19 3.1 Hypokalemia 21 5 20 5 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). † Graded per NCI CTCAE v4.03 First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The safety of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Reference ID: 5482742 24 Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin. The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases. KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%). The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. Previously Untreated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator’s choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty- eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had treated brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042. Reference ID: 5482742 25 Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=636 Chemotherapy n=615 All Grades* (%) Grades 3-5 (%) All Grades (%) Grades 3-5 (%) General Fatigue† 25 3.1 33 3.9 Pyrexia 10 0.3 8 0 Metabolism and Nutrition Decreased appetite 17 1.7 21 1.5 Respiratory, Thoracic and Mediastinal Dyspnea 17 2.0 11 0.8 Cough 16 0.2 11 0.3 Skin and Subcutaneous Tissue Rash‡ 15 1.3 8 0.2 Gastrointestinal Constipation 12 0 21 0.2 Diarrhea 12 0.8 12 0.5 Nausea 12 0.5 32 1.1 Endocrine Hypothyroidism 12 0.2 1.5 0 Infections Pneumonia 12 7 9 6 Investigations Weight loss 10 0.9 7 0.2 * Graded per NCI CTCAE v4.03 † Includes fatigue and asthenia ‡ Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Chemotherapy All Grades† % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 52 4.7 51 5 Increased ALT 33 4.8 34 2.9 Hypoalbuminemia 33 2.2 29 1.0 Increased AST 31 3.6 32 1.7 Hyponatremia 31 9 32 8 Increased alkaline phosphatase 29 2.3 29 0.3 Hypocalcemia 25 2.5 19 0.7 Hyperkalemia 23 3.0 20 2.2 Increased prothrombin INR 21 2.0 15 2.9 Hypophosphatemia 20 4.7 17 4.3 Hematology Anemia 43 4.4 79 19 Lymphopenia 30 7 42 13 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 585 to 598 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173. † Graded per NCI CTCAE v4.03 Previously Treated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic Reference ID: 5482742 26 corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease. In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010. Table 14: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010 Adverse Reaction KEYTRUDA 2 or 10 mg/kg every 3 weeks n=682 Docetaxel 75 mg/m2 every 3 weeks n=309 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Metabolism and Nutrition Decreased appetite 25 1.5 23 2.6 Respiratory, Thoracic and Mediastinal Dyspnea 23 3.7 20 2.6 Cough 19 0.6 14 0 Gastrointestinal Nausea 20 1.3 18 0.6 Constipation 15 0.6 12 0.6 Vomiting 13 0.9 10 0.6 Skin and Subcutaneous Tissue Rash‡ 17 0.4 8 0 Pruritus 11 0 3 0.3 Musculoskeletal and Connective Tissue Arthralgia 11 1.0 9 0.3 Back pain 11 1.5 8 0.3 * Adverse reactions occurring at same or higher incidence than in docetaxel arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%). Reference ID: 5482742 27 Table 15: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010 Laboratory Test† KEYTRUDA 2 or 10 mg/kg every 3 weeks Docetaxel 75 mg/m2 every 3 weeks All Grades‡ % Grades 3-4 % All Grades‡ % Grades 3-4 % Chemistry Hyponatremia 32 8 27 2.9 Increased alkaline phosphatase 28 3.0 16 0.7 Increased AST 26 1.6 12 0.7 Increased ALT 22 2.7 9 0.4 Hypocalcemia 20 0.9 20 1.8 * Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. † Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 271 to 277 patients). ‡ Graded per NCI CTCAE v4.0 Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (32% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4). Neoadjuvant and Adjuvant Treatment of Resectable NSCLC The safety of KEYTRUDA in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.2)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino. Adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. Neoadjuvant Phase of KEYNOTE-671 A total of 396 patients received at least 1 dose of KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 34% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the 396 KEYTRUDA-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. Reference ID: 5482742 28 The most frequent (≥1%) adverse reactions that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). Of the 325 KEYTRUDA-treated patients who received surgery, 3.1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions. Of the 325 KEYTRUDA-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of KEYNOTE-671 A total of 290 patients in the KEYTRUDA arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent KEYTRUDA as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%). Adjuvant Treatment of Resected NSCLC The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.2)]. A total of 1161 patients received KEYTRUDA 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. The median duration of exposure to KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty- eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. Malignant Pleural Mesothelioma (MPM) First-line treatment of unresectable advanced or metastatic MPM with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and platinum chemotherapy (either carboplatin or cisplatin) was investigated in KEYNOTE-483, a multicenter, open-label, randomized (1:1), active- controlled trial in patients with previously untreated, unresectable advanced or metastatic MPM [see Clinical Studies (14.3)]. A total of 473 patients received KEYTRUDA 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by KEYTRUDA (n=241), or pemetrexed and platinum chemotherapy every 3 weeks for up to 6 cycles (n=232). Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 6.9 months (range: 1 day to 25.2 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Reference ID: 5482742 29 HNSCC First-line treatment of metastatic or unresectable, recurrent HNSCC The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.4)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab. The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin. KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%). Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048. Reference ID: 5482742 30 Table 16: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=300 KEYTRUDA 200 mg every 3 weeks Platinum FU n=276 Cetuximab Platinum FU n=287 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) General Fatigue† 33 4 49 11 48 8 Pyrexia 13 0.7 16 0.7 12 0 Mucosal inflammation 4.3 1.3 31 10 28 5 Gastrointestinal Constipation 20 0.3 37 0 33 1.4 Nausea 17 0 51 6 51 6 Diarrhea‡ 16 0.7 29 3.3 35 3.1 Vomiting 11 0.3 32 3.6 28 2.8 Dysphagia 8 2.3 12 2.9 10 2.1 Stomatitis 3 0 26 8 28 3.5 Skin Rash§ 20 2.3 17 0.7 70 8 Pruritus 11 0 8 0 10 0.3 Respiratory, Thoracic and Mediastinal Cough¶ 18 0.3 22 0 15 0 Dyspnea# 14 2.0 10 1.8 8 1.0 Endocrine Hypothyroidism 18 0 15 0 6 0 Metabolism and Nutrition Decreased appetite 15 1.0 29 4.7 30 3.5 Weight loss 15 2 16 2.9 21 1.4 Infections PneumoniaÞ 12 7 19 11 13 6 Nervous System Headache 12 0.3 11 0.7 8 0.3 Dizziness 5 0.3 10 0.4 13 0.3 Peripheral sensory neuropathyβ 1 0 14 1.1 7 1 Musculoskeletal Myalgiaà 12 1.0 13 0.4 11 0.3 Neck pain 6 0.7 10 1.1 7 0.7 Psychiatric Insomnia 7 0.7 10 0 8 0 * Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis § Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis ¶ Includes cough, productive cough # Includes dyspnea, exertional dyspnea Þ Includes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal β Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia à Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia Reference ID: 5482742 31 Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048 Laboratory Test* KEYTRUDA 200 mg every 3 weeks KEYTRUDA 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU All Grades† (%) Grades 3- 4 (%) All Grades† (%) Grades 3- 4 (%) All Grades† (%) Grades 3-4 (%) Hematology Lymphopenia 54 25 70 35 75 46 Anemia 52 7 89 29 79 20 Thrombocytopenia 12 3.8 73 18 76 18 Neutropenia 8 1.4 68 37 73 43 Chemistry Hyperglycemia 47 3.8 54 6 65 4.7 Hyponatremia 46 18 55 20 59 20 Hypoalbuminemia 44 3.5 46 3.9 49 1.1 Increased AST 28 3.1 25 1.9 37 3.6 Increased ALT 25 2.1 22 1.5 38 1.8 Increased alkaline phosphatase 25 2.1 26 1.1 33 1.1 Hypercalcemia 22 4.5 16 4.2 13 2.5 Hypocalcemia 22 1.0 32 3.8 58 6 Hyperkalemia 21 2.8 28 4.2 29 4.6 Hypophosphatemia 20 5 34 12 49 20 Hypokalemia 19 5 33 12 47 15 Increased creatinine 17 1.0 36 2.3 27 2.1 Hypomagnesemia 15 0.4 40 1.7 76 9 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 240 to 267 patients), KEYTRUDA (range: 245 to 292 patients), cetuximab/chemotherapy (range: 249 to 282 patients). † Graded per NCI CTCAE v4.0 Previously treated recurrent or metastatic HNSCC Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012. The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease. KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.1)]. Relapsed or Refractory cHL KEYNOTE-204 The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.5)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or Reference ID: 5482742 32 brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/µL, platelet count ≥75,000/µL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment. Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia. Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Table 18 summarizes adverse reactions in KEYNOTE-204. Reference ID: 5482742 33 Table 18: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=148 Brentuximab Vedotin 1.8 mg/kg every 3 weeks N=152 All Grades* (%) Grades 3- 4 (%) All Grades* (%) Grades 3- 4† (%) Infections Upper respiratory tract infection‡ 41 1.4 24 0 Urinary tract infection 11 0 3 0.7 Musculoskeletal and Connective Tissue Musculoskeletal pain§ 32 0 29 1.3 Gastrointestinal Diarrhea¶ 22 2.7 17 1.3 Nausea 14 0 24 0.7 Vomiting 14 1.4 20 0 Abdominal pain# 11 0.7 13 1.3 General Pyrexia 20 0.7 13 0.7 FatigueÞ 20 0 22 0.7 Skin and Subcutaneous Tissue Rashβ 20 0 19 0.7 Pruritus 18 0 12 0 Respiratory, Thoracic and Mediastinal Coughà 20 0.7 14 0.7 Pneumonitisè 11 5 3 1.3 Dyspneað 11 0.7 7 0.7 Endocrine Hypothyroidism 19 0 3 0 Nervous System Peripheral neuropathyø 11 0.7 43 7 Headacheý 11 0 11 0 * Graded per NCI CTCAE v4.0 † Adverse reactions in BV arm were Grade 3 only. ‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection § Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity ¶ Includes diarrhea, gastroenteritis, colitis, enterocolitis # Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper Þ Includes fatigue, asthenia β Includes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular‚ rash maculo-papular, rash papular, rash pruritic, toxic skin eruption à Includes cough, productive cough è Includes pneumonitis, interstitial lung disease ð Includes dyspnea, dyspnea exertional, wheezing ø Includes dysesthesia, hypoesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy ý Includes headache, migraine, tension headache Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare. Table 19 summarizes laboratory abnormalities in KEYNOTE-204. Reference ID: 5482742 34 Table 19: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204 Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks Brentuximab Vedotin 1.8 mg/kg every 3 weeks All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Chemistry Hyperglycemia 45 4.1 36 2.0 Increased AST 38 4.7 38 2.0 Increased ALT 31 5 43 2.6 Hypophosphatemia 31 4.9 17 2.8 Increased creatinine 26 3.4 13 2.6 Hypomagnesemia 23 0 13 0 Hyponatremia 24 4.1 20 3.3 Hypocalcemia 21 2.0 15 0 Increased alkaline phosphatase 19 2.1 21 2.0 Hypoalbuminemia 16 0.7 18 0.7 Hyperbilirubinemia 15 1.4 8 0.7 Hematology Lymphopenia 34 8 32 13 Thrombocytopenia 32 9 24 4.0 Neutropenia 27 8 42 16 Anemia 22 4.1 32 7 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148 patients) and BV (range: 145 to 152 patients); hypomagnesemia: KEYTRUDA n=52 and BV n=47. † Graded per NCI CTCAE v4.0 KEYNOTE-087 Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087. Reference ID: 5482742 35 Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=210 All Grades* (%) Grade 3 (%) General Fatigue† 26 1.0 Pyrexia 24 1.0 Respiratory, Thoracic and Mediastinal Cough‡ 24 0.5 Dyspnea§ 11 1.0 Musculoskeletal and Connective Tissue Musculoskeletal pain¶ 21 1.0 Arthralgia 10 0.5 Gastrointestinal Diarrhea# 20 1.4 Vomiting 15 0 Nausea 13 0 Skin and Subcutaneous Tissue Rash Þ 20 0.5 Pruritus 11 0 Endocrine Hypothyroidism 14 0.5 Infections Upper respiratory tract infection 13 0 Nervous System Headache 11 0.5 Peripheral neuropathyβ 10 0 * Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes cough, productive cough § Includes dyspnea, dyspnea exertional, wheezing ¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrheic dermatitis, dermatitis psoriasiform β Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each). Reference ID: 5482742 36 Table 21: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087 Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Chemistry Hypertransaminasemia‡ 35 2.4 Increased alkaline phosphatase 17 0 Increased creatinine 15 0.5 Hematology Anemia 30 6 Thrombocytopenia 27 4.3 Neutropenia 25 7 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4). PMBCL Among the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.6)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170. Reference ID: 5482742 37 Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=53 All Grades* (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal pain† 30 0 Infections Upper respiratory tract infection‡ 28 0 General Pyrexia 28 0 Fatigue§ 23 2 Respiratory, Thoracic and Mediastinal Cough¶ 26 2 Dyspnea 21 11 Gastrointestinal Diarrhea# 13 2 Abdominal pain Þ 13 0 Nausea 11 0 Cardiac Arrhythmia β 11 4 Nervous System Headache 11 0 * Graded per NCI CTCAE v4.0 † Includes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain ‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection § Includes fatigue, asthenia ¶ Includes allergic cough, cough, productive cough # Includes diarrhea, gastroenteritis Þ Includes abdominal pain, abdominal pain upper β Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each). Table 23: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170 Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Hematology Anemia 23 0 Leukopenia 47 12 Lymphopenia 27 10 Neutropenia 39 15 Chemistry Hyperglycemia 33 2.2 Hypophosphatemia 24 11 Hypertransaminasemia‡ 24 4.4 Hypoglycemia 20 0 Increased creatinine 16 0 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 41 to 45 patients) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT Reference ID: 5482742 38 Urothelial Cancer Patients with urothelial cancer in combination with enfortumab vedotin The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.7)]. A total of 440 patients received KEYTRUDA 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received KEYTRUDA and enfortumab vedotin, the median duration of exposure to KEYTRUDA was 8.5 months (range: 9 days to 28.5 months). Fatal adverse reactions occurred in 3.9% of patients treated with KEYTRUDA in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). Dose interruptions of KEYTRUDA occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%). Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-A39. Reference ID: 5482742 39 Table 24: Adverse Reactions ≥20% (All Grades) in Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-A39 Adverse Reaction KEYTRUDA in combination with Enfortumab Vedotin n=440 Chemotherapy n=433 All Grades* % Grades 3-4 % All Grades* % Grades 3-4 % Skin and subcutaneous tissue disorders Rash† 68 15 15 0 Pruritus 41 1.1 7 0 Alopecia 35 0.5 8 0.2 General disorders and administration site conditions Fatigue† 51 6 57 7 Nervous system disorders Peripheral neuropathy† 67 8 14 0 Dysgeusia 21 0 9 0 Metabolism and nutrition disorders Decreased appetite 33 1.8 26 1.8 Gastrointestinal disorders Diarrhea 38 4.5 16 1.4 Nausea 26 1.6 41 2.8 Constipation 26 0 34 0.7 Investigations Weight loss 33 3.6 9 0.2 Eye disorders Dry eye† 24 0 2.1 0 Infections and infestations Urinary tract infection 21 5 19 8 * Graded per NCI CTCAE v4.03 † Includes multiple terms Clinically relevant adverse reactions (<20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%). Reference ID: 5482742 40 Table 25: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-A39 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Enfortumab Vedotin Chemotherapy All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Chemistry Increased aspartate aminotransferase 75 4.6 39 3.3 Increased creatinine 71 3.2 68 2.6 Hyperglycemia 66 14 54 4.7 Increased alanine aminotransferase 59 5 49 3.3 Hyponatremia 46 13 47 13 Hypophosphatemia 44 9 36 9 Hypoalbuminemia 39 1.8 35 0.5 Hypokalemia 26 5 16 3.1 Hyperkalemia 24 1.4 36 4.0 Hypercalcemia 21 1.2 14 0.2 Hematology Lymphopenia 58 15 59 17 Anemia 53 7 89 33 Neutropenia 30 9 80 50 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 407 to 439 patients) † Graded per NCI CTCAE v4.03 Cisplatin-ineligible patients with urothelial cancer in combination with enfortumab vedotin The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer and who are not eligible for cisplatin-based chemotherapy [see Clinical Studies (14.7)]. A total of 121 patients received KEYTRUDA 200 mg on Day 1, and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle. The median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 29.6 months). Fatal adverse reactions occurred in 5% of patients treated with KEYTRUDA in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA and enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%). Permanent discontinuation of KEYTRUDA occurred in 32% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%). Dose interruptions of KEYTRUDA occurred in 69% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), lipase increased (5%), acute kidney injury (3.3%), ALT increased (2.5%), and COVID-19 (2.5%). Tables 26 and 27 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-869. Reference ID: 5482742 41 Table 26: Adverse Reactions Occurring in ≥20% of Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-869 Adverse Reaction KEYTRUDA in combination with Enfortumab Vedotin n=121 All Grades* % Grade 3-4 % Skin and subcutaneous tissue disorders Rash† 71 21 Alopecia 52 0 Pruritus 40 3.3 Dry skin 21 0.8 Nervous system disorders Peripheral neuropathy‡ 65 3.3 Dysgeusia 35 0 Dizziness 23 0 General disorders and administration site conditions Fatigue 60 11 Peripheral edema 26 0 Investigations Weight loss 48 5 Gastrointestinal disorders Diarrhea 45 7 Nausea 36 0.8 Constipation 27 0 Metabolism and nutrition disorders Decreased appetite 38 0.8 Infections and infestations Urinary tract infection 30 12 Eye disorders Dry eye 25 0 Musculoskeletal and connective tissue disorders Arthralgia 23 1.7 * Graded per NCI CTCAE v4.03 † Includes: blister, conjunctivitis, dermatitis, dermatitis bullous, dermatitis exfoliative generalized, erythema, erythema multiforme, exfoliative rash, palmar-plantar erythrodysesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, skin exfoliation, and stomatitis ‡ Includes: dysesthesia, hypoesthesia, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and gait disturbance Clinically relevant adverse reactions (<20%) include vomiting (19.8%), fever (18%), hypothyroidism (11%), pneumonitis/ILD (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%). Reference ID: 5482742 42 Table 27: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-869 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Enfortumab Vedotin All Grades† % Grades 3-4 % Chemistry Hyperglycemia 74 13 Increased aspartate aminotransferase 73 9 Increased creatinine 69 3.3 Hyponatremia 60 19 Increased alanine aminotransferase 60 7 Increased lipase 59 32 Hypoalbuminemia 59 4.2 Hypophosphatemia 51 15 Hypokalemia 35 8 Increased potassium 27 1.7 Increased calcium 27 4.2 Hematology Anemia 69 15 Lymphopenia 64 17 Neutropenia 32 12 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 114 to 121 patients) † Graded per NCI CTCAE v4.03 Platinum-Ineligible Patients with Urothelial Carcinoma The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.7)]. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent. Table 28 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052. Reference ID: 5482742 43 Table 28: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-052 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=370 All Grades* (%) Grades 3–4 (%) General Fatigue† 38 6 Pyrexia 11 0.5 Weight loss 10 0 Musculoskeletal and Connective Tissue Musculoskeletal pain‡ 24 4.9 Arthralgia 10 1.1 Metabolism and Nutrition Decreased appetite 22 1.6 Hyponatremia 10 4.1 Gastrointestinal Constipation 21 1.1 Diarrhea§ 20 2.4 Nausea 18 1.1 Abdominal pain¶ 18 2.7 Elevated LFTs# 13 3.5 Vomiting 12 0 Skin and Subcutaneous Tissue RashÞ 21 0.5 Pruritus 19 0.3 Edema peripheralβ 14 1.1 Infections Urinary tract infection 19 9 Blood and Lymphatic System Anemia 17 7 Respiratory, Thoracic, and Mediastinal Cough 14 0 Dyspnea 11 0.5 Renal and Urinary Increased blood creatinine 11 1.1 Hematuria 13 3.0 * Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain § Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements ¶ Includes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper # Includes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases, hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests Þ Includes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized β Includes edema peripheral, peripheral swelling Previously Treated Urothelial Carcinoma The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator’s choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.7)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Reference ID: 5482742 44 The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045. Table 29: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-045 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=266 Chemotherapy* n=255 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) General Fatigue‡ 38 4.5 56 11 Pyrexia 14 0.8 13 1.2 Musculoskeletal and Connective Tissue Musculoskeletal pain§ 32 3.0 27 2.0 Skin and Subcutaneous Tissue Pruritus 23 0 6 0.4 Rash¶ 20 0.4 13 0.4 Gastrointestinal Nausea 21 1.1 29 1.6 Constipation 19 1.1 32 3.1 Diarrhea# 18 2.3 19 1.6 Vomiting 15 0.4 13 0.4 Abdominal pain 13 1.1 13 2.7 Metabolism and Nutrition Decreased appetite 21 3.8 21 1.2 Infections Urinary tract infection 15 4.9 14 4.3 Respiratory, Thoracic and Mediastinal CoughÞ 15 0.4 9 0 Dyspneaß 14 1.9 12 1.2 Renal and Urinary Hematuria à 12 2.3 8 1.6 * Chemotherapy: paclitaxel, docetaxel, or vinflunine † Graded per NCI CTCAE v4.0 ‡ Includes asthenia, fatigue, malaise, lethargy § Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain ¶ Includes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes cough, productive cough ß Includes dyspnea, dyspnea exertional, wheezing à Includes blood urine present, hematuria, chromaturia Reference ID: 5482742 45 Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Chemotherapy All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Chemistry Hyperglycemia 52 8 60 7 Anemia 52 13 68 18 Lymphopenia 45 15 55 26 Hypoalbuminemia 43 1.7 50 3.8 Hyponatremia 37 9 47 13 Increased alkaline phosphatase 37 7 33 4.9 Increased creatinine 35 4.4 28 2.9 Hypophosphatemia 29 8 34 14 Increased AST 28 4.1 20 2.5 Hyperkalemia 28 0.8 27 6 Hypocalcemia 26 1.6 34 2.1 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: KEYTRUDA n=232 and chemotherapy n=222. † Graded per NCI CTCAE v4.0 BCG-unresponsive High-risk NMIBC The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057. Reference ID: 5482742 46 Table 31: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-057 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=148 All Grades* (%) Grades 3–4 (%) General Fatigue† 29 0.7 Peripheral edema‡ 11 0 Gastrointestinal Diarrhea§ 24 2.0 Nausea 13 0 Constipation 12 0 Skin and Subcutaneous Tissue Rash¶ 24 0.7 Pruritus 19 0.7 Musculoskeletal and Connective Tissue Musculoskeletal pain# 19 0 Arthralgia 14 1.4 Renal and Urinary Hematuria 19 1.4 Respiratory, Thoracic, and Mediastinal CoughÞ 19 0 Infections Urinary tract infection 12 2.0 Nasopharyngitis 10 0 Endocrine Hypothyroidism 11 0 * Graded per NCI CTCAE v4.03 † Includes asthenia, fatigue, malaise ‡ Includes edema peripheral, peripheral swelling § Includes diarrhea, gastroenteritis, colitis ¶ Includes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis # Includes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain Þ Includes cough, productive cough Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057 Laboratory Test* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Chemistry Hyperglycemia 59 7 Increased ALT 25 2.7 Hyponatremia 24 7 Hypophosphatemia 24 6 Hypoalbuminemia 24 1.4 Hyperkalemia 23 1.4 Hypocalcemia 22 0.7 Increased AST 20 2.7 Increased creatinine 20 0.7 Hematology Anemia 35 1.4 Lymphopenia 29 1.6 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 124 to 147 patients) † Graded per NCI CTCAE v4.03 Reference ID: 5482742 47 Microsatellite Instability-High or Mismatch Repair Deficient Cancer The safety of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.8)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer Among the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.9)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Gastric Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma The safety of KEYTRUDA was evaluated in 433 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 217 patients treated with KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients treated with placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.10)]. The median duration of exposure to KEYTRUDA was 5.8 months (range: 1 day to 17.7 months). The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1. KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma The safety of KEYTRUDA was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with KEYTRUDA 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.10)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 33.7 months). Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). Reference ID: 5482742 48 Permanent discontinuation of KEYTRUDA due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of KEYTRUDA in ≥1% were infections (1.8%) and diarrhea (1.0%). Dosage interruptions of KEYTRUDA due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%). Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-859. Table 33: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-859 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=785 Placebo and FP or CAPOX n=787 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) Nervous System Peripheral neuropathy† 47 5 48 6 Gastrointestinal Nausea 46 3.7 46 4.4 Diarrhea 36 6 32 5 Vomiting 34 5 27 5 Abdominal Pain‡ 26 2.8 24 2.9 Constipation 22 0.5 21 0.8 General Fatigue§ 40 8 39 9 Metabolism and Nutrition Decreased appetite 29 3.3 29 2.5 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 25 3.1 22 1.8 Investigations Weight loss 20 2.8 19 2.7 * Graded per NCI CTCAE v4.03 † Includes dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy ‡ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal tenderness, abdominal pain upper, epigastric discomfort, gastrointestinal pain § Includes asthenia, fatigue Reference ID: 5482742 49 Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-859 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and FP or CAPOX Placebo and FP or CAPOX All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 65 15 69 13 Thrombocytopenia 64 12 62 10 Neutropenia 63 25 58 20 Leukopenia 59 7 56 6 Lymphopenia 57 20 51 16 Chemistry Increased AST 57 4.7 48 3.6 Hypoalbuminemia 55 4.1 52 2.9 Hyperglycemia 53 6 52 4.6 Hypocalcemia 49 3.6 45 3.3 Increased alkaline phosphatase 48 6 41 5 Hyponatremia 40 13 40 12 Increased ALT 40 4.2 29 2.9 Hypokalemia 35 10 27 9 Bilirubin increased 32 5 30 5 Hypophosphatemia 30 10 27 8 Hypomagnesemia 29 0.3 22 0.7 Increased creatinine 21 3.5 18 1.7 Hyperkalemia 20 3.7 18 2.9 Increased INR 20 1.4 22 0 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA/FP or CAPOX (range: 210 to 766 patients) and placebo/FP or CAPOX (range: 190 to 762 patients) † Graded per NCI CTCAE v4.03 Esophageal Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.11)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU. The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%). Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590. Reference ID: 5482742 50 Table 35: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-590 Adverse Reaction KEYTRUDA 200 mg every 3 weeks Cisplatin FU n=370 Placebo Cisplatin FU n=370 All Grades* (%) Grades 3-4† (%) All Grades* (%) Grades 3-4† (%) Gastrointestinal Nausea 67 7 63 7 Constipation 40 0 40 0 Diarrhea 36 4.1 33 3 Vomiting 34 7 32 5 Stomatitis 27 6 26 3.8 General Fatigue‡ 57 12 46 9 Metabolism and Nutrition Decreased appetite 44 4.1 38 5 Investigations Weight loss 24 3.0 24 5 * Graded per NCI CTCAE v4.03 † One fatal event of diarrhea was reported in each arm. ‡ Includes asthenia, fatigue Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving KEYTRUDA in KEYNOTE-590 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Cisplatin FU Chemotherapy (Cisplatin and FU) All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 84 21 87 25 Neutropenia 77 44 73 41 Leukopenia 73 21 73 17 Lymphopenia 57 23 53 18 Thrombocytopenia 43 5 46 8 Chemistry Hyperglycemia 56 7 55 6 Hyponatremia 53 19 53 19 Hypoalbuminemia 53 2.8 52 2.3 Increased creatinine 45 2.5 42 2.5 Hypocalcemia 44 3.9 37 2 Hypophosphatemia 37 9 31 10 Hypokalemia 30 12 34 15 Increased alkaline phosphatase 29 1.9 29 1.7 Hyperkalemia 28 3.6 28 2.5 Increased AST 25 4.4 22 2.8 Increased ALT 23 3.6 18 1.7 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 353 to 365 patients) and placebo/cisplatin/FU (range: 347 to 359 patients) † Graded per NCI CTCAE v4.03 Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.11)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required Reference ID: 5482742 51 immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy The safety of KEYTRUDA in combination with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18, a placebo-controlled, randomized (1:1), multicenter, double-blind trial including 594 patients with FIGO 2014 Stage III-IVA cervical cancer [see Clinical Studies (14.12)]. Two hundred ninety-two patients received KEYTRUDA in combination with chemoradiotherapy and 302 patients received placebo in combination with chemoradiotherapy. The median duration of exposure to KEYTRUDA was 12.1 months (range: 1 day to 27 months). Fatal adverse reactions occurred in 1.4% of patients receiving KEYTRUDA in combination with chemoradiotherapy, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of patients included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were anemia (8%), COVID-19 (6%), SARS-CoV-2 test positive (3.1%), decreased neutrophil count (2.7%), diarrhea (2.7%), urinary tract infection (2.7%), and increased ALT (2.4%). Table 37 and Table 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-A18. Table 37: Adverse Reactions Occurring in ≥10% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving KEYTRUDA in KEYNOTE-A18 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy n=292 Placebo with chemoradiotherapy n=302 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) Gastrointestinal Nausea 56 0 61 2.3 Diarrhea 50 3.8 50 4.3 Vomiting 33 1 34 1.7 Constipation 18 0 18 0.7 Abdominal pain 12 0.7 12 1.7 Infections Urinary tract infection† 32 4.1 31 4.6 General Fatigue‡ 26 1 27 1.3 Pyrexia 12 0.3 13 0 Endocrine Hypothyroidism§ 20 0.7 5 0 Hyperthyroidism 11 0.3 2.6 0 Metabolism and Nutrition Decreased appetite 17 0.7 17 0.3 Investigations Weight loss 17 1.4 18 1 Reference ID: 5482742 52 Renal and Urinary Dysuria 11 0.3 12 0 Skin and Subcutaneous Tissue Disorders Rash¶ 11 0.7 7 0.3 Reproductive System Pelvic pain 10 1 13 1.3 * Graded per NCI CTCAE v5.0 † Includes urinary tract infection, urinary tract infection pseudomonal, pyelonephritis acute, cystitis, Escherichia urinary tract infection ‡ Includes fatigue, asthenia § Includes hypothyroidism, autoimmune hypothyroidism ¶ Includes erythema multiforme, dermatitis, drug eruption, eczema, rash, skin exfoliation, dermatitis bullous, rash maculo-papular, lichen planus, dyshidrotic eczema, dermatitis acneiform Table 38: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving KEYTRUDA in KEYNOTE-A18 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy Placebo with chemoradiotherapy All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Hematology Lymphopenia 99 96 99 92 Leukopenia 96 46 94 49 Anemia 88 31 81 25 Neutropenia 75 32 74 33 Thrombocytopenia 65 8 61 6 Chemistry Hypomagnesemia 59 4.2 63 3.4 Hyponatremia 54 3.8 47 4 Increased AST 45 1 39 1.7 Increased ALT 44 2.1 44 1 Hypocalcemia 43 4.8 40 4.3 Hypokalemia 42 14 38 10 Increased creatinine 41 6 43 6 Hypoalbuminemia 37 0.7 35 1.7 Increased alkaline phosphatase 34 0.3 33 0.3 * Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA + chemoradiotherapy (range: 286 to 291 patients) and placebo + chemoradiotherapy (range: 298 to 300 patients) † Graded per NCI CTCAE v5.0 Persistent, Recurrent, or Metastatic Cervical Cancer The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.12)]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks. The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months). Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases Reference ID: 5482742 53 due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). Table 39 and Table 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826. Table 39: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and chemotherapy* with or without bevacizumab n=307 Placebo and chemotherapy* with or without bevacizumab n=309 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Nervous System Peripheral neuropathy‡ 58 4.2 57 6 Skin and Subcutaneous Tissue Alopecia 56 0 58 0 Rash§ 22 3.6 15 0.3 General Fatigue¶ 47 7 46 6 Gastrointestinal Nausea 40 2 44 1.6 Diarrhea 36 2 30 2.6 Constipation 28 0.3 33 1 Vomiting 26 2.6 27 1.9 Musculoskeletal and Connective Tissue Arthralgia 27 0.7 26 1.3 Vascular Hypertension 24 9 23 11 Infections Urinary tract infection 24 9 26 8 * Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Graded per NCI CTCAE v4.0 ‡ Includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia § Includes rash, rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular ¶ Includes fatigue, asthenia Reference ID: 5482742 54 Table 40: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and chemotherapy† with or without bevacizumab n=307 Placebo and chemotherapy† with or without bevacizumab n=309 All Grades‡ (%) Grades 3-4 (%) All Grades‡ (%) Grades 3-4 (%) Hematology Anemia 80 35 77 33 Leukopenia 76 27 69 19 Neutropenia 73 43 62 32 Lymphopenia 64 35 59 35 Thrombocytopenia 57 19 53 15 Chemistry Hyperglycemia 51 4.7 46 2.3 Hypoalbuminemia 46 1.4 37 5 Hyponatremia 39 14 38 11 Increased ALT 40 7 38 6 Increased AST 40 6 36 3.0 Increased alkaline phosphatase 38 3.4 40 2.3 Hypocalcemia 37 4.1 31 5 Increased creatinine 34 5 32 6 Hypokalemia 29 7 26 7 Hyperkalemia 23 3.7 27 4.7 Hypercalcemia 21 1.0 20 1.3 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA plus chemotherapy (range: 296 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients) † Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) ‡ Graded per NCI CTCAE v4.0 Previously Treated Recurrent or Metastatic Cervical Cancer Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.12)], the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158. Reference ID: 5482742 55 Table 41: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=98 All Grades* (%) Grades 3–4 (%) General Fatigue† 43 5 Pain‡ 22 2.0 Pyrexia 19 1.0 Edema peripheral§ 15 2.0 Musculoskeletal and Connective Tissue Musculoskeletal pain¶ 27 5 Gastrointestinal Diarrhea# 23 2.0 Abdominal painÞ 22 3.1 Nausea 19 0 Vomiting 19 1.0 Constipation 14 0 Metabolism and Nutrition Decreased appetite 21 0 Vascular Hemorrhageß 19 5 Infections UTIà 18 6 Infection (except UTI)è 16 4.1 Skin and Subcutaneous Tissue Rashð 17 2.0 Endocrine Hypothyroidism 11 0 Nervous System Headache 11 2.0 Respiratory, Thoracic and Mediastinal Dyspnea 10 1.0 * Graded per NCI CTCAE v4.0 † Includes asthenia, fatigue, lethargy, malaise ‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache § Includes edema peripheral, peripheral swelling ¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity # Includes colitis, diarrhea, gastroenteritis Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper ß Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage à Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis è Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis ð Includes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular Reference ID: 5482742 56 Table 42: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158 Laboratory Test* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Hematology Anemia 54 24 Lymphopenia 45 9 Chemistry Hypoalbuminemia 44 5 Increased alkaline phosphatase 40 1.3 Hyponatremia 38 13 Hyperglycemia 38 1.3 Increased AST 34 3.9 Increased creatinine 32 5 Hypocalcemia 27 0 Increased ALT 21 3.9 Hypokalemia 20 6 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 76 to 79 patients) † Graded per NCI CTCAE v4.0 Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (17% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (10% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4). HCC Previously Treated HCC The safety of KEYTRUDA was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC. Patients were randomized (2:1) and received KEYTRUDA 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.13)]. The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the KEYTRUDA arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. KEYTRUDA was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). Adverse reactions leading to interruption of KEYTRUDA occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%). Tables 43 and 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-394. Reference ID: 5482742 57 Table 43: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving KEYTRUDA in KEYNOTE-394 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=299 Placebo n=153 All Grades* (%) Grades 3-5 (%) All Grades* (%) Grades 3-5 (%) General Pyrexia 18 0.7 14 0 Skin and Subcutaneous Tissue Rash† 18 0.7 7 0 Pruritus 12 0 4 0 Gastrointestinal Diarrhea 16 1.7 9 0 Metabolism and Nutrition Decreased appetite 15 0.3 9 0 Infections Upper respiratory tract infection 11 1.0 7 0.7 Respiratory, Thoracic, and Mediastinal Cough 11 0 9 0 Endocrine Hypothyroidism 10 0 7 0 * Graded per NCI CTCAE v4.03 † Includes dermatitis, dermatitis allergic, dermatitis bullous, rash, rash erythematous, rash maculo-papular, rash pustular, and blister. Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with HCC Receiving KEYTRUDA in KEYNOTE-394 Laboratory Test* KEYTRUDA Placebo All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Chemistry Increased AST 54 14 44 12 Increased bilirubin 47 11 36 7 Increased ALT 47 7 32 4.6 Increased gamma-glutamyl transferase (GGT) 40 20 39 15 Hypoalbuminemia 40 0.7 20 0.7 Increased alkaline phosphatase 39 4.1 34 4 Hyperglycemia 36 3.3 26 1.4 Hyponatremia 36 11 28 5 Hypophosphatemia 30 6 17 4 Hypocalcemia 24 1.4 15 0.7 Hematology Lymphopenia 44 11 34 4.6 Anemia 36 7 30 3.3 Decreased platelets 32 4.7 29 2 Leukopenia 30 1.3 21 0.7 Neutropenia 25 4.4 21 2 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 223 to 297 patients) and placebo (range: 144 to 151 patients). † Graded per NCI CTCAE v4.03 BTC The safety of KEYTRUDA in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.14)]. A total of 1063 patients received either KEYTRUDA 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks. Reference ID: 5482742 58 The median duration of exposure to KEYTRUDA was 6 months (range: 1 day to 28 months). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In the KEYTRUDA plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with KEYTRUDA versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence in laboratory abnormalities between patients treated with KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. MCC Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.15)], the median duration of exposure to KEYTRUDA was 6.3 months (range 1 day to 28 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%). RCC In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426) The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.16)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren’s syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months). The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80. Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure. Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving Reference ID: 5482742 59 KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426. Table 45: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and Axitinib n=429 Sunitinib n=425 All Grades* (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Diarrhea† 56 11 45 5 Nausea 28 0.9 32 0.9 Constipation 21 0 15 0.2 General Fatigue/Asthenia 52 5 51 10 Vascular Hypertension‡ 48 24 48 20 Hepatobiliary Hepatotoxicity§ 39 20 25 4.9 Endocrine Hypothyroidism 35 0.2 32 0.2 Metabolism and Nutrition Decreased appetite 30 2.8 29 0.7 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 28 5 40 3.8 Stomatitis/Mucosal inflammation 27 1.6 41 4 Rash¶ 25 1.4 21 0.7 Respiratory, Thoracic and Mediastinal Dysphonia 25 0.2 3.3 0 Cough 21 0.2 14 0.5 * Graded per NCI CTCAE v4.03 † Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic ‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension § Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug- induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased ¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash Reference ID: 5482742 60 Table 46: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Axitinib Sunitinib All Grades† % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 62 9 54 3.2 Increased ALT 60 20 44 5 Increased AST 57 13 56 5 Increased creatinine 43 4.3 40 2.4 Hyponatremia 35 8 29 8 Hyperkalemia 34 6 22 1.7 Hypoalbuminemia 32 0.5 34 1.7 Hypercalcemia 27 0.7 15 1.9 Hypophosphatemia 26 6 49 17 Increased alkaline phosphatase 26 1.7 30 2.7 Hypocalcemia‡ 22 0.2 29 0.7 Blood bilirubin increased 22 2.1 21 1.9 Activated partial thromboplastin time prolonged§ 22 1.2 14 0 Hematology Lymphopenia 33 11 47 9 Anemia 29 2.1 65 8 Thrombocytopenia 27 1.4 78 14 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 421 patients). † Graded per NCI CTCAE v4.03 ‡ Corrected for albumin § Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity. In combination with lenvatinib in the first-line treatment of advanced RCC (KEYNOTE-581) The safety of KEYTRUDA was evaluated in KEYNOTE-581 [see Clinical Studies (14.16)]. Patients received KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of KEYTRUDA and lenvatinib was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients treated with KEYTRUDA in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of either of KEYTRUDA, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving KEYTRUDA in combination with lenvatinib; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with lenvatinib. KEYTRUDA was interrupted in 55% of Reference ID: 5482742 61 patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of KEYTRUDA were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%). Fifteen percent (15%) of patients treated with KEYTRUDA in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581. Table 47: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with Lenvatinib N=352 Sunitinib 50 mg N=340 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue* 63 9 56 8 Gastrointestinal Diarrhea† 62 10 50 6 Stomatitis‡ 43 2 43 2 Nausea 36 3 33 1 Abdominal pain§ 27 2 18 1 Vomiting 26 3 20 1 Constipation 25 1 19 0 Musculoskeletal and Connective Tissue Musculoskeletal disorders¶ 58 4 41 3 Endocrine Hypothyroidism# 57 1 32 0 Vascular HypertensionÞ 56 29 43 20 Hemorrhagic eventsß 27 5 26 4 Metabolism Decreased appetiteà 41 4 31 1 Skin and Subcutaneous Tissue Rashè 37 5 17 1 Palmar-plantar erythrodysesthesia syndromeð 29 4 38 4 Investigations Weight loss 30 8 9 0.3 Respiratory, Thoracic and Mediastinal Dysphonia 30 0 4 0 Renal and Urinary Proteinuriaø 30 8 13 3 Acute kidney injuryý 21 5 16 2 Hepatobiliary Hepatotoxicity£ 25 9 21 5 Nervous System Headache 23 1 16 1 * Includes asthenia, fatigue, lethargy, malaise † Includes diarrhea, gastroenteritis ‡ Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, stomatitis § Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain ¶ Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw Reference ID: 5482742 62 # Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism Þ Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure ß Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage à Includes decreased appetite, early satiety è Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular ð Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema ø Includes hemoglobinuria, nephrotic syndrome, proteinuria ý Includes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic £ Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gamma-glutamyltransferase increased Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDA with lenvatinib were myocardial infarction (3%) and angina pectoris (1%). Reference ID: 5482742 63 Table 48: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581 Laboratory Test* KEYTRUDA 200 mg every 3 weeks with Lenvatinib Sunitinib 50 mg All Grades %† Grade 3-4 %† All Grades %† Grade 3-4 %† Chemistry Hypertriglyceridemia 80 15 71 15 Hypercholesterolemia 64 5 43 1 Increased lipase 61 34 59 28 Increased creatinine 61 5 61 2 Increased amylase 59 17 41 9 Increased AST 58 7 57 3 Hyperglycemia 55 7 48 3 Increased ALT 52 7 49 4 Hyperkalemia 44 9 28 6 Hypoglycemia 44 2 27 1 Hyponatremia 41 12 28 9 Decreased albumin 34 0.3 22 0 Increased alkaline phosphatase 32 4 32 1 Hypocalcemia 30 2 22 1 Hypophosphatemia 29 7 50 8 Hypomagnesemia 25 2 15 3 Increased creatine phosphokinase 24 6 36 5 Hypermagnesemia 23 2 22 3 Hypercalcemia 21 1 11 1 Hematology Lymphopenia 54 9 66 15 Thrombocytopenia 39 2 73 13 Anemia 38 3 66 8 Leukopenia 34 1 77 8 Neutropenia 31 4 72 16 * With at least one Grade increase from baseline † Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post- baseline laboratory measurement for each parameter: KEYTRUDA with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients). Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3). Adjuvant treatment of RCC The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.16)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia. Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), Reference ID: 5482742 64 increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 49 and 50 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564. Table 49: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-564 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=488 Placebo n=496 All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal pain‡ 41 1.2 36 0.6 General Fatigue§ 40 1.2 31 0.2 Skin and Subcutaneous Tissue Rash¶ 30 1.4 15 0.4 Pruritus 23 0.2 13 0 Gastrointestinal Diarrhea# 27 2.7 23 0.2 Nausea 16 0.4 10 0 Abdominal painÞ 11 0.4 13 0.2 Endocrine Hypothyroidism 21 0.2 3.6 0 Hyperthyroidism 12 0.2 0.2 0 Respiratory, Thoracic and Mediastinal Cough ß 17 0 12 0 Nervous System Headacheà 15 0.2 13 0 Hepatobiliary Hepatotoxicityè 14 3.7 7 0.6 Renal and Urinary Acute kidney injuryð 13 1.2 10 0.2 * Adverse reactions occurring at same or higher incidence than in placebo arm † Graded per NCI CTCAE v4.0 ‡ Includes arthralgia, back pain, myalgia, arthritis, pain in extremity, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort § Includes asthenia, fatigue ¶ Includes rash, rash maculo-papular, rash papular, skin exfoliation, lichen planus, rash erythematous, eczema, rash macular, dermatitis acneiform, dermatitis, rash pruritic, Stevens-Johnson Syndrome, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome # Includes diarrhea, colitis, enterocolitis, frequent bowel movements, enteritis Þ Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort, gastrointestinal pain ß Includes upper-airway cough syndrome, productive cough, cough à Includes tension headache, headache, sinus headache, migraine with aura è Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, transaminases increased, gamma-glutamyltransferase increased, bilirubin conjugated increased ð Includes acute kidney injury, blood creatinine increased, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic Reference ID: 5482742 65 Table 50: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-564 Laboratory Test† KEYTRUDA 200 mg every 3 weeks Placebo All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 48 8 45 4.5 Increased creatinine 39 1.1 28 0.2 Increased INR 29 1.0 20 0.9 Hyponatremia 21 3.3 13 1.9 Increased ALT 20 3.6 11 0.2 Hematology Anemia 28 0.5 20 0.4 * Laboratory abnormalities occurring at same or higher incidence than placebo † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: KEYTRUDA n=199 and placebo n=224. ‡ Graded per NCI CTCAE v4.03 Endometrial Carcinoma Primary Advanced or Recurrent Endometrial Carcinoma The safety of KEYTRUDA in combination with chemotherapy (paclitaxel and carboplatin) was investigated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial that enrolled patients with advanced or recurrent endometrial carcinoma [see Clinical Studies (14.17)]. A total of 759 patients received KEYTRUDA 200 mg every 3 weeks and chemotherapy for 6 cycles followed by KEYTRUDA 400 mg every 6 weeks for up to 14 cycles (n=382) or placebo and chemotherapy for 6 cycles followed by placebo for up to 14 cycles (n=377). The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 24.0 months). Serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy. Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%), and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Chemotherapy dose reduction was required in 29% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 23% of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone with the exception of rash (33% all Grades; 2.9% Grades 3-4). In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H. The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.17)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325). For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months). Reference ID: 5482742 66 Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%). Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%). Tables 51 and 52 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775. Table 51: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Adverse Reaction KEYTRUDA 200 mg every 3 weeks and Lenvatinib n=342 Doxorubicin or Paclitaxel n=325 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) Endocrine Hypothyroidism† 67 0.9 0.9 0 Vascular Hypertension‡ 67 39 6 2.5 Hemorrhagic events§ 25 2.6 15 0.9 General Fatigue¶ 58 11 54 6 Gastrointestinal Diarrhea# 55 8 20 2.8 Nausea 49 2.9 47 1.5 Vomiting 37 2.3 21 2.2 StomatitisÞ 35 2.6 26 1.2 Abdominal painß 34 2.6 21 1.2 Constipation 27 0 25 0.6 Musculoskeletal and Connective Tissue Musculoskeletal disordersà 53 5 27 0.6 Metabolism Decreased appetiteè 44 7 21 0 Investigations Weight loss 34 10 6 0.3 Renal and Urinary Proteinuriað 29 6 3.4 0.3 Infections Urinary tract infectionø 31 5 13 1.2 Nervous System Headache 26 0.6 9 0.3 Respiratory, Thoracic and Mediastinal Dysphonia 22 0 0.6 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesiaý 23 2.9 0.9 0 Rash£ 20 2.3 4.9 0 * Graded per NCI CTCAE v4.03 † Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, secondary hypothyroidism Reference ID: 5482742 67 ‡ Includes hypertension, blood pressure increased, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, blood pressure fluctuation § Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, melena, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, vessel puncture site bruise ¶ Includes fatigue, asthenia, malaise, lethargy # Includes diarrhea, gastroenteritis Þ Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration ß Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, epigastric discomfort à Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw è Includes decreased appetite, early satiety ð Includes proteinuria, protein urine present, hemoglobinuria ø Includes urinary tract infection, cystitis, pyelonephritis ý Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema £ Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, application site rash Reference ID: 5482742 68 Table 52: Laboratory Abnormalities Worsened from Baseline* Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Laboratory Test† KEYTRUDA 200 mg every 3 weeks and Lenvatinib Doxorubicin or Paclitaxel All Grades‡ % Grades 3-4 % All Grades‡ % Grades 3-4 % Chemistry Hypertriglyceridemia 70 6 45 1.7 Hypoalbuminemia 60 2.7 42 1.6 Increased aspartate aminotransferase 58 9 23 1.6 Hyperglycemia 58 8 45 4.4 Hypomagnesemia 46 0 27 1.3 Increased alanine aminotransferase 55 9 21 1.2 Hypercholesteremia 53 3.2 23 0.7 Hyponatremia 46 15 28 7 Increased alkaline phosphatase 43 4.7 18 0.9 Hypocalcemia 40 4.7 21 1.9 Increased lipase 36 14 13 3.9 Increased creatinine 35 4.7 18 1.9 Hypokalemia 34 10 24 5 Hypophosphatemia 26 8 17 3.2 Increased amylase 25 7 8 1 Hyperkalemia 23 2.4 12 1.2 Increased creatine kinase 19 3.7 7 0 Increased bilirubin 18 3.6 6 1.6 Hematology Lymphopenia 51 18 66 23 Thrombocytopenia 50 8 30 4.7 Anemia 49 8 84 14 Leukopenia 43 3.5 83 43 Neutropenia 34 8 80 60 * With at least one grade increase from baseline † Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post- baseline laboratory measurement for each parameter: KEYTRUDA and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). ‡ Graded per NCI CTCAE v4.03 As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.17)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. TMB-H Cancer The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.18)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Reference ID: 5482742 69 cSCC Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.19)], the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%). TNBC Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The safety of KEYTRUDA in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC. A total of 778 patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.20)]. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months). Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%). Reference ID: 5482742 70 Tables 53 and 54 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522. Table 53: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with chemotherapy/KEYTRUDA n=778 Placebo with chemotherapy/Placebo n=389 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) General Fatigue‡ 70 8 66 3.9 Pyrexia 28 1.3 19 0.3 Gastrointestinal Nausea 67 3.7 66 1.8 Constipation 42 0 39 0.3 Diarrhea 41 3.2 34 1.8 Stomatitis§ 34 2.7 29 1 Vomiting 31 2.7 28 1.5 Abdominal pain¶ 24 0.5 23 0.8 Skin and Subcutaneous Tissue Alopecia 61 0 58 0 Rash# 52 5 41 0.5 Nervous System Peripheral neuropathyÞ 41 3.3 42 2.3 Headache 30 0.5 29 1 Musculoskeletal and Connective Tissue Arthralgia 29 0.5 31 0.3 Myalgia 20 0.5 19 0 Respiratory, Thoracic and Mediastinal Coughß 26 0.1 24 0 Metabolism and Nutrition Decreased appetite 23 0.9 17 0.3 Psychiatric Insomnia 21 0.5 19 0 * Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide † Graded per NCI CTCAE v4.0 ‡ Includes asthenia, fatigue § Includes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oral mucosal eruption, oral pain, stomatitis, tongue blistering, tongue ulceration ¶ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness # Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, incision site rash, injection site rash, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash rubelliform, skin exfoliation, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash Þ Includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy ß Includes cough, productive cough, upper-airway cough syndrome Reference ID: 5482742 71 Table 54: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522 Laboratory Test* KEYTRUDA 200 mg every 3 weeks with chemotherapy†/KEYTRUDA Placebo with chemotherapy†/Placebo All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 97 22 96 19 Leukopenia 93 41 91 32 Neutropenia 88 62 89 62 Lymphopenia 79 28 74 22 Thrombocytopenia 57 10 56 8 Chemistry Increased ALT 70 9 67 3.9 Increased AST 65 6 56 1.5 Hyperglycemia 63 4.3 61 2.8 Increased alkaline phosphatase 37 1 35 0.5 Hyponatremia 35 9 25 4.6 Hypoalbuminemia 34 1.0 30 1.3 Hypocalcemia 31 2.2 28 3.1 Hypokalemia 31 6 22 2.8 Hypophosphatemia 20 6 15 4.2 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA in combination with chemotherapy followed by KEYTRUDA as a single agent (range: 762 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 381 to 389 patients). † Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide † Graded per NCI CTCAE v4.0 Locally Recurrent Unresectable or Metastatic TNBC The safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.20)]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. The median duration of exposure to KEYTRUDA was 5.7 months (range: 1 day to 33.0 months). Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. Serious adverse reactions in ≥2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%). Tables 55 and 56 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355. Reference ID: 5482742 72 Table 55: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with chemotherapy n=596 Placebo every 3 weeks with chemotherapy n=281 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) General Fatigue† 48 5 49 4.3 Gastrointestinal Nausea 44 1.7 47 1.8 Diarrhea 28 1.8 23 1.8 Constipation 28 0.5 27 0.4 Vomiting 26 2.7 22 3.2 Skin and Subcutaneous Tissue Alopecia 34 0.8 35 1.1 Rash‡ 26 2 16 0 Respiratory, Thoracic and Mediastinal Cough§ 23 0 20 0.4 Metabolism and Nutrition Decreased appetite 21 0.8 14 0.4 Nervous System Headache¶ 20 0.7 23 0.7 * Graded per NCI CTCAE v4.03 † Includes fatigue and asthenia ‡ Includes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash, rash erythematous, eyelid rash § Includes cough, productive cough, upper-airway cough syndrome ¶ Includes headache, migraine, tension headache Table 56: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355 Laboratory Test* KEYTRUDA 200 mg every 3 weeks with chemotherapy Placebo every 3 weeks with chemotherapy All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 90 20 85 19 Leukopenia 85 39 86 39 Neutropenia 78 50 79 53 Lymphopenia 73 28 71 19 Thrombocytopenia 54 19 53 21 Chemistry Increased ALT 60 11 58 8 Increased AST 57 9 55 6 Hyperglycemia 52 4.4 51 2.2 Hypoalbuminemia 36 2.0 32 2.2 Increased alkaline phosphatase 35 3.9 39 2.2 Hypocalcemia 29 3.3 27 1.8 Hyponatremia 28 5 26 6 Hypophosphatemia 21 7 18 4.8 Hypokalemia 20 4.4 18 4.0 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients). † Graded per NCI CTCAE v4.03 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of KEYTRUDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 5482742 73 Gastrointestinal: Exocrine pancreatic insufficiency Hepatobiliary: sclerosing cholangitis 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response. 8.2 Lactation Risk Summary There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to KEYTRUDA are unknown. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)]. Contraception KEYTRUDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose. 8.4 Pediatric Use The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, cHL, PMBCL, MCC, MSI-H or dMMR cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1, 14.5, 14.6, 14.8, 14.15, 14.18)]. Reference ID: 5482742 74 In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive or MSI-H solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Laboratory abnormalities that occurred at a ≥10% higher rate in pediatric patients when compared to adults were leukopenia (30%), neutropenia (28%), thrombocytopenia (22%), and Grade 3 anemia (17%). The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)]. 8.5 Geriatric Use Of 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 48% were 65 years and over and 17% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 years and over had a higher incidence of serious adverse reactions (50%) than patients aged younger than 65 years (24%). Clinical studies of KEYTRUDA in cHL did not include sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from that in younger patients. Of 506 adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 596 adult patients with TNBC who were treated with KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 406 adult patients with endometrial carcinoma who were treated with KEYTRUDA in combination with lenvatinib in KEYNOTE-775, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Of the 432 patients randomized to KEYTRUDA in combination with axitinib in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger. Of 292 adult patients with FIGO 2014 Stage III-IVA cervical cancer who were treated with KEYTRUDA in combination with CRT in KEYNOTE-A18, 42 (14%) were 65 years and over. No overall differences in safety or efficacy were observed between elderly and younger patients. 11 DESCRIPTION Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of Reference ID: 5482742 75 solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. In syngeneic mouse tumor models, combination treatment of a PD-1 blocking antibody and kinase inhibitor lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth compared to either treatment alone. 12.2 Pharmacodynamics There are no clinically significant exposure-response relationships for efficacy or safety at pembrolizumab dosages of 200 mg or 2 mg/kg every 3 weeks regardless of cancer type. There are no clinically significant exposure-response relationships for efficacy or safety at pembrolizumab dosages of 200 mg or 2 mg/kg every 3 weeks and 400 mg every 6 weeks in patients with solid tumors based on observed data in adult patients with melanoma. The exposure-response relationships for efficacy or safety at pembrolizumab dosages of 400 mg every 6 weeks in patients with classical Hodgkin lymphoma or mediastinal large B-cell lymphoma have not been fully characterized. 12.3 Pharmacokinetics The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks. Distribution The geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%). Elimination Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t1/2) is 22 days (32%). Specific Populations The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥15 mL/min/1.73 m2), mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST), or tumor burden. The impact of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on the pharmacokinetics of pembrolizumab is unknown. Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (10 months to 17 years) are comparable to those of adults at the same dose. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence Reference ID: 5482742 76 of ADA in the studies described in this section with the incidence of ADA in other studies, including those of KEYTRUDA or of other pembrolizumab products. Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the KEYTRUDA-treated patients with a pembrolizumab concentration below the drug tolerance level of the ADA assay. In clinical studies in patients treated with KEYTRUDA at a dosage of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 27 (2.1%) of 1,289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom 6 (0.5%) patients had neutralizing antibodies against pembrolizumab. There were no identified clinically significant effects of ADA on pembrolizumab pharmacokinetics or on the risk of infusion reactions. Because of the low occurrence of ADA, the effect of these ADA on the effectiveness of KEYTRUDA is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity. Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1/PD-L1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 and PD-L1 knockout mice and mice receiving PD-L1-blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab. 14 CLINICAL STUDIES 14.1 Melanoma Ipilimumab-Naive Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid Reference ID: 5482742 77 Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DoR). The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 66% had no prior systemic therapy for metastatic disease; 69% ECOG PS of 0; 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay; 65% had M1c stage disease; 68% with normal LDH; 36% with reported BRAF mutation- positive melanoma; and 9% with a history of brain metastases. Among patients with BRAF mutation- positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor. The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 57 and Figure 1. Table 57: Efficacy Results in KEYNOTE-006 Endpoint KEYTRUDA 10 mg/kg every 3 weeks n=277 KEYTRUDA 10 mg/kg every 2 weeks n=279 Ipilimumab 3 mg/kg every 3 weeks n=278 OS Deaths (%) 92 (33%) 85 (30%) 112 (40%) Hazard ratio* (95% CI) 0.69 (0.52, 0.90) 0.63 (0.47, 0.83) --- p-Value (stratified log-rank) 0.004 <0.001 --- PFS by BICR Events (%) 157 (57%) 157 (56%) 188 (68%) Median in months (95% CI) 4.1 (2.9, 6.9) 5.5 (3.4, 6.9) 2.8 (2.8, 2.9) Hazard ratio* (95% CI) 0.58 (0.47, 0.72) 0.58 (0.46, 0.72) --- p-Value (stratified log-rank) <0.001 <0.001 --- Best objective response by BICR ORR (95% CI) 33% (27, 39) 34% (28, 40) 12% (8, 16) Complete response rate 6% 5% 1% Partial response rate 27% 29% 10% * Hazard ratio (KEYTRUDA compared to ipilimumab) based on the stratified Cox proportional hazard model Reference ID: 5482742 78 Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006* Based on the final analysis with an additional follow-up of 9 months (total of 383 deaths as pre-specified in the protocol) Ipilimumab-Refractory Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-002 (NCT01704287), a multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of KEYTRUDA in a blinded fashion or investigator’s choice chemotherapy. The treatment arms consisted of KEYTRUDA 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator’s choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every 3 weeks (26%), temozolomide 200 mg/m2 orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 mg/mL/min intravenously plus paclitaxel 225 mg/m2 intravenously every 3 weeks for four cycles then carboplatin AUC of 5 mg/mL/min plus paclitaxel 175 mg/m2 every 3 weeks (25%), paclitaxel 175 mg/m2 intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 mg/mL/min intravenously every 3 weeks (8%). Randomization was stratified by ECOG PS (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received KEYTRUDA until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician’s decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. The major efficacy outcomes were PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Additional efficacy outcome measures were confirmed ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. 0 4 8 12 16 20 24 28 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA 10 mg/kg every 2 weeks KEYTRUDA 10 mg/kg every 3 weeks ipilimumab 278 213 170 145 122 110 28 0 279 249 221 202 176 156 44 0 277 251 215 184 174 156 43 0 Number at Risk KEYTRUDA 10 mg/kg every 2 weeks: KEYTRUDA 10 mg/kg every 3 weeks: ipilimumab: Reference ID: 5482742 79 The study population characteristics were: median age of 62 years (range: 15 to 89), 43% age 65 or older; 61% male; 98% White; and 55% ECOG PS of 0 and 45% ECOG PS of 1. Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease. The study demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared to control arm. There was no statistically significant difference between KEYTRUDA 2 mg/kg and chemotherapy or between KEYTRUDA 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive KEYTRUDA. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 58 and Figure 2. Table 58: Efficacy Results in KEYNOTE-002 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=180 KEYTRUDA 10 mg/kg every 3 weeks n=181 Chemotherapy n=179 PFS Number of Events, n (%) 129 (72%) 126 (70%) 155 (87%) Progression, n (%) 105 (58%) 107 (59%) 134 (75%) Death, n (%) 24 (13%) 19 (10%) 21 (12%) Median in months (95% CI) 2.9 (2.8, 3.8) 2.9 (2.8, 4.7) 2.7 (2.5, 2.8) p-Value (stratified log-rank) <0.001 <0.001 --- Hazard ratio (95% CI) 0.57 (0.45, 0.73) 0.50 (0.39, 0.64) --- OS† Deaths (%) 123 (68%) 117 (65%) 128 (72%) Hazard ratio* (95% CI) 0.86 (0.67, 1.10) 0.74 (0.57, 0.96) --- p-Value (stratified log-rank) 0.117 0.011‡ --- Median in months (95% CI) 13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8) Objective Response Rate ORR (95% CI) 21% (15, 28) 25% (19, 32) 4% (2, 9) Complete response rate 2% 3% 0% Partial response rate 19% 23% 4% * Hazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model † With additional follow-up of 18 months after the PFS analysis ‡ Not statistically significant compared to multiplicity adjusted significance level of 0.01 Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002 0 2 4 6 8 10 12 14 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Progression-Free Survival (%) Treatment arm KEYTRUDA 10 mg/kg every 3 weeks KEYTRUDA 2 mg/kg every 3 weeks Chemotherapy 179 128 43 22 15 4 2 1 180 153 74 53 26 9 4 2 181 158 82 55 39 15 5 1 Number at Risk Chemotherapy: KEYTRUDA 10 mg/kg: KEYTRUDA 2 mg/kg: Reference ID: 5482742 80 Adjuvant Treatment of Resected Stage IIB or IIC Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-716 (NCT03553836), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIB or IIC melanoma. Patients were randomized to KEYTRUDA 200 mg or the pediatric (≥12 years old) dose of KEYTRUDA 2 mg/kg intravenously (up to a maximum of 200 mg) every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by AJCC 8th edition T Stage (>2.0-4.0 mm with ulceration vs. >4.0 mm without ulceration vs. >4.0 mm with ulceration). Patients must not have been previously treated for melanoma beyond complete surgical resection for their melanoma prior to study entry. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) (defined as the time between the date of randomization and the date of first recurrence [local, in-transit or regional lymph nodes or distant recurrence] or death, whichever occurred first). New primary melanomas were excluded from the definition of RFS. Distant metastasis- free survival (DMFS), defined as a spread of tumor to distant organs or distant lymph nodes, was an additional efficacy outcome measure. Patients underwent imaging every six months for one year from randomization, every 6 months from years 2 to 4, and then once in year 5 from randomization or until recurrence, whichever came first. The study population characteristics were: median age of 61 years (range: 16 to 87), 39% age 65 or older; 60% male; 98% White; and 93% ECOG PS of 0 and 7% ECOG PS of 1. Sixty-four percent had Stage IIB and 35% had Stage IIC. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 59 and Figure 3. Table 59: Efficacy Results in KEYNOTE-716 Endpoint KEYTRUDA 200 mg every 3 weeks n=487 Placebo n=489 RFS Number (%) of patients with event 54 (11%) 82 (17%) Median in months (95% CI) NR (22.6, NR) NR (NR, NR) Hazard ratio,† (95% CI) 0.65 (0.46, 0.92) p-Value† 0.0132‡ DMFS Number (%) of patients with event 63 (13%) 95 (19%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratio,† (95% CI) 0.64 (0.47, 0.88) p-Value† 0.0058§ * Based on the stratified Cox proportional hazard model † Based on a log-rank test stratified by American Joint Committee on Cancer 8th edition (AJCC) stage ‡ p-Value is compared with 0.0202 of the allocated alpha for this interim analysis. § p-Value is compared with 0.0256 of the allocated alpha for this interim analysis. NR = not reached Reference ID: 5482742 81 Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-716 Adjuvant Treatment of Stage III Resected Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. New primary melanomas were excluded from the definition of RFS. DMFS in the whole population and in the population with PD-L1 positive tumors were additional efficacy outcome measures. DMFS was defined as a spread of tumor to distant organs or distant lymph nodes. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD- L1 positive melanoma with TPS ≥1% according to an IUO assay. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 60 and Figure 4. Reference ID: 5482742 82 Table 60: Efficacy Results in KEYNOTE-054 Endpoint KEYTRUDA 200 mg every 3 weeks n=514 Placebo n=505 RFS Number (%) of patients with event 135 (26%) 216 (43%) Median in months (95% CI) NR 20.4 (16.2, NR) Hazard ratio,† (95% CI) 0.57 (0.46, 0.70) p-Value† (log-rank) <0.001± DMFS Number (%) of patients with event 173 (34%) 245 (49%) Median in months (95% CI) NR (49.6, NR) 40.0 (27.7, NR) Hazard ratio,† (95% CI) 0.60 (0.49, 0.73) p-Value† (log-rank) <0.0001§ * Based on the stratified Cox proportional hazard model † Stratified by American Joint Committee on Cancer 7th edition (AJCC) stage ± p-Value is compared with 0.016 of the allocated alpha for this interim analysis. § p-Value is compared with 0.028 of the allocated alpha for this analysis. NR = not reached For patients with PD-L1 positive tumors, the RFS HR was 0.54 (95% CI: 0.42, 0.69); p<0.0001. For patients with PD-L1 positive tumors, the DMFS HR was 0.61 (95% CI: 0.49, 0.76); p<0.0001. The RFS and DMFS benefit for KEYTRUDA compared to placebo was observed regardless of tumor PD-L1 expression. Figure 4: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054 14.2 Non-Small Cell Lung Cancer First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active- controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 0 3 6 9 12 15 18 21 24 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Recurrence-Free Survival (%) Treatment arm KEYTRUDA Placebo 514 438 413 392 313 182 73 15 0 505 415 363 323 264 157 60 15 0 Number at Risk KEYTRUDA: Placebo: Reference ID: 5482742 83 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms: • KEYTRUDA 200 mg, pemetrexed 500 mg/m2, and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. • Placebo, pemetrexed 500 mg/m2, and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks. Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 61 and Figure 5 summarize the efficacy results for KEYNOTE-189. Reference ID: 5482742 84 Table 61: Efficacy Results in KEYNOTE-189 Endpoint KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=410 Placebo Pemetrexed Platinum Chemotherapy n=206 OS Number (%) of patients with event 127 (31%) 108 (52%) Median in months (95% CI) NR (NR, NR) 11.3 (8.7, 15.1) Hazard ratio* (95% CI) 0.49 (0.38, 0.64) p-Value† <0.0001 PFS Number of patients with event (%) 245 (60%) 166 (81%) Median in months (95% CI) 8.8 (7.6, 9.2) 4.9 (4.7, 5.5) Hazard ratio* (95% CI) 0.52 (0.43, 0.64) p-Value† <0.0001 Objective Response Rate ORR‡ (95% CI) 48% (43, 53) 19% (14, 25) Complete response 0.5% 0.5% Partial response 47% 18% p-Value§ <0.0001 Duration of Response Median in months (range) 11.2 (1.1+, 18.0+) 7.8 (2.1+, 16.4+) * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response § Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status NR = not reached At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with pemetrexed and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69). Reference ID: 5482742 85 Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189* Based on the protocol-specified final OS analysis First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The efficacy of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi- center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD- L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. • Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks. Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time Reference ID: 5482742 86 of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. An additional efficacy outcome measure was DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel. The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 62 and Figure 6 summarize the efficacy results for KEYNOTE-407. Table 62: Efficacy Results in KEYNOTE-407 Endpoint KEYTRUDA 200 mg every 3 weeks Carboplatin Paclitaxel/Paclitaxel protein-bound n=278 Placebo Carboplatin Paclitaxel/Paclitaxel protein-bound n=281 OS Number of events (%) 85 (31%) 120 (43%) Median in months (95% CI) 15.9 (13.2, NE) 11.3 (9.5, 14.8) Hazard ratio (95% CI) 0.64 (0.49, 0.85) p-Value† 0.0017 PFS Number of events (%) 152 (55%) 197 (70%) Median in months (95% CI) 6.4 (6.2, 8.3) 4.8 (4.2, 5.7) Hazard ratio* (95% CI) 0.56 (0.45, 0.70) p-Value† <0.0001 n=101 n=103 Objective Response Rate‡ ORR (95% CI) 58% (48, 68) 35% (26, 45) Difference (95% CI) 23.6% (9.9, 36.4) p-Value§ 0.0008 Duration of Response‡ Median duration of response in months (range) 7.2 (2.4, 12.4+) 4.9 (2.0, 12.4+) * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ ORR primary analysis and DoR analysis were conducted with the first 204 patients enrolled. § Based on a stratified Miettinen-Nurminen test NE = not estimable At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm was 17.1 months (95% CI: 14.4, 19.9) compared to 11.6 months (95% CI: 10.1, 13.7) in the placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm, with an HR of 0.71 (95% CI: 0.58, 0.88). Reference ID: 5482742 87 Figure 6: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407* Based on the protocol-specified final OS analysis First-line treatment of metastatic NSCLC as a single agent KEYNOTE-042 The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of either of the following platinum-containing chemotherapy regimens: • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies. Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST- defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease Reference ID: 5482742 88 progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC. The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to KEYTRUDA as compared with chemotherapy. Table 63 and Figure 7 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%. Table 63: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042 TPS ≥1% TPS ≥50% Endpoint KEYTRUDA 200 mg every 3 weeks n=637 Chemotherapy n=637 KEYTRUDA 200 mg every 3 weeks n=299 Chemotherapy n=300 OS Number of events (%) 371 (58%) 438 (69%) 157 (53%) 199 (66%) Median in months (95% CI) 16.7 (13.9, 19.7) 12.1 (11.3, 13.3) 20.0 (15.4, 24.9) 12.2 (10.4, 14.2) Hazard ratio (95% CI) 0.81 (0.71, 0.93) 0.69 (0.56, 0.85) p-Value† 0.0036 0.0006 PFS Number of events (%) 507 (80%) 506 (79%) 221 (74%) 233 (78%) Median in months (95% CI) 5.4 (4.3, 6.2) 6.5 (6.3, 7.0) 6.9 (5.9, 9.0) 6.4 (6.1, 6.9) Hazard ratio, ‡ (95% CI) 1.07 (0.94, 1.21) 0.82 (0.68, 0.99) p-Value† -‡ NS§ Objective Response Rate ORR‡ (95% CI) 27% (24, 31) 27% (23, 30) 39% (33.9, 45.3) 32% (26.8, 37.6) Complete response rate 0.5% 0.5% 0.7% 0.3% Partial response rate 27% 26% 39% 32% Duration of Response % with duration ≥12 months¶ 47% 16% 42% 17% % with duration ≥18 months¶ 26% 6% 25% 5% Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test; compared to a p-Value boundary of 0.0291 ‡ Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints § Not significant compared to a p-Value boundary of 0.0291 ¶ Based on observed duration of response The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11). Reference ID: 5482742 89 Figure 7: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%) KEYNOTE-024 The efficacy of KEYTRUDA was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit were eligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of any of the following platinum-containing chemotherapy regimens: • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; • Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; • Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles; • Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles; • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies). Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. 0 6 12 18 24 30 36 42 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA Chemotherapy 637 463 365 214 112 35 2 0 637 485 316 166 88 24 1 0 Number at Risk KEYTRUDA: Chemotherapy: Reference ID: 5482742 90 The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG PS of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression. The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 64 and Figure 8 summarize the efficacy results for KEYNOTE-024. Table 64: Efficacy Results in KEYNOTE-024 Endpoint KEYTRUDA 200 mg every 3 weeks n=154 Chemotherapy n=151 PFS Number (%) of patients with event 73 (47%) 116 (77%) Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2) Hazard ratio* (95% CI) 0.50 (0.37, 0.68) p-Value (stratified log-rank) <0.001 OS Number (%) of patients with event 44 (29%) 64 (42%) Median in months (95% CI)† 30.0 (18.3, NR) 14.2 (9.8, 19.0) Hazard ratio* (95% CI) 0.60 (0.41, 0.89) p-Value (stratified log-rank) 0.005‡ Objective Response Rate ORR (95% CI) 45% (37, 53) 28% (21, 36) Complete response rate 4% 1% Partial response rate 41% 27% p-Value (Miettinen-Nurminen) 0.001 Median duration of response in months (range) NR (1.9+, 14.5+) 6.3 (2.1+, 12.6+) * Based on the stratified Cox proportional hazard model for the interim analysis † Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. ‡ p-Value is compared with 0.0118 of the allocated alpha for the interim analysis NR = not reached Reference ID: 5482742 91 Figure 8: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024* Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. Previously treated NSCLC The efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG PS (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA 2 mg/kg intravenously every 3 weeks, KEYTRUDA 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and DoR in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG PS of 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum- doublet regimen, 29% received two or more prior therapies for their metastatic disease. 0 3 6 9 12 15 18 21 24 27 30 33 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA Chemotherapy 154 136 121 112 106 96 89 83 52 22 5 0 151 123 107 88 80 70 61 55 31 16 5 0 Number at Risk KEYTRUDA: Chemotherapy: Reference ID: 5482742 92 Tables 65 and 66 and Figure 9 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively. Table 65: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=139 KEYTRUDA 10 mg/kg every 3 weeks n=151 Docetaxel 75 mg/m2 every 3 weeks n=152 OS Deaths (%) 58 (42%) 60 (40%) 86 (57%) Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7) Hazard ratio (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) --- p-Value (stratified log-rank) <0.001 <0.001 --- PFS Events (%) 89 (64%) 97 (64%) 118 (78%) Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3) Hazard ratio* (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78) --- p-Value (stratified log-rank) <0.001 <0.001 --- Objective Response Rate ORR† (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13) p-Value (Miettinen-Nurminen) <0.001 <0.001 --- Median duration of response in months (range) NR (0.7+, 16.8+) NR (2.1+, 17.8+) 8.1 (2.1+, 8.8+) * Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model † All responses were partial responses NR = not reached Table 66: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=344 KEYTRUDA 10 mg/kg every 3 weeks n=346 Docetaxel 75 mg/m2 every 3 weeks n=343 OS Deaths (%) 172 (50%) 156 (45%) 193 (56%) Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8) Hazard ratio* (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) --- p-Value (stratified log-rank) <0.001 <0.001 --- PFS Events (%) 266 (77%) 255 (74%) 257 (75%) Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2) Hazard ratio* (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94) --- p-Value (stratified log-rank) 0.068 0.005 --- Objective Response Rate ORR† (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13) p-Value (Miettinen-Nurminen) <0.001 <0.001 --- Median duration of response in months (range) NR (0.7+, 20.1+) NR (2.1+, 17.8+) 6.2 (1.4+, 8.8+) * Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model † All responses were partial responses NR = not reached Reference ID: 5482742 93 Figure 9: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%) Neoadjuvant and adjuvant treatment of resectable NSCLC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial conducted in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or a history of interstitial lung disease or pneumonitis that required steroids were ineligible. Randomization was stratified by stage (II vs. III), tumor PD-L1 expression (TPS ≥50% or <50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms: • Treatment Arm A: neoadjuvant KEYTRUDA 200 mg on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, KEYTRUDA 200 mg was administered every 3 weeks for up to 13 cycles. • Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, placebo was administered every 3 weeks for up to 13 cycles. All study medications were administered via intravenous infusion. Treatment with KEYTRUDA or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumor status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. 0 5 10 15 20 25 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA 2 mg/kg KEYTRUDA 10 mg/kg Docetaxel 343 212 79 33 1 0 344 259 115 49 12 0 346 255 124 56 6 0 Number at Risk KEYTRUDA 2 mg/kg: KEYTRUDA 10 mg/kg: Docetaxel: Reference ID: 5482742 94 The major efficacy outcome measures were OS and investigator-assessed event-free survival (EFS). Additional efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review. The study population characteristics were: median age of 64 years (range: 26 to 83); 45% age 65 or older and 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino; 63% ECOG PS of 0 and 37% ECOG PS of 1. Thirty percent had Stage II and 70% had Stage III disease; 33% had TPS ≥50% and 67% had TPS <50%; 43% had tumors with squamous histology and 57% had tumors with non-squamous histology; 31% were from the East Asian region. Eighty-one percent of patients in the KEYTRUDA in combination with platinum-containing chemotherapy arm received definitive surgery compared to 76% of patients in the placebo in combination with platinum-containing chemotherapy arm. The trial demonstrated statistically significant improvements in OS and EFS for patients randomized to KEYTRUDA in combination with platinum-containing chemotherapy followed by KEYTRUDA as a single agent compared with patients randomized to placebo in combination with platinum-containing chemotherapy followed by placebo alone. Table 67 and Figure 10 summarize the efficacy results for KEYNOTE-671. Table 67: Efficacy Results in KEYNOTE-671 Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy/KEYTRUDA n=397 Placebo with chemotherapy/Placebo n=400 OS Number of patients with event (%) 110 (28%) 144 (36%) Median in months* (95% CI) NR (NR, NR) 52.4 (45.7, NR) Hazard ratio† (95% CI) 0.72 (0.56, 0.93) p-Value‡,§ 0.0103 EFS Number of patients with event (%) 139 (35%) 205 (51%) Median in months* (95% CI) NR (34.1, NR) 17.0 (14.3, 22.0) Hazard ratio† (95% CI) 0.58 (0.46, 0.72) p-Value‡,¶ <0.0001 * Based on Kaplan-Meier estimates † Based on Cox regression model with treatment as a covariate stratified by stage, tumor PD-L1 expression, histology, and geographic region ‡ Based on stratified log-rank test § Compared to a two-sided p-Value boundary of 0.0109 ¶ Compared to a two-sided p-Value boundary of 0.0092 NR = not reached Reference ID: 5482742 95 Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-671 The trial demonstrated a statistically significant difference in pCR rate (18.1% vs. 4.0%; p<0.0001) and mPR rate (30.2% vs. 11.0%; p<0.0001). Adjuvant treatment of resected NSCLC The efficacy of KEYTRUDA was investigated in KEYNOTE-091 (NCT02504372), a multicenter, randomized, triple-blind, placebo-controlled trial conducted in 1177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC by AJCC 7th edition. Patients had not received neoadjuvant radiotherapy or chemotherapy. Adjuvant chemotherapy up to 4 cycles was optional. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. Randomization was stratified by stage (IB vs. II vs. IIIA), receipt of adjuvant chemotherapy (yes vs. no), PD-L1 status (TPS <1% [negative] vs. TPS 1-49% vs. TPS ≥50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomized (1:1) to receive KEYTRUDA 200 mg or placebo intravenously every 3 weeks. Treatment continued until RECIST v1.1-defined disease recurrence as determined by the investigator, unacceptable toxicity or up to one year. Tumor assessments were conducted every 12 weeks for the first year, then every 6 months for years 2 to 3, and then annually through year 5. After year 5, imaging was Overall Survival (%) Number at Risk KEYTRUDA Control Treatment arm KEYTRUDA Control Time in Months Reference ID: 5482742 96 performed as per local standard of care. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). An additional efficacy outcome measure was OS. Of 1177 patients randomized, 1010 (86%) received adjuvant platinum-based chemotherapy following resection. Among these 1010 patients, the median age was 64 years (range: 35 to 84), 49% age 65 or older; 68% male; 77% White, 18% Asian; 86% current or former smokers; and 39% with ECOG PS of 1. Eleven percent had Stage IB, 57% had Stage II, and 31% had Stage IIIA disease. Thirty-nine percent had PD-L1 TPS <1% [negative], 33% had TPS 1-49%, and 28% had TPS ≥50%. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World. The trial met its primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population for patients randomized to the KEYTRUDA arm compared to patients randomized to the placebo arm. In an exploratory subgroup analysis of the 167 patients (14%) who did not receive adjuvant chemotherapy, the DFS HR was 1.25 (95% CI: 0.76, 2.05). OS results were not mature with only 42% of pre-specified OS events in the overall population. Table 68 and Figure 11 summarize the efficacy results for KEYNOTE-091 in patients who received adjuvant chemotherapy. Table 68: Efficacy Results in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy Endpoint KEYTRUDA 200 mg every 3 weeks n=506 Placebo n=504 DFS Number (%) of patients with event 177 (35%) 231 (46%) Median in months (95% CI) 58.7 (39.2, NR) 34.9 (28.6, NR) Hazard ratio* (95% CI) 0.73 (0.60, 0.89) * Based on the unstratified univariate Cox regression model NR = not reached Reference ID: 5482742 97 Figure 11: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy 14.3 Malignant Pleural Mesothelioma First-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma (MPM) with pemetrexed and platinum chemotherapy The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-483 (NCT02784171), a multicenter, randomized, open-label, active-controlled trial that enrolled 440 patients with unresectable advanced or metastatic MPM and no prior systemic therapy for advanced/metastatic disease. Patients were enrolled regardless of tumor PD-L1 expression. Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by histological subtype (epithelioid vs. non-epithelioid). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. Treatment arm KEYTRUDA Placebo Disease-Free Survival (%) Time in Months Number at Risk KEYTRUDA Placebo Reference ID: 5482742 98 • Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles. Treatment with KEYTRUDA continued until disease progression as determined by the investigator according to modified RECIST 1.1 for mesothelioma (mRECIST), unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks for 18 weeks, followed by every 12 weeks thereafter. The main efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR, and DoR, as assessed by BICR according to mRECIST. The study population characteristics were: median age of 70 years (77% age 65 or older); 76% male; 79% White, 21% race not reported or unknown; 2% Hispanic or Latino; and 53% ECOG performance status of 1. Seventy-eight percent had epithelioid and 22% had non-epithelioid histology; 60% had tumors with PD-L1 CPS ≥1 and 30% had tumors with PD-L1 CPS <1. The trial demonstrated a statistically significant improvement in OS, PFS, and ORR in patients randomized to KEYTRUDA in combination with chemotherapy compared with patients randomized to chemotherapy alone. Table 69 and Figure 12 summarize the efficacy results for KEYNOTE-483. Table 69: Efficacy Results in KEYNOTE-483 Endpoint KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy (n=222) Pemetrexed Platinum Chemotherapy (n=218) OS Number (%) of patients with event 167 (75%) 175 (80%) Median in months (95% CI) 17.3 (14.4, 21.3) 16.1 (13.1, 18.2) Hazard ratio* (95% CI) 0.79 (0.64, 0.98) p-Value† 0.0162 PFS Number (%) of patients with event 190 (86%) 166 (76%) Median in months (95% CI) 7.1 (6.9, 8.1) 7.1 (6.8, 7.7) Hazard ratio* (95% CI) 0.80 (0.65, 0.99) p-Value† 0.0194 Objective Response Rate ORR % (95% CI) 52% (45.5, 59.0) 29% (23.0, 35.4) Complete responses 1 (0.5%) 0 (0%) Partial responses 115 (52%) 63 (29%) p-Value‡ <0.00001 Duration of Response§ Median in months (95% CI) 6.9 (5.8, 8.3) 6.8 (5.5, 8.5) * Based on stratified Cox proportional hazard model † Based on stratified log-rank test ‡ Based on Miettinen and Nurminen method stratified by histological subtype at randomization (epithelioid vs. non-epithelioid) § Based on patients with a best overall response as confirmed complete or partial response; n=116 for patients in the KEYTRUDA combination arm; n=63 for patients in the chemotherapy arm Reference ID: 5482742 99 Figure 12: Kaplan-Meier Curve for Overall Survival in KEYNOTE-483 In a pre-specified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology (n=345), the hazard ratio (HR) for OS was 0.89 (95% CI: 0.70, 1.13), with median OS of 19.8 months in KEYTRUDA in combination with chemotherapy and 18.2 months in chemotherapy alone. In the subgroup of patients with non-epithelioid histology (n=95), the HR for OS was 0.57 (95% CI: 0.36, 0.89), with median OS of 12.3 months in KEYTRUDA in combination with chemotherapy and 8.2 months in chemotherapy alone. 14.4 Head and Neck Squamous Cell Cancer First-line treatment of metastatic or unresectable, recurrent HNSCC The efficacy of KEYTRUDA was investigated in KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (TPS ≥50% or <50%) according to the Treatment arm KEYTRUDA + Chemotherapy Control Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemotherapy Control Reference ID: 5482742 100 PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks • KEYTRUDA 200 mg intravenously every 3 weeks, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) • Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population. The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% had ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients’ tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20. The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population. Table 70 and Figure 13 summarize efficacy results for KEYTRUDA in combination with chemotherapy. Reference ID: 5482742 101 Table 70: Efficacy Results* for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048 Endpoint KEYTRUDA 200 mg every 3 weeks Platinum FU n=281 Cetuximab Platinum FU n=278 OS Number (%) of patients with event 197 (70%) 223 (80%) Median in months (95% CI) 13.0 (10.9, 14.7) 10.7 (9.3, 11.7) Hazard ratio† (95% CI) 0.77 (0.63, 0.93) p-Value‡ 0.0067 PFS Number of patients with event (%) 244 (87%) 253 (91%) Median in months (95% CI) 4.9 (4.7, 6.0) 5.1 (4.9, 6.0) Hazard ratio† (95% CI) 0.92 (0.77, 1.10) p-Value‡ 0.3394 Objective Response Rate ORR§ (95% CI) 36% (30.0, 41.5) 36% (30.7, 42.3) Complete response rate 6% 3% Partial response rate 30% 33% Duration of Response Median in months (range) 6.7 (1.6+, 30.4+) 4.3 (1.2+, 27.9+) * Results at a pre-specified interim analysis † Based on the stratified Cox proportional hazard model ‡ Based on stratified log-rank test § Response: Best objective response as confirmed complete response or partial response At the pre-specified final OS analysis for the ITT population, the hazard ratio was 0.72 (95% CI: 0.60, 0.87). In addition, KEYNOTE-048 demonstrated a statistically significant improvement in OS for the subgroups of patients with PD-L1 CPS ≥1 (HR=0.65, 95% CI: 0.53, 0.80) and CPS ≥20 (HR=0.60, 95% CI: 0.45, 0.82). Reference ID: 5482742 102 Figure 13: Kaplan-Meier Curve for Overall Survival for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048* * At the time of the protocol-specified final analysis. The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to KEYTRUDA as a single agent compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis. At the time of the interim and final analyses, there was no significant difference in OS between the KEYTRUDA single agent arm and the control arm for the overall population. Table 71 summarizes efficacy results for KEYTRUDA as a single agent in the subgroups of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC. Figure 14 summarizes the OS results in the subgroup of patients with CPS ≥1 HNSCC. 0 5 10 15 20 25 30 35 40 45 50 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA + Chemo Standard 281 227 169 122 94 77 55 29 5 0 0 278 227 147 100 66 45 23 6 1 0 0 Number at Risk KEYTRUDA + Chemo: Standard: Reference ID: 5482742 103 Table 71: Efficacy Results* for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20) Endpoint CPS ≥1 CPS ≥20 KEYTRUDA 200 mg every 3 weeks n=257 Cetuximab Platinum FU n=255 KEYTRUDA 200 mg every 3 weeks n=133 Cetuximab Platinum FU n=122 OS Number of events (%) 177 (69%) 206 (81%) 82 (62%) 95 (78%) Median in months (95% CI) 12.3 (10.8, 14.9) 10.3 (9.0, 11.5) 14.9 (11.6, 21.5) 10.7 (8.8, 12.8) Hazard ratio† (95% CI) 0.78 (0.64, 0.96) 0.61 (0.45, 0.83) p-Value‡ 0.0171 0.0015 PFS Number of events (%) 225 (88%) 231 (91%) 113 (85%) 111 (91%) Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 5.8) 3.4 (3.2, 3.8) 5.0 (4.8, 6.2) Hazard ratio† (95% CI) 1.15 (0.95, 1.38) 0.97 (0.74, 1.27) Objective Response Rate ORR§ (95% CI) 19% (14.5, 24.4) 35% (29.1, 41.1) 23% (16.4, 31.4) 36% (27.6, 45.3) Complete response rate 5% 3% 8% 3% Partial response rate 14% 32% 16% 33% Duration of Response Median in months (range) 20.9 (1.5+, 34.8+) 4.5 (1.2+, 28.6+) 20.9 (2.7, 34.8+) 4.2 (1.2+, 22.3+) * Results at a pre-specified interim analysis † Based on the stratified Cox proportional hazard model ‡ Based on a stratified log-rank test § Response: Best objective response as confirmed complete response or partial response At the pre-specified final OS analysis comparing KEYTRUDA as a single agent to cetuximab in combination with chemotherapy, the hazard ratio for the subgroup of patients with CPS ≥1 was 0.74 (95% CI: 0.61, 0.90) and the hazard ratio for the subgroup of patients with CPS ≥20 was 0.58 (95% CI: 0.44, 0.78). In an exploratory subgroup analysis for patients with CPS 1-19 HNSCC at the time of the pre-specified final OS analysis, the median OS was 10.8 months (95% CI: 9.0, 12.6) for KEYTRUDA as a single agent and 10.1 months (95% CI: 8.7, 12.1) for cetuximab in combination with chemotherapy, with an HR of 0.86 (95% CI: 0.66, 1.12). Reference ID: 5482742 104 Figure 14: Kaplan-Meier Curve for Overall Survival for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1)* * At the time of the protocol-specified final analysis. Previously treated recurrent or metastatic HNSCC The efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), a multicenter, non- randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible. Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. The study population characteristics were median age of 60 years, 32% age 65 or older; 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2. 0 5 10 15 20 25 30 35 40 45 50 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA Standard 257 197 152 110 91 70 43 21 13 1 0 255 207 131 89 59 40 21 9 5 0 0 Number at Risk KEYTRUDA: Standard: Reference ID: 5482742 105 The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median DoR had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and DoR were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status. 14.5 Classical Hodgkin Lymphoma KEYNOTE-204 The efficacy of KEYTRUDA was investigated in KEYNOTE-204 (NCT02684292), a randomized, open- label, active controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized (1:1) to receive: • KEYTRUDA 200 mg intravenously every 3 weeks or • Brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks Treatment was continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (up to approximately 2 years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse <12 months after completion vs. relapse ≥12 months after completion). The main efficacy measure was PFS as assessed by BICR using 2007 revised International Working Group criteria. The study population characteristics were: median age of 35 years (range: 18 to 84); 57% male; 77% White, 9% Asian, 3.9% Black. The median number of prior therapies was 2 (range: 1 to 10) in the KEYTRUDA arm and 3 (range: 1 to 11) in the BV arm, with 18% in both arms having 1 prior line. Forty- two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy. Efficacy is summarized in Table 72 and Figure 15. Table 72: Efficacy Results in Patients with cHL in KEYNOTE-204 Endpoint KEYTRUDA 200 mg every 3 weeks n=151 Brentuximab Vedotin 1.8 mg/kg every 3 weeks n=153 PFS Number of patients with event (%) 81 (54%) 88 (58%) Median in months (95% CI)* 13.2 (10.9, 19.4) 8.3 (5.7, 8.8) Hazard ratio† (95% CI) 0.65 (0.48, 0.88) p-Value‡ 0.0027 Objective Response Rate ORR§ (95% CI) 66% (57, 73) 54% (46, 62) Complete response 25% 24% Partial response 41% 30% Duration of Response Median in months (range)* 20.7 (0.0+, 33.2+) 13.8 (0.0+, 33.9+) * Based on Kaplan-Meier estimates. † Based on the stratified Cox proportional hazard model. ‡ Based on a stratified log-rank test. One-sided p-Value, with a prespecified boundary of 0.0043. § Difference in ORR is not statistically significant. + Denotes a censored value. Reference ID: 5482742 106 Figure 15: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-204 KEYNOTE-087 The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), a multicenter, non- randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non- infectious pneumonitis, an allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria. The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior autologous HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy. Efficacy results for KEYNOTE-087 are summarized in Table 73. Reference ID: 5482742 107 Table 73: Efficacy Results in Patients with cHL in KEYNOTE-087 Endpoint KEYTRUDA 200 mg every 3 weeks n=210* Objective Response Rate ORR (95% CI) 69% (62, 75) Complete response rate 22% Partial response rate 47% Duration of Response Median in months (range) 11.1 (0.0+, 11.1)† * Median follow-up time of 9.4 months † Based on patients (n=145) with a response by independent review 14.6 Primary Mediastinal Large B-Cell Lymphoma The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open- label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR. The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy. For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 74. Table 74: Efficacy Results in Patients with PMBCL in KEYNOTE-170 Endpoint KEYTRUDA 200 mg every 3 weeks n=53* Objective Response Rate ORR (95% CI) 45% (32, 60) Complete response rate 11% Partial response rate 34% Duration of Response Median in months (range) NR (1.1+, 19.2+)† * Median follow-up time of 9.7 months † Based on patients (n=24) with a response by independent review NR = not reached 14.7 Urothelial Cancer In Combination with Enfortumab Vedotin for the Treatment of Patients with Urothelial Cancer The efficacy of KEYTRUDA in combination with enfortumab vedotin was evaluated in KEYNOTE-A39 (NCT04223856), an open-label, randomized, multicenter trial that enrolled 886 patients with locally advanced or metastatic urothelial cancer who received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded. Patients were randomized 1:1 to receive either: Reference ID: 5482742 108 • KEYTRUDA 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. KEYTRUDA was given approximately 30 minutes after enfortumab vedotin. Treatment was continued until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, KEYTRUDA was continued for up to 2 years. • Gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m2 or carboplatin (AUC = 4.5 or 5) on Day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity for up to 6 cycles. Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases. The median age was 69 years (range: 22 to 91); 77% were male; 67% were White, 22% were Asian, 1% were Black or African American, and 10% were unknown or other; 12% were Hispanic or Latino. Patients had a baseline ECOG performance status of 0 (49%), 1 (47%), or 2 (3%). Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% of patients had metastatic urothelial cancer, including 72% with visceral and 22% with liver metastases, and 5% had locally advanced urothelial cancer. Eighty-five percent of patients had urothelial carcinoma (UC) histology including 6% with UC mixed squamous differentiation and 2% with UC mixed other histologic variants. Forty-six percent of patients were considered cisplatin-ineligible and 54% were considered cisplatin-eligible at time of randomization. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR. The trial demonstrated statistically significant improvements in OS, PFS, and ORR for patients randomized to KEYTRUDA in combination with enfortumab vedotin as compared to platinum-based chemotherapy. Efficacy results were consistent across all stratified patient subgroups. Table 75 and Figures 16 and 17 summarize the efficacy results for KEYNOTE-A39. Table 75: Efficacy Results in KEYNOTE-A39 Endpoint KEYTRUDA 200 mg every 3 weeks in combination with Enfortumab Vedotin n=442 Cisplatin or carboplatin with gemcitabine n=444 OS Number (%) of patients with event 133 (30%) 226 (51%) Median in months (95% CI) 31.5 (25.4, NR) 16.1 (13.9, 18.3) Hazard ratio* (95% CI) 0.47 (0.38, 0.58) p-Value† <0.0001 PFS Number (%) of patients with event 223 (50%) 307 (69%) Median in months (95% CI) 12.5 (10.4, 16.6) 6.3 (6.2, 6.5) Hazard ratio* (95% CI) 0.45 (0.38, 0.54) p-Value† <0.0001 Confirmed Objective Response Rate‡ ORR§ % (95% CI) 68% (63, 72) 44% (40, 49) p-Value¶ <0.0001 Complete response 29% 12% Partial response 39% 32% * Based on the stratified Cox proportional hazard regression model † Two-sided p-Value based on stratified log-rank test ‡ Includes only patients with measurable disease at baseline (n=437 for KEYTRUDA in combination with enfortumab vedotin, n=441 for chemotherapy). § Based on patients with a best overall response as confirmed complete or partial response ¶ Two-sided p-Value based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility and liver metastases NR = not reached Reference ID: 5482742 109 Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-A39 Treatment arm KEYTRUDA + EV Chemotherapy Overall Survival (%) Time in Months Number at Risk KEYTRUDA + EV Chemotherapy Reference ID: 5482742 110 Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A39 In Combination with Enfortumab Vedotin for the Treatment of Cisplatin-Ineligible Patients with Urothelial Cancer The efficacy of KEYTRUDA in combination with enfortumab vedotin was evaluated in KEYNOTE-869 (NCT03288545), an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded from participating in the study. Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received enfortumab vedotin 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by KEYTRUDA 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients were treated until disease progression or unacceptable toxicity. A total of 121 patients received KEYTRUDA in combination with enfortumab vedotin. The median age was 71 years (range: 51 to 91); 74% were male; 85% were White, 5% were Black, 4% were Asian and 6% were other, unknown or not reported. Ten percent of patients were Hispanic or Latino. Forty-five Treatment arm KEYTRUDA + EV Chemotherapy Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA + EV Chemotherapy Reference ID: 5482742 111 percent of patients had an ECOG performance status of 1 and 15% had an ECOG performance status of 2. Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. Reasons for cisplatin-ineligibility included: 60% with baseline creatinine clearance of 30-59 mL/min, 10% with ECOG PS of 2, 13% with Grade 2 or greater hearing loss, and 16% with more than one cisplatin-ineligibility criteria. At baseline, 97.5% of patients had metastatic urothelial cancer and 2.5% of patients had locally advanced urothelial cancer. Thirty-seven percent of patients had upper tract disease. Eighty-four percent of patients had visceral metastasis at baseline, including 22% with liver metastases. Thirty-nine percent of patients had TCC histology; 13% had TCC with squamous differentiation, and 48% had TCC with other histologic variants. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1. The median follow-up time for the dose escalation cohort + Cohort A was 44.7 months (range 0.7 to 52.4) and for Cohort K was 14.8 months (range: 0.6 to 26.2). Efficacy results are presented in Table 76 below. Table 76: Efficacy Results in KEYNOTE-869, Combined Dose Escalation Cohort, Cohort A, and Cohort K Endpoint KEYTRUDA in combination with Enfortumab Vedotin n=121 Confirmed ORR (95% CI) 68% (58.7, 76.0) Complete response rate 12% Partial response rate 55% The median duration of response for the dose escalation cohort + Cohort A was 22.1 months (range: 1.0+ to 46.3+) and for Cohort K was not reached (range: 1.2 to 24.1+). Platinum-Ineligible Patients with Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open- label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities, including patients who were not eligible for any platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 74 years; 77% male; and 89% White. Eighty- seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Fifty percent of patients had baseline creatinine clearance of <60 mL/min, 32% had ECOG PS of 2, 9% had ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% had one or more of Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss. Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. The median follow-up time for 370 patients treated with KEYTRUDA was 11.4 months (range 0.1 to 63.8 months). Efficacy results are summarized in Table 77. Reference ID: 5482742 112 Table 77: Efficacy Results in KEYNOTE-052 Endpoint KEYTRUDA 200 mg every 3 weeks All Subjects n=370 Objective Response Rate ORR (95% CI) 29% (24, 34) Complete response rate 10% Partial response rate 20% Duration of Response Median in months (range) 33.4 (1.4+, 60.7+) + Denotes ongoing response Platinum-Eligible Patients with Previously Untreated Urothelial Carcinoma The efficacy of KEYTRUDA for the first-line treatment of platinum-eligible patients with locally advanced or metastatic urothelial carcinoma was investigated in KEYNOTE-361 (NCT02853305), a multicenter, randomized, open-label, active-controlled study in 1010 previously untreated patients. The safety and efficacy of KEYTRUDA in combination with platinum-based chemotherapy for previously untreated patients with locally advanced or metastatic urothelial carcinoma has not been established. The study compared KEYTRUDA with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. Among the patients receiving KEYTRUDA plus platinum-based chemotherapy, 44% received cisplatin and 56% received carboplatin. The study did not meet its major efficacy outcome measures of improved PFS or OS in the KEYTRUDA plus chemotherapy arm compared to the chemotherapy-alone arm. Additional efficacy endpoints, including improvement of OS in the KEYTRUDA monotherapy arm, could not be formally tested. Previously Treated Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients were randomized to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=90), docetaxel 75 mg/m2 (n=92), or vinflunine 320 mg/m2 (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. The study population characteristics were: median age of 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0 and 56% ECOG PS of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum- containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens. Reference ID: 5482742 113 The study demonstrated statistically significant improvements in OS and ORR for patients randomized to KEYTRUDA as compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 78 and Figure 18 summarize the efficacy results for KEYNOTE-045. Table 78: Efficacy Results in KEYNOTE-045 KEYTRUDA 200 mg every 3 weeks n=270 Chemotherapy n=272 OS Deaths (%) 155 (57%) 179 (66%) Median in months (95% CI) 10.3 (8.0, 11.8) 7.4 (6.1, 8.3) Hazard ratio* (95% CI) 0.73 (0.59, 0.91) p-Value (stratified log-rank) 0.004 PFS by BICR Events (%) 218 (81%) 219 (81%) Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.3, 3.5) Hazard ratio* (95% CI) 0.98 (0.81, 1.19) p-Value (stratified log-rank) 0.833 Objective Response Rate ORR (95% CI) 21% (16, 27) 11% (8, 16) Complete response rate 7% 3% Partial response rate 14% 8% p-Value (Miettinen-Nurminen) 0.002 Median duration of response in months (range) NR (1.6+, 15.6+) 4.3 (1.4+, 15.4+) * Hazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model + Denotes ongoing response NR = not reached Figure 18: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045 0 2 4 6 8 10 12 14 16 18 20 22 24 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA Chemotherapy 272 232 171 138 109 89 55 27 14 3 0 0 0 270 226 194 169 147 131 87 54 27 13 4 0 0 Number at Risk KEYTRUDA: Chemotherapy: Reference ID: 5482742 114 BCG-unresponsive High-Risk Non-Muscle Invasive Bladder Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-057 (NCT02625961), a multicenter, open- label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non- muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor- free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The study population characteristics were: median age of 73 years (range: 44 to 92); 44% age ≥75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12. The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarized in Table 79. Table 79: Efficacy Results in KEYNOTE-057 Endpoint KEYTRUDA 200 mg every 3 weeks n=96 Complete Response Rate (95% CI) 41% (31, 51) Duration of Response* Median in months (range) 16.2 (0.0+, 30.4+) % (n) with duration ≥12 months 46% (18) * Based on patients (n=39) that achieved a complete response; reflects period from the time complete response was achieved + Denotes ongoing response 14.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer The efficacy of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancers enrolled in three multicenter, non-randomized, open-label, multi-cohort trials: KEYNOTE-164 (NCT02460198), KEYNOTE-158 (NCT02628067), and KEYNOTE-051 (NCT02332668). All trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumor status was determined using polymerase chain reaction (PCR; local or central) or immunohistochemistry (IHC; local or central), respectively. • KEYNOTE-164 enrolled 124 patients with advanced MSI-H or dMMR colorectal cancer (CRC) that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan +/- anti-VEGF/EGFR mAb-based therapy. • KEYNOTE-158 enrolled 373 patients with advanced MSI-H or dMMR non-colorectal cancers (non-CRC) who had disease progression following prior therapy. Patients were either prospectively Reference ID: 5482742 115 enrolled with MSI-H/dMMR tumors (Cohort K) or retrospectively identified in one of 10 solid tumor cohorts (Cohorts A-J). • KEYNOTE-051 enrolled 7 pediatric patients with MSI-H or dMMR cancers. Adult patients received KEYTRUDA 200 mg every 3 weeks (pediatric patients received 2 mg/kg every 3 weeks) until unacceptable toxicity, disease progression, or a maximum of 24 months. In KEYNOTE-164 and KEYNOTE-158, assessment of tumor status was performed every 9 weeks through the first year, then every 12 weeks thereafter. In KEYNOTE-051, assessment of tumor status was performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST v1.1 in KEYNOTE-051. In KEYNOTE-164 and KEYNOTE-158, the study population characteristics were median age of 60 years, 36% age 65 or older; 44% male; 78% White, 14% Asian, 4% American Indian or Alaska Native, and 3% Black; and 45% ECOG PS of 0 and 55% ECOG PS of 1. Ninety-two percent of patients had metastatic disease and 4% had locally advanced, unresectable disease. Thirty-seven percent of patients received one prior line of therapy and 61% received two or more prior lines of therapy. In KEYNOTE-051, the study population characteristics were median age of 11 years (range: 3 to 16); 71% female; 86% White and 14% Asian; and 57% had a Lansky/Karnofsky Score of 100. Seventy-one percent of patients had Stage IV and 14% had Stage III disease. Fifty-seven percent of patients received one prior line of therapy and 29% received two prior lines of therapy. Discordant results were observed between local MSI-H or dMMR tests and central testing among patients enrolled in Cohort K of KEYNOTE-158. Among 104 tumor samples that were MSI-H or dMMR by local testing and also tested using the FoundationOne®CDx (F1CDx) test, 59 (56.7%) were MSI-H and 45 (43.3%) were not MSI-H. Among 169 tumor samples that were MSI-H or dMMR by local testing and also tested using the VENTANA MMR RxDx Panel, 105 (62.1%) were dMMR and 64 (37.9%) were pMMR. Efficacy results are summarized in Tables 80 and 81. Table 80: Efficacy Results for Patients with MSI-H/dMMR Cancer Endpoint KEYTRUDA n=504* Objective Response Rate ORR (95% CI)† 33.3% (29.2, 37.6) Complete response rate 10.3% Partial response rate 23.0% Duration of Response n=168 Median in months (range) 63.2 (1.9+, 63.9+) % with duration ≥12 months 77% % with duration ≥36 months 39% * Median follow-up time of 20.1 months (range 0.1 to 71.4 months) † Of the 7 pediatric patients from KEYNOTE-051, 1 patient had a radiographic complete response after initial growth of their tumor but is not reflected in the results. + Denotes ongoing response Reference ID: 5482742 116 Table 81: Response by Tumor Type Objective Response Rate Duration of Response range N n (%) 95% CI (months) CRC 124 42 (34%) (26%, 43%) (4.4, 58.5+) Non-CRC* 380 126 (33%) (28%, 38%) (1.9+, 63.9+) Endometrial cancer 94 47 (50%) (40%, 61%) (2.9, 63.2) Gastric or GE junction cancer 51 20 (39%) (26%, 54%) (1.9+, 63.0+) Small intestinal cancer 27 16 (59%) (39%, 78%) (3.7+, 57.3+) Brain cancer 27† 1 (4%)‡ (0%, 19%) 18.9 Ovarian cancer 25 8 (32%) (15%, 54%) (4.2, 56.6+) Biliary cancer 22 9 (41%) (21%, 64%) (6.2, 49.0+) Pancreatic cancer 22 4 (18%) (5%, 40%) (8.1, 24.3+) Sarcoma 14 3 (21%) (5%, 51%) (35.4+, 57.2+) Breast cancer 13 1 (8%) (0%,36%) 24.3+ Other§ 13 4 (31%) (9%, 61%) (6.2+, 32.3+) Cervical cancer 11 1 (9%) (0%, 41%) 63.9+ Neuroendocrine cancer 11 1 (9%) (0%, 41%) 13.3 Prostate cancer 8 1 (13%) (0%, 53%) 24.5+ Adrenocortical cancer 7 1 (14%) (0%, 58%) 4.2 Mesothelioma 7 0 (0%) (0%, 41%) Thyroid cancer 7 1 (14%) (0%, 58%) 8.2 Small cell lung cancer 6 2 (33%) (4%, 78%) (20.0, 47.5) Bladder cancer 6 3 (50%) (12%, 88%) (35.6+, 57.5+) Salivary cancer 5 2 (40%) (5%, 85%) (42.6+, 57.8+) Renal cell cancer 4 1 (25%) (0%, 81%) 22.0 * Results include patients in Cohort K of KEYNOTE-158 that were later determined to be pMMR or not MSI-H by central testing † Includes 6 pediatric patients with brain cancer ‡ In addition to the 1 adult responder, 1 pediatric patient had a radiographic complete response after initial growth of their tumor. § Includes tumor type (n): anal (3), HNSCC (1), nasopharyngeal (1), retroperitoneal (1), testicular (1), vaginal (1), vulvar (1), appendiceal adenocarcinoma, NOS (1), hepatocellular carcinoma (1), and carcinoma of unknown origin (1). Includes 1 pediatric patient with abdominal adenocarcinoma. + Denotes ongoing response Exploratory analysis by TMB In an exploratory analysis performed in 138 patients (Cohort K of KEYNOTE-158) who were tested retrospectively for tumor mutation burden (TMB) using an FDA-approved test, 45 (33%) had tumors with TMB score of <10 mut/Mb; ORR in these 45 patients was 6.7% (95% CI: 1.4, 18.3). Among the 45 patients with TMB score of <10 mut/Mb, 39 of the patients were not MSI-H/dMMR when tested using an FDA-approved test. 14.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-177 (NCT02563002), a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC. MSI or MMR tumor status was determined locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of the following chemotherapy regimens given intravenously every 2 weeks: • mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly. • FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly. Reference ID: 5482742 117 Treatment with KEYTRUDA or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measures were PFS (as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) and OS. Additional efficacy outcome measures were ORR and DoR. A total of 307 patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range: 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an ECOG PS of 0 and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among 154 patients randomized to receive chemotherapy,143 received chemotherapy per the protocol. Of the 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI. The trial demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA compared with chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy in the final OS analysis. Sixty percent of the patients who had been randomized to receive chemotherapy had crossed over to receive subsequent anti-PD-1/PD-L1 therapies including KEYTRUDA. The median follow-up time at the final analysis was 38.1 months (range: 0.2 to 58.7 months). Table 82 and Figure 19 summarize the key efficacy measures for KEYNOTE-177. Table 82: Efficacy Results in Patients with MSI-H or dMMR CRC in KEYNOTE-177 Endpoint KEYTRUDA 200 mg every 3 weeks n=153 Chemotherapy n=154 PFS Number (%) of patients with event 82 (54%) 113 (73%) Median in months (95% CI) 16.5 (5.4, 32.4) 8.2 (6.1, 10.2) Hazard ratio* (95% CI) 0.60 (0.45, 0.80) p-Value† 0.0004 OS‡ Number (%) of patients with event 62 (41%) 78 (51%) Median in months (95% CI) NR (49.2, NR) 36.7 (27.6, NR) Hazard ratio* (95% CI) 0.74 (0.53, 1.03) p-Value§ 0.0718 Objective Response Rate¶ ORR (95% CI) 44% (35.8, 52.0) 33% (25.8, 41.1) Complete response rate 11% 4% Partial response rate 33% 29% Duration of Response¶,# Median in months (range) NR (2.3+, 41.4+) 10.6 (2.8, 37.5+) % with duration ≥12 monthsÞ 75% 37% % with duration ≥24 monthsÞ 43% 18% * Based on Cox regression model † Two-sided p-Value based on log-rank test (compared to a significance level of 0.0234) ‡ Final OS analysis § Two-sided p-Value based on log-rank test (compared to a significance level of 0.0492) ¶ Based on confirmed response by BICR review # Based on n=67 patients with a response in the KEYTRUDA arm and n=51 patients with a response in the chemotherapy arm Þ Based on observed duration of response + Denotes ongoing response NR = not reached Reference ID: 5482742 118 Figure 19: Kaplan-Meier Curve for PFS in KEYNOTE-177 14.10 Gastric Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma The efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 698 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx™ kit. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms: • KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle. • Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. In an interim efficacy analysis, the major outcome measures assessed were ORR and DoR by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Reference ID: 5482742 119 At the time of the interim analysis, ORR and DoR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range: 19 to 84), 41% age 65 or older; 82% male; 63% White, 31% Asian, and 0.8% Black; 47% ECOG PS of 0 and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Ninety-one percent (n=240) had tumors that were not MSI-H, 1% (n=2) had tumors that were MSI-H, and in 8% (n=22) the status was not known. Eighty-seven percent of patients received CAPOX. A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results are summarized in Table 83. Table 83: Efficacy Results for KEYNOTE-811 Endpoint KEYTRUDA 200 mg every 3 weeks Trastuzumab Fluoropyrimidine and Platinum Chemotherapy n=133 Placebo Trastuzumab Fluoropyrimidine and Platinum Chemotherapy n=131 Objective Response Rate ORR* (95% CI) 74% (66, 82) 52% (43, 61) Complete response rate 11% 3.1% Partial response rate 63% 49% p-Value† <0.0001 Duration of Response n=99 n=68 Median in months (range) 10.6 (1.1+, 16.5+) 9.5 (1.4+, 15.4+) % with duration ≥6 months‡ 65% 53% * Response: Best objective response as confirmed complete response or partial response † p-Value based on stratified Miettinen and Nurminen method (compared to an alpha boundary of 0.002) ‡ Based on observed duration of response + Denotes ongoing response In a pre-specified subgroup analysis of ORR based on PD-L1 status, the ORR in patients with PD-L1- positive disease (CPS ≥1) was 76% (95% CI: 67, 83) in the pembrolizumab arm (n=117) versus 51% (95% CI: 41, 60) in the control arm (n=112). In patients with tumors that were PD-L1 CPS<1, the ORR was 63% (95% CI: 35, 85) in the pembrolizumab arm (n=16) versus 58% (95% CI: 34, 80) in the control arm (n=19). In a subsequent interim analysis of pre-specified subgroups based on PD-L1 status in the full study population (n=698), the HR for PFS and OS in patients with PD-L1 CPS<1 (N=104) was 1.03 (95% CI: 0.65, 1.64) and 1.41 (95% CI: 0.90, 2.20), respectively. First-line Treatment of Locally Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma The efficacy of KEYTRUDA in combination with fluoropyrimidine- and platinum-containing chemotherapy was investigated in KEYNOTE-859 (NCT03675737), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (FP or CAPOX), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms; treatment was administered prior to chemotherapy on Day 1 of each cycle: • KEYTRUDA 200 mg, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5- FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). Reference ID: 5482742 120 • Placebo, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Platinum agents could be administered for 6 or more cycles following local guidelines. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. The major efficacy outcome measure was OS. Additional secondary efficacy outcome measures included PFS, ORR, and DoR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The population characteristics were: median age of 62 years (range: 21 to 86), 39% age 65 or older; 68% male and 32% female; 55% White, 34% Asian, 4.6% Multiple, 4.2% American Indian or Alaskan Native, 1.3% Black, and 0.2% Native Hawaiian or other Pacific Islander; 76% Not Hispanic or Latino and 21% Hispanic or Latino; 37% ECOG PS of 0 and 63% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Seventy-eight percent had tumors that expressed PD-L1 with a CPS ≥1 and 5% (n=74) had tumors that were MSI-H. Eighty-six percent of patients received CAPOX. A statistically significant improvement in OS, PFS, and ORR was demonstrated in patients randomized to KEYTRUDA in combination with chemotherapy compared with placebo in combination with chemotherapy at the time of a pre-specified interim analysis of OS. Efficacy results are summarized in Table 84 and Figures 20 and 21. Reference ID: 5482742 121 Table 84: Efficacy Results* for KEYNOTE-859 Endpoint KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=790 Placebo and FP or CAPOX n=789 KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=618 Placebo and FP or CAPOX n=617 KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=279 Placebo and FP or CAPOX n=272 All Patients CPS≥1 CPS≥10 OS Number (%) of patients with event 603 (76) 666 (84) 464 (75) 526 (85) 188 (67) 226 (83) Median in months (95% CI) 12.9 (11.9, 14.0) 11.5 (10.6, 12.1) 13.0 (11.6, 14.2) 11.4 (10.5, 12.0) 15.7 (13.8, 19.3) 11.8 (10.3, 12.7) Hazard ratio† (95% CI) 0.78 (0.70, 0.87) 0.74 (0.65, 0.84) 0.65 (0.53, 0.79) p-Value (stratified log- rank)‡ <0.0001 <0.0001 <0.0001 PFS Number (%) of patients with event 572 (72) 608 (77) 443 (72%) 483 (78%) 190 (68) 210 (77) Median in months (95% CI) 6.9 (6.3, 7.2) 5.6 (5.5, 5.7) 6.9 (6.0, 7.2) 5.6 (5.4, 5.7) 8.1 (6.8, 8.5) 5.6 (5.4, 6.7) Hazard ratio† (95% CI) 0.76 (0.67, 0.85) 0.72 (0.63, 0.82) 0.62 (0.51, 0.76) p-Value (stratified log- rank)‡ <0.0001 <0.0001 <0.0001 Objective Response Rate ORR§ (95% CI) 51% (48, 55) 42% (38, 45) 52% (48, 56) 43% (39, 47) 61% (55, 66) 43% (37, 49) Complete response rate 9% 6% 10% 6% 13% 5% Partial response rate 42% 36% 42% 37% 48% 38% p-Value¶ <0.0001 0.0004 <0.0001 Duration of Response n=405 n=331 n=322 n=263 n=169 n=117 Median in months# (95% CI) Range in months 8.0 (7.0, 9.7) 1.2+, 41.5+ 5.7 (5.5, 6.9) 1.3+, 34.7+ 8.3 (7.0, 10.9) 1.2+, 41.5+ 5.6 (5.4, 6.9) 1.3+, 34.2+ 10.9 (8.0, 13.8) 1.2+, 41.5+ 5.8 (5.3, 7.0) 1.4+, 31.2+ * Based on a pre-specified interim analysis † Based on the stratified Cox proportional hazard model ‡ One-sided p-Value based on stratified log-rank test § Response: Best objective response as confirmed complete response or partial response ¶ One-sided p-Value based on stratified Miettinen & Nurminen method # Based on Kaplan-Meier estimates + Denotes ongoing response Reference ID: 5482742 122 Figure 20: Kaplan-Meier Curve for Overall Survival by Treatment Arm in KEYNOTE-859 Treatment arm KEYTRUDA + Chemo Chemo Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo Chemo Reference ID: 5482742 123 Figure 21: Kaplan-Meier Curve for Overall Survival in KEYNOTE-859 (CPS≥1) In an exploratory subgroup analysis in patients with PD-L1 CPS<1 (n=344) at the time of the pre-specified interim analysis of OS, the median OS was 12.7 months (95% CI: 11.4, 15.0) for the KEYTRUDA arm and 12.2 months (95% CI: 9.5, 14.0) for the placebo arm, with a HR of 0.92 (95% CI: 0.73, 1.17). 14.11 Esophageal Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal/Gastroesophageal Junction Cancer KEYNOTE-590 The efficacy of KEYTRUDA was investigated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients with active autoimmune disease, a medical condition that required immunosuppression, or who received Time in Months Number at Risk KEYTRUDA + Chemo Chemo Treatment arm KEYTRUDA + Chemo Chemo Overall Survival (%) Reference ID: 5482742 124 prior systemic therapy in the locally advanced or metastatic setting were ineligible. Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months. • Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months. Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, CPS ≥10, and in all patients. Additional efficacy outcome measures were ORR and DoR, according to modified RECIST v1.1, as assessed by the investigator. The study population characteristics were: median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% White, 53% Asian, and 1% Black; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy, compared to chemotherapy. Table 85 and Figure 22 summarize the efficacy results for KEYNOTE-590 in all patients. Reference ID: 5482742 125 Table 85: Efficacy Results in Patients with Locally Advanced Unresectable or Metastatic Esophageal Cancer in KEYNOTE-590 Endpoint KEYTRUDA 200 mg every 3 weeks Cisplatin FU n=373 Placebo Cisplatin FU n=376 OS Number (%) of events 262 (70) 309 (82) Median in months (95% CI) 12.4 (10.5, 14.0) 9.8 (8.8, 10.8) Hazard ratio* (95% CI) 0.73 (0.62, 0.86) p-Value† <0.0001 PFS Number of events (%) 297 (80) 333 (89) Median in months (95% CI) 6.3 (6.2, 6.9) 5.8 (5.0, 6.0) Hazard ratio* (95% CI) 0.65 (0.55, 0.76) p-Value† <0.0001 Objective Response Rate ORR, %‡ (95% CI) 45 (40, 50) 29 (25, 34) Number (%) of complete responses 24 (6) 9 (2.4) Number (%) of partial responses 144 (39) 101 (27) p-Value§ <0.0001 Duration of Response Median in months (range) 8.3 (1.2+, 31.0+) 6.0 (1.5+, 25.0+) * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ Confirmed complete response or partial response § Based on the stratified Miettinen and Nurminen method Reference ID: 5482742 126 Figure 22: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590 In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n=383), the median was 13.5 months (95% CI: 11.1, 15.6) for the KEYTRUDA arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n=347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the KEYTRUDA arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10). Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer KEYNOTE-181 The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued Reference ID: 5482742 127 until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator’s treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS ≥10. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator’s treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirty- three percent of patients received prior treatment with a taxane. The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 86 and Figure 23 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10. Table 86: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS ≥10) in KEYNOTE-181 Endpoint KEYTRUDA 200 mg every 3 weeks n=85 Chemotherapy n=82 OS Number (%) of patients with event 68 (80%) 72 (88%) Median in months (95% CI) 10.3 (7.0, 13.5) 6.7 (4.8, 8.6) Hazard ratio* (95% CI) 0.64 (0.46, 0.90) PFS Number (%) of patients with event 76 (89%) 76 (93%) Median in months (95% CI) 3.2 (2.1, 4.4) 2.3 (2.1, 3.4) Hazard ratio* (95% CI) 0.66 (0.48, 0.92) Objective Response Rate ORR (95% CI) 22 (14, 33) 7 (3, 15) Number (%) of complete responses 4 (5) 1 (1) Number (%) of partial responses 15 (18) 5 (6) Median duration of response in months (range) 9.3 (2.1+, 18.8+) 7.7 (4.3, 16.8+) * Based on the Cox regression model stratified by geographic region (Asia vs. ex-Asia) Reference ID: 5482742 128 Figure 23: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS ≥10) KEYNOTE-180 The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, non- randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS ≥10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease. The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer. 14.12 Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy The efficacy of KEYTRUDA in combination with CRT (cisplatin and external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1060 patients with cervical 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Time in Months 0 10 20 30 40 50 60 70 80 90 100 Overall Survival (%) Treatment arm KEYTRUDA Control 85 79 70 56 51 43 40 30 27 21 11 7 4 3 1 0 0 82 74 54 42 34 23 18 14 10 8 4 4 3 2 2 1 0 Number at Risk KEYTRUDA: Control: Reference ID: 5482742 129 cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. There were 596 patients with FIGO 2014 Stage III-IVA (tumor involvement of the lower vagina with or without extension onto pelvic sidewall or hydronephrosis/non-functioning kidney or has spread to adjacent pelvic organs) with either node-positive or node-negative disease, and 462 patients with FIGO 2014 Stage IB2-IIB (tumor lesions >4 cm or clinically visible lesions that have spread beyond the uterus but have not extended onto the pelvic wall or to the lower third of vagina) with node-positive disease; two patients had FIGO 2014 Stage IVB disease. Randomization was stratified by planned type of EBRT (Intensity-modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT] vs. non-IMRT and non-VMAT), stage at screening of cervical cancer (FIGO 2014 Stage IB2-IIB vs. FIGO 2014 Stage III-IVA), and planned total radiotherapy dose (EBRT + brachytherapy dose of <70 Gy vs. ≥70 Gy as per equivalent dose [EQD2]). Patients were randomized (1:1) to one of two treatment arms: • KEYTRUDA 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by KEYTRUDA 400 mg IV every 6 weeks (15 cycles) • Placebo IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by placebo IV every 6 weeks (15 cycles) Treatment continued until RECIST v1.1-defined progression of disease as determined by investigator or unacceptable toxicity. Assessment of tumor status was performed every 12 weeks from completion of CRT for the first two years, followed by every 24 weeks in year 3, and then annually. The major efficacy outcome measures were PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, or histopathologic confirmation, and OS. Among the 596 patients with FIGO 2014 Stage III-IVA disease, the baseline characteristics were: median age of 52 years (range: 22 to 87), 17% age 65 or older; 36% White, 34% Asian, 1% Black; 38% Hispanic or Latino; 68% ECOG PS 0 and 32% ECOG PS 1; 93% with CPS ≥1; 70% had positive pelvic and/or positive para-aortic lymph node(s) and 30% had neither positive pelvic nor para-aortic lymph node(s); 83% had squamous cell carcinoma and 17% had non-squamous histology. Regarding radiation, 85% of patients received IMRT or VMAT EBRT, and the median EQD2 dose was 87 Gy (range: 7 to 114). The trial demonstrated a statistically significant improvement in PFS in the overall population. In an exploratory subgroup analysis for the 462 patients (44%) with FIGO 2014 Stage IB2-IIB disease, the PFS HR estimate was 0.91 (95% CI: 0.63, 1.31), indicating that the PFS improvement in the overall population was primarily attributed to the results seen in the subgroup of patients with FIGO 2014 Stage III-IVA disease. OS data were not mature at the time of PFS analysis, with 10% deaths in the overall population. The efficacy results in the exploratory subgroup analysis of 596 patients with FIGO 2014 Stage III-IVA disease are summarized in Table 87 and Figure 24. Table 87: Efficacy Results in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer) Endpoint KEYTRUDA 200 mg every 3 weeks and 400 mg every 6 weeks with CRT n=293 Placebo with CRT n=303 PFS by Investigator Number of patients with event (%) 61 (21%) 94 (31%) Median in months (95% CI) NR (NR, NR) NR (18.8, NR) 12-month PFS rate (95% CI) 81% (75, 85) 70% (64, 76) Hazard ratio* (95% CI) 0.59 (0.43, 0.82) * Based on the unstratified Cox proportional hazard model CRT = Chemoradiotherapy NR = not reached Reference ID: 5482742 130 Figure 24: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer) Persistent, Recurrent, or Metastatic Cervical Cancer The efficacy of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups: • Treatment Group 1: KEYTRUDA 200 mg plus chemotherapy with or without bevacizumab • Treatment Group 2: Placebo plus chemotherapy with or without bevacizumab The investigator selected one of the following four treatment regimens prior to randomization: 1. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA + CRT CRT Treatment arm KEYTRUDA + CRT CRT Reference ID: 5482742 131 2. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg 3. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min 4. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg All study medications were administered as an intravenous infusion. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each 3-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every 9 weeks for the first year, followed by every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by investigator. Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. The baseline characteristics of the 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, 6% American Indian or Alaska Native, and 1% Black; 37% Hispanic or Latino; 56% ECOG performance status 0 and 43% ECOG performance status 1. Seventy-five percent had squamous cell carcinoma, 21% adenocarcinoma, and 5% adenosquamous histology, and 32% of patients had metastatic disease at diagnosis. At study entry, 21% of patients had metastatic disease only and 79% had persistent or recurrent disease with or without distant metastases, of whom 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery. A statistically significant improvement in OS and PFS was demonstrated in patients randomized to receive KEYTRUDA compared with patients randomized to receive placebo. An updated OS analysis was conducted at the time of final analysis when 354 deaths in the CPS ≥1 population were observed. Table 88 and Figure 25 summarize the key efficacy measures for KEYNOTE-826 for patients with tumors expressing PD-L1 (CPS ≥1). Reference ID: 5482742 132 Table 88: Efficacy Results in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-826 Endpoint KEYTRUDA 200 mg every 3 weeks and chemotherapy* with or without bevacizumab n=273 Placebo and chemotherapy* with or without bevacizumab n=275 OS Number of patients with event (%) 118 (43.2) 154 (56.0) Median in months (95% CI) NR (19.8, NR) 16.3 (14.5, 19.4) Hazard ratio† (95% CI) 0.64 (0.50, 0.81) p-Value‡ 0.0001 Updated OS Number of patients with event (%) 153 (56.0%) 201 (73.1%) Median in months (95% CI) 28.6 (22.1, 38.0) 16.5 (14.5, 20.0) Hazard ratio† (95% CI) 0.60 (0.49, 0.74) PFS Number of patients with event (%) 157 (57.5) 198 (72.0) Median in months (95% CI) 10.4 (9.7, 12.3) 8.2 (6.3, 8.5) Hazard ratio† (95% CI) 0.62 (0.50, 0.77) p-Value§ < 0.0001 Objective Response Rate ORR¶ (95% CI) 68% (62, 74) 50% (44, 56) Complete response rate 23% 13% Partial response rate 45% 37% Duration of Response Median in months (range) 18.0 (1.3+, 24.2+) 10.4 (1.5+, 22.0+) * Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Based on the stratified Cox proportional hazard model ‡ p-Value (one-sided) is compared with the allocated alpha of 0.0055 for this interim analysis (with 72% of the planned number of events for final analysis) § p-Value (one-sided) is compared with the allocated alpha of 0.0014 for this interim analysis (with 82% of the planned number of events for final analysis) ¶ Response: Best objective response as confirmed complete response or partial response + Denotes ongoing response NR = not reached Reference ID: 5482742 133 Figure 25: Kaplan-Meier Curve for Overall Survival in KEYNOTE-826 (CPS ≥1)* ,† Treatment arms include KEYTRUDA plus chemotherapy, with or without bevacizumab, versus placebo plus chemotherapy, with or without bevacizumab. †Based on the protocol-specified final OS analysis Previously Treated Recurrent or Metastatic Cervical Cancer The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; Treatment arm KEYTRUDA + Chemotherapy Chemotherapy Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemotherapy Chemotherapy Reference ID: 5482742 134 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS ˂1). Efficacy results are summarized in Table 89 for patients with PD-L1 expression (CPS ≥1). Table 89: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158 Endpoint KEYTRUDA 200 mg every 3 weeks n=77 Objective Response Rate ORR (95% CI) 14.3% (7.4, 24.1) Complete response rate 2.6% Partial response rate 11.7% Duration of Response Median in months (range) NR (4.1, 18.6+)† % with duration ≥6 months 91% * Median follow-up time of 11.7 months (range 0.6 to 22.7 months) † Based on patients (n=11) with a response by independent review + Denotes ongoing response NR = not reached 14.13 Hepatocellular Carcinoma Previously Treated HCC The efficacy of KEYTRUDA was investigated in KEYNOTE-394 (NCT03062358), a multicenter, randomized, placebo-controlled, double-blind trial conducted in Asia in patients with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC, who were previously treated with sorafenib or oxaliplatin-based chemotherapy and who were not amenable to or were refractory to local-regional therapy. Patients were also required to have Child-Pugh A liver function. Patients with hepatitis B had treated controlled disease (HBV viral load <2000 IU/mL or <104 copies/mL). Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Patients with hepatic encephalopathy, main branch portal venous invasion, clinically apparent ascites, or esophageal or gastric variceal bleeding within the last 6 months were also ineligible. Randomization was stratified by prior treatment: sorafenib vs. oxaliplatin-based chemotherapy, macrovascular invasion, and etiology (active HBV vs. others (active HCV, non-infected)). Patients were randomized (2:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or placebo. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks. The main efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR, and DoR, as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study enrolled 453 patients, and 360 (79%) had active hepatitis B. The population characteristics in patients with active hepatitis B were: median age of 52 years (range: 23 to 82), 16% age 65 or older; 86% male; 100% Asian; 42% ECOG PS of 0 and 58% ECOG PS of 1; 90% received prior sorafenib and 10% received prior oxaliplatin-based chemotherapy. Patient characteristics also included extrahepatic disease (77%), macrovascular invasion (10%), BCLC stage C (93%) and B (7%), and baseline AFP ≥200 ng/mL (57%). KEYNOTE-394 demonstrated improved OS in patients with HCC secondary to hepatitis B randomized to KEYTRUDA compared with placebo. Efficacy results are summarized in Table 90 and Figure 26. Reference ID: 5482742 135 Table 90: Efficacy Results in Patients with Hepatocellular Carcinoma in KEYNOTE-394 Endpoint KEYTRUDA 200 mg every 3 weeks n=236 Placebo n=124 OS* Number (%) of patients with events 172 (73) 105 (85) Median in months (95% CI) 13.9 (12.5, 17.9) 13.0 (10.1, 15.6) Hazard ratio† (95% CI) 0.78 (0.61, 0.99) PFS‡ Number (%) of patients with events 189 (80) 108 (87) Median in months (95% CI) 2 (1.4, 2.7) 2.3 (1.4, 2.8) Hazard ratio† (95% CI) 0.78 (0.61, 1.00) Objective Response Rate‡ ORR§ (95% CI) 11% (7, 16) 1.6% (0.2, 5.7) Number (%) of complete responses 2 (0.9%) 1 (0.8%) Number (%) of partial responses 24 (10%) 1 (0.8%) Duration of Response* n=28 n=2 Median in months¶ (range) 23.9 (2.6+, 44.4+) 5.6 (3.0+, 5.6) * Results at the pre-specified final OS analysis † Based on the stratified Cox proportional hazard model ‡ Results at pre-specified interim OS analysis § Confirmed complete response or partial response ¶ Based on Kaplan-Meier estimate + Denotes ongoing response Reference ID: 5482742 136 Figure 26: Kaplan-Meier Curve for Overall Survival in KEYNOTE-394 14.14 Biliary Tract Cancer The efficacy of KEYTRUDA in combination with gemcitabine and cisplatin chemotherapy was investigated in KEYNOTE-966 (NCT04003636), a multicenter, randomized, double-blind, placebo- controlled trial that enrolled 1069 patients with locally advanced unresectable or metastatic BTC, who had not received prior systemic therapy in the advanced disease setting. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by region (Asia vs. non-Asia), locally advanced versus metastatic, and site of origin (gallbladder, intrahepatic or extrahepatic cholangiocarcinoma). Patients were randomized (1:1) to KEYTRUDA 200 mg on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks, or placebo on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks. Study medications were administered via intravenous infusion. Treatment continued until unacceptable toxicity or disease progression. For pembrolizumab, treatment continued for a maximum of 35 cycles, or approximately 24 months. For gemcitabine, treatment could be continued beyond 8 cycles while for cisplatin, treatment could be administered for a maximum of 8 cycles. Treatment arm KEYTRUDA Placebo Overall Survival (%) Time in Months Number at Risk KEYTRUDA Placebo Reference ID: 5482742 137 Administration of KEYTRUDA with chemotherapy was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Assessment of tumor status was performed at baseline and then every 6 weeks through 54 weeks, followed by every 12 weeks thereafter. Study population characteristics were median age of 64 years (range: 23 to 85), 47% age 65 or older; 52% male; 49% White, 46% Asian, 1.3% Black or African American; 10% Hispanic or Latino; 46% ECOG PS of 0 and 54% ECOG PS of 1; 31% of patients had a history of hepatitis B infection, and 3% had a history of hepatitis C infection. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Table 91 and Figure 27 summarize the efficacy results for KEYNOTE-966. Table 91: Efficacy Results in KEYNOTE-966 Endpoint KEYTRUDA 200 mg every 3 weeks with gemcitabine/cisplatin n=533 Placebo with gemcitabine/cisplatin n=536 OS* Number of patients with event (%) 414 (78%) 443 (83%) Median in months (95% CI) 12.7 (11.5, 13.6) 10.9 (9.9, 11.6) Hazard ratio† (95% CI) 0.83 (0.72, 0.95) p-Value‡ 0.0034 PFS§ Number (%) of patients with event 361 (68%) 391 (73%) Median in months (95% CI) 6.5 (5.7, 6.9) 5.6 (5.1, 6.6) Hazard ratio† (95% CI) 0.86 (0.75, 1.00) p-Value‡ NS Objective Response Rate§ ORR¶ (95% CI) 29% (25, 33) 29% (25, 33) Number (%) of complete responses 11 (2.1%) 7 (1.3%) Number (%) of partial responses 142 (27%) 146 (27%) p-Value # NS Duration of Response* n=156 n=152 Median in months Þ (95% CI) 8.3 (6.9, 10.2) 6.8 (5.7, 7.1) * Results at the pre-specified final OS analysis † Based on the stratified Cox proportional hazard model ‡ One-sided p-Value based on a stratified log-rank test § Results at pre-specified final analysis of PFS and ORR ¶ Confirmed complete response or partial response # One-sided p-Value based on the stratified Miettinen and Nurminen analysis Þ Based on Kaplan-Meier estimate NS = not significant Reference ID: 5482742 138 Figure 27: Kaplan-Meier Curve for Overall Survival in KEYNOTE-966 14.15 Merkel Cell Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603) and KEYNOTE-913 (NCT03783078), two multicenter, non-randomized, open-label trials that enrolled 105 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 2 mg/kg (KEYNOTE-017) or 200 mg (KEYNOTE-913) every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1. Among the 105 patients enrolled, the median age was 73 years (range: 38 to 91), 79% were age 65 or older; 62% were male; 80% were White, race in 19% was unknown or missing, and 1% were Asian; 53% had ECOG PS of 0, and 47% had ECOG PS of 1. Thirteen percent had stage IIIB disease and 84% had stage IV. Seventy-six percent of patients had prior surgery and 51% had prior radiation therapy. Treatment arm KEYTRUDA + Chemotherapy Placebo + Chemotherapy Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemotherapy Placebo + Chemotherapy Reference ID: 5482742 139 Efficacy results are summarized in Table 92. Table 92: Efficacy Results in KEYNOTE-017 and KEYNOTE-913 Endpoint KEYNOTE-017 KEYTRUDA 2 mg/kg every 3 weeks n=50 KEYNOTE-913 KEYTRUDA 200 mg or 2 mg/kg every 3 weeks n=55 Objective Response Rate ORR (95% CI) 56% (41, 70) 49% (35, 63) Complete responses, n (%) 12 (24%) 9 (16%) Partial responses, n (%) 16 (32%) 18 (33%) Duration of Response n=28 n=27 Median DoR in months (range) NR (5.9, 34.5+) NR (4.8, 25.4+) Patients with duration ≥6 months, n (%) 27 (96%) 25 (93%) Patients with duration ≥12 months, n (%) 15 (54%) 19 (70%) + Denotes ongoing response NR = not reached 14.16 Renal Cell Carcinoma First-line treatment with axitinib KEYNOTE-426 The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”). Patients were randomized (1:1) to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity. • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks. Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter. The study population characteristics were: median age of 62 years (range: 26 to 90), 38% age 65 or older; 73% male; 79% White and 16% Asian; 20% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate, and 13% poor. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the first pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. An updated OS analysis was conducted when 418 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 93 and Figure 28 summarize the efficacy results for KEYNOTE-426. Reference ID: 5482742 140 Table 93: Efficacy Results in KEYNOTE-426 Endpoint KEYTRUDA 200 mg every 3 weeks and Axitinib n=432 Sunitinib n=429 OS Number of patients with event (%) 59 (14%) 97 (23%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratio* (95% CI) 0.53 (0.38, 0.74) p-Value† <0.0001‡ Updated OS Number of patients with event (%) 193 (45%) 225 (52%) Median in months (95% CI) 45.7 (43.6, NR) 40.1 (34.3, 44.2) Hazard ratio* (95% CI) 0.73 (0.60, 0.88) PFS Number of patients with event (%) 183 (42%) 213 (50%) Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5) Hazard ratio* (95% CI) 0.69 (0.56, 0.84) p-Value† 0.0001§ Objective Response Rate ORR¶ (95% CI) 59% (54, 64) 36% (31, 40) Complete response rate 6% 2% Partial response rate 53% 34% p-Value# <0.0001 * Based on the stratified Cox proportional hazard model † Based on stratified log-rank test ‡ p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis). § p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis). ¶ Response: Best objective response as confirmed complete response or partial response # Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region NR = not reached Reference ID: 5482742 141 Figure 28: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-426 In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR of 1.17 (95% CI: 0.76, 1.80), 0.67 (95% CI: 0.52, 0.86), 0.64 (95% CI: 0.52, 0.80), and 0.51 (95% CI: 0.32, 0.81), respectively. First-line treatment with lenvatinib KEYNOTE-581 The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-581 (NCT02811861), a multicenter, open-label, randomized trial conducted in 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America versus Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable versus intermediate versus poor risk). Patients were randomized (1:1:1) to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with lenvatinib 20 mg orally once daily. • Lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily. • Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks. Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA was continued for a Reference ID: 5482742 142 maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks. The study population characteristics were: median age of 62 years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate, and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%). The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. KEYTRUDA in combination with lenvatinib demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. An updated OS analysis was conducted when 304 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 94 and Figures 29 and 30 summarize the efficacy results for KEYNOTE-581. Table 94: Efficacy Results in KEYNOTE-581 Endpoint KEYTRUDA 200 mg every 3 weeks and Lenvatinib n=355 Sunitinib n=357 Progression-Free Survival (PFS) Number of events, n (%) 160 (45%) 205 (57%) Progressive disease 145 (41%) 196 (55%) Death 15 (4%) 9 (3%) Median PFS in months (95% CI) 23.9 (20.8, 27.7) 9.2 (6.0, 11.0) Hazard ratio* (95% CI) 0.39 (0.32, 0.49) p-Value† <0.0001 Overall Survival (OS) Number of deaths, n (%) 80 (23%) 101 (28%) Median OS in months (95% CI) NR (33.6, NR) NR (NR, NR) Hazard ratio* (95% CI) 0.66 (0.49, 0.88) p-Value† 0.0049 Updated OS Number of deaths, n (%) 149 (42%) 159 (45%) Median OS in months (95% CI) 53.7 (48.7, NR) 54.3 (40.9, NR) Hazard ratio* (95% CI) 0.79 (0.63, 0.99) Objective Response Rate (Confirmed) ORR, n (%) 252 (71%) 129 (36%) (95% CI) (66, 76) (31, 41) Complete response rate 16% 4% Partial response rate 55% 32% p-Value‡ <0.0001 Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR. Data cutoff date = 28 Aug 2020, Updated OS cutoff date = 31 July 2022 CI = confidence interval; NR= Not reached * Hazard ratio is based on a Cox Proportional Hazards Model. Stratified by geographic region and MSKCC prognostic groups. † Two-sided p-Value based on stratified log-rank test. ‡ Two-sided p-Value based upon CMH test. Reference ID: 5482742 143 Figure 29: Kaplan-Meier Curve for PFS in KEYNOTE-581 Reference ID: 5482742 144 Figure 30: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-581 KEYNOTE-B61 The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-B61 (NCT04704219), a multicenter, single-arm trial that enrolled 160 patients with advanced or metastatic non-clear cell RCC in the first-line setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 400 mg every 6 weeks in combination with lenvatinib 20 mg orally once daily. KEYTRUDA was continued for a maximum of 24 months; however, lenvatinib could be continued beyond 24 months. Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit. Among the 158 treated patients, the baseline characteristics were: median age of 60 years (range: 24 to 87 years); 71% male; 86% White, 8% Asian, and 3% Black; <1% Hispanic or Latino; 22% and 78% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; histologic subtypes were 59% papillary, 18% chromophobe, 4% translocation, <1% medullary, 13% unclassified, and 6% other; patient distribution by IMDC risk categories was 35% favorable, 54% intermediate, and 10% poor. Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%). Reference ID: 5482742 145 The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures included DOR as assessed by BICR using RECIST 1.1. Efficacy results are summarized in Table 95. Table 95: Efficacy Results in KEYNOTE-B61 Endpoint KEYTRUDA 400 mg every 6 weeks and Lenvatinib n=158 Objective Response Rate (Confirmed) ORR (95% CI) 51% (43, 59) Complete response 8% Partial response 42% Duration of Response* Median in months (range) 19.5 (1.5+, 23.5+) CI = confidence interval * Based on Kaplan-Meier estimates + Denotes ongoing response Adjuvant Treatment of RCC (KEYNOTE-564) The efficacy of KEYTRUDA was investigated as adjuvant therapy for RCC in KEYNOTE-564 (NCT03142334), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease (NED). The intermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Grade without nodal involvement (N0) or distant metastases (M0). The high risk category included: pT4, any Grade N0 and M0; any pT, any Grade with nodal involvement and M0. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins ≥4 weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. Patients were randomized to KEYTRUDA 200 mg administered intravenously every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Randomization was stratified by metastasis status (M0, M1 NED); M0 group was further stratified by ECOG PS (0,1) and geographic region (US, non-US). The study population characteristics were: median age of 60 years (range: 25 to 84), 33% age 65 or older; 71% male; 75% White, 14% Asian, 9% Unknown, 1% Black or African American, 1% American Indian or Alaska Native, 1% Multiracial; 13% Hispanic or Latino, 78% Not Hispanic or Latino, 8% Unknown; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-four percent of patients enrolled had N0 disease; 11% had sarcomatoid features; 86% were intermediate-high risk; 8% were high risk; and 6% were M1 NED. Ninety-two percent of patients had a radical nephrectomy, and 8% had a partial nephrectomy. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS), defined as time to recurrence, metastasis, or death. An additional outcome measure was OS. Statistically significant improvements in DFS and OS were demonstrated at pre-specified interim analyses in patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 96 and Figures 31 and 32. Reference ID: 5482742 146 Table 96: Efficacy Results in KEYNOTE-564 Endpoint KEYTRUDA 200 mg every 3 weeks n=496 Placebo n=498 DFS Number (%) of patients with event 109 (22%) 151 (30%) Median in months (95% CI) NR NR Hazard ratio* (95% CI) 0.68 (0.53, 0.87) p-Value† 0.0010‡ 24-month DFS rate (95% CI) 77% (73, 81) 68% (64, 72) OS Number (%) of patients with event 55 (11%) 86 (17%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratio* (95% CI) 0.62 (0.44, 0.87) p-Value† 0.0024§ 48-month OS rate (95% CI) 91% (88, 93) 86% (83, 89) * Based on the stratified Cox proportional hazard model † Based on stratified log-rank test ‡ p-Value (one-sided) is compared with a boundary of 0.0114. § p-Value (one-sided) is compared with a boundary of 0.0072. NR = not reached Figure 31: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-564 Reference ID: 5482742 147 Figure 32: Kaplan-Meier Curve for Overall Survival in KEYNOTE-564 14.17 Endometrial Carcinoma In Combination with Paclitaxel and Carboplatin for the Treatment of Primary Advanced or Recurrent Endometrial Carcinoma The efficacy of KEYTRUDA in combination with paclitaxel and carboplatin was investigated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial in 810 patients with advanced or recurrent endometrial carcinoma. The study design included two separate cohorts based on MMR status; 222 (27%) patients were in dMMR cohort, 588 (73%) patients were in pMMR cohort. The trial enrolled measurable Stage III, measurable Stage IVA, Stage IVB or recurrent endometrial cancer (with or without measurable disease). Patients who had not received prior systemic therapy or had received prior chemotherapy in the adjuvant setting were eligible. Patients who had received prior adjuvant chemotherapy were only eligible if their chemotherapy-free interval was at least 12 months. Patients with endometrial sarcoma, including carcinosarcoma, or patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified according to MMR status, ECOG PS (0 or 1 vs. 2), and prior adjuvant chemotherapy. Patients were randomized (1:1) to one of the following treatment arms: Treatment arm KEYTRUDA Placebo Time in Months Number at Risk KEYTRUDA Placebo Overall Survival (%) Reference ID: 5482742 148 • KEYTRUDA 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by KEYTRUDA 400 mg every 6 weeks for up to 14 cycles. • Placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles. All study medications were administered as an intravenous infusion on Day 1 of each treatment cycle. Treatment continued until disease progression, unacceptable toxicity, or a maximum of 20 cycles (up to approximately 24 months). Patients with measurable disease who had RECIST-defined stable disease or partial response at the completion of cycle 6 were permitted to continue receiving paclitaxel and carboplatin with KEYTRUDA or placebo for up to 10 cycles as determined by the investigator. Assessment of tumor status was performed every 9 weeks for the first 9 months and then every 12 weeks thereafter. The major efficacy outcome measure was PFS as assessed by the investigator according to RECIST 1.1. An additional efficacy outcome measure was OS. The dMMR population characteristics were: median age of 66 years (range: 37 to 86), 55% age 65 or older; 79% White, 9% Black, and 3% Asian; 5% Hispanic or Latino; 64% ECOG PS of 0, 33% ECOG PS of 1, and 3% ECOG PS of 2; 61% had recurrent disease and 39% had primary or persistent disease; 5% received prior adjuvant chemotherapy and 43% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (81%), adenocarcinoma NOS (11%), serous carcinoma (2%), and other (6%). The pMMR population characteristics were: median age of 66 years (range: 29 to 94), 54% age 65 or older; 72% White, 16% Black, and 5% Asian; 6% Hispanic or Latino; 67% ECOG PS of 0, 30% ECOG PS of 1, and 3% ECOG PS of 2; 56% had recurrent disease and 44% had primary or persistent disease; 26% received prior adjuvant chemotherapy and 41% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (52%), serous carcinoma (26%), adenocarcinoma NOS (10%), clear cell carcinoma (7%), and other (5%). The trial demonstrated statistically significant improvements in PFS for patients randomized to KEYTRUDA in combination with paclitaxel and carboplatin compared to placebo in combination with paclitaxel and carboplatin in both the dMMR and pMMR populations. Table 97 and Figures 33 and 34 summarize the efficacy results for KEYNOTE-868 by MMR status. At the time of the PFS analysis, OS data were not mature with 12% deaths in the dMMR population and 17% deaths in the pMMR population. Table 97: Efficacy Results in KEYNOTE-868 Endpoint dMMR Population pMMR Population KEYTRUDA with paclitaxel and carboplatin n=110 Placebo with paclitaxel and carboplatin n=112 KEYTRUDA with paclitaxel and carboplatin n=294 Placebo with paclitaxel and carboplatin n=294 PFS* Number (%) of patients with event 26 (24%) 57 (51%) 91 (31%) 124 (42%) Median in months (95% CI) NR (30.7, NR) 6.5 (6.4, 8.7) 11.1 (8.7, 13.5) 8.5 (7.2, 8.8) Hazard ratio† (95% CI) 0.30 (0.19, 0.48) 0.60 (0.46, 0.78) p-Value‡ <0.0001 <0.0001 * Based on interim PFS analysis; the information fractions for interim analyses were 49% for dMMR and 55% for pMMR. † Based on the stratified Cox proportional hazard model ‡ Based on the stratified log-rank test NR = not reached Reference ID: 5482742 149 Figure 33: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-868 (dMMR Population) Chemotherapy (paclitaxel and carboplatin) Progression-Free Survival (%) Number at Risk KEYTRUDA+Chemotherapy Chemotherapy* Time in Months Treatment arm KEYTRUDA+Chemotherapy* Chemotherapy* Reference ID: 5482742 150 Figure 34: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-868 (pMMR Population) Chemotherapy (paclitaxel and carboplatin) In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775 (NCT03517449), a multicenter, open-label, randomized, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum- based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were pMMR (using the VENTANA MMR RxDx Panel test) or not MSI-H were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomized (1:1) to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily. • Investigator’s choice, consisting of either doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off. Treatment arm KEYTRUDA+Chemotherapy Chemotherapy* Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA+Chemotherapy* Chemotherapy* Reference ID: 5482742 151 Treatment with KEYTRUDA and lenvatinib continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for KEYTRUDA, a maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit, and the treatment was tolerated. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR and DoR, as assessed by BICR. Among the 697 pMMR patients, 346 patients were randomized to KEYTRUDA in combination with lenvatinib, and 351 patients were randomized to investigator’s choice of doxorubicin (n=254) or paclitaxel (n=97). The pMMR population characteristics were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy. Efficacy results for the pMMR or not MSI-H patients are summarized in Table 98 and Figures 35 and 36. Table 98: Efficacy Results in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Endpoint KEYTRUDA 200 mg every 3 weeks and Lenvatinib n=346 Doxorubicin or Paclitaxel n=351 OS Number (%) of patients with event 165 (48%) 203 (58%) Median in months (95% CI) 17.4 (14.2, 19.9) 12.0 (10.8, 13.3) Hazard ratio* (95% CI) 0.68 (0.56, 0.84) p-Value† 0.0001 PFS Number (%) of patients with event 247 (71%) 238 (68%) Median in months (95% CI) 6.6 (5.6, 7.4) 3.8 (3.6, 5.0) Hazard ratio* (95% CI) 0.60 (0.50, 0.72) p-Value† <0.0001 Objective Response Rate ORR‡ (95% CI) 30% (26, 36) 15% (12, 19) Complete response rate 5% 3% Partial response rate 25% 13% p-Value§ <0.0001 Duration of Response n=105 n=53 Median in months (range) 9.2 (1.6+, 23.7+) 5.7 (0.0+, 24.2+) * Based on the stratified Cox regression model † Based on stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response § Based on Miettinen and Nurminen method stratified by ECOG performance status, geographic region, and history of pelvic radiation Reference ID: 5482742 152 Figure 35: Kaplan-Meier Curve for Overall Survival in KEYNOTE-775 (pMMR or Not MSI-H) Reference ID: 5482742 153 Figure 36: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-775 (pMMR or Not MSI-H) As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial enrolled 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in Cohorts D and K who received at least one dose of KEYTRUDA. MSI or MMR tumor status was determined using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 90 patients evaluated, the baseline characteristics were: median age of 64 years (range: 42 to 86); 83% White, 8% Asian, and 3% Black; 12% Hispanic or Latino; 39% ECOG PS of 0 and 61% ECOG PS of 1; 96% had M1 disease and 4% had M0 disease at study entry; and 51% had one and 48% had two or more prior lines of therapy. Nine patients received only adjuvant therapy and one patient received only neoadjuvant and adjuvant therapy before participating in the study. Efficacy results are summarized in Table 99. Reference ID: 5482742 154 Table 99: Efficacy Results in Patients with Advanced MSI-H or dMMR Endometrial Carcinoma in KEYNOTE-158 Endpoint KEYTRUDA n=90* Objective Response Rate ORR (95% CI) 46% (35, 56) Complete response rate 12% Partial response rate 33% Duration of Response n=41 Median in months (range) NR (2.9, 55.7+) % with duration ≥12 months 68% % with duration ≥24 months 44% * Median follow-up time of 16.0 months (range 0.5 to 62.1 months) + Denotes ongoing response NR = not reached 14.18 Tumor Mutational Burden-High Cancer The efficacy of KEYTRUDA was investigated in a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with high tumor mutation burden (TMB-H) who were enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumor status was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The statistical analysis plan pre-specified ≥10 and ≥13 mutations per megabase using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The major efficacy outcome measures were ORR and DoR in patients who received at least one dose of KEYTRUDA as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mutations per megabase. Among the 102 patients with TMB-H advanced solid tumors, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older; 34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy. Efficacy results are summarized in Tables 100 and 101. Reference ID: 5482742 155 Table 100: Efficacy Results for Patients with TMB-H Cancer in KEYNOTE-158 Endpoint KEYTRUDA 200 mg every 3 weeks TMB ≥10 mut/Mb n=102* TMB ≥13 mut/Mb n=70 Objective Response Rate ORR (95% CI) 29% (21, 39) 37% (26, 50) Complete response rate 4% 3% Partial response rate 25% 34% Duration of Response n=30 n=26 Median in months (range)† NR (2.2+, 34.8+) NR (2.2+, 34.8+) % with duration ≥12 months 57% 58% % with duration ≥24 months 50% 50% * Median follow-up time of 11.1 months † From product-limit (Kaplan-Meier) method for censored data + Denotes ongoing response NR = not reached Table 101: Response by Tumor Type (TMB ≥10 mut/Mb) Objective Response Rate Duration of Response range N n (%) 95% CI (months) Overall* 102 30 (29%) (21%, 39%) (2.2+, 34.8+) Small cell lung cancer 34 10 (29%) (15%, 47%) (4.1, 32.5+) Cervical cancer 16 5 (31%) (11%, 59%) (3.7+, 34.8+) Endometrial cancer 15 7 (47%) (21%, 73%) (8.4+, 33.9+) Anal cancer 14 1 (7%) (0.2%, 34%) 18.8+ Vulvar cancer 12 2 (17%) (2%, 48%) (8.8, 11.0) Neuroendocrine cancer 5 2 (40%) (5%, 85%) (2.2+, 32.6+) Salivary cancer 3 PR, SD, PD 31.3+ Thyroid cancer 2 CR, CR (8.2, 33.2+) Mesothelioma cancer 1 PD * No TMB-H patients were identified in the cholangiocarcinoma cohort CR = complete response PR = partial response SD = stable disease PD = progressive disease In an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses. 14.19 Cutaneous Squamous Cell Carcinoma The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC or locally advanced cSCC enrolled in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every 6 weeks during the first year, and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 105 patients with recurrent or metastatic cSCC treated, the study population characteristics were: median age of 72 years (range: 29 to 95), 71% age 65 or older; 76% male; 71% White, 25% race Reference ID: 5482742 156 unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty-seven percent received one or more prior lines of therapy; 74% received prior radiation therapy. Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range: 35 to 95), 80% age 65 or older; 72% male; 83% White, 13% race unknown; 41% ECOG PS of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy. Efficacy results are summarized in Table 102. Table 102: Efficacy Results in KEYNOTE-629 Endpoint KEYTRUDA Recurrent or Metastatic cSCC n=105 KEYTRUDA Locally Advanced cSCC n=54 Objective Response Rate ORR (95% CI) 35% (26, 45) 50% (36, 64) Complete response rate 11% 17% Partial response rate 25% 33% Duration of Response* n=37 n=27 Median in months (range) NR (2.7, 30.4+) NR (1.0+, 17.2+) % with duration ≥6 months 76% 81% % with duration ≥12 months 68% 37% * Median follow-up time: recurrent or metastatic cSCC: 23.8 months; locally advanced cSCC: 13.4 months + Denotes ongoing response 14.20 Triple-Negative Breast Cancer Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522 (NCT03036488), a randomized (2:1), multicenter, double-blind, placebo-controlled trial conducted in 1174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 cm but ≤2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by nodal status (positive vs. negative), tumor size (T1/T2 vs. T3/T4), and choice of carboplatin (dosed every 3 weeks vs. weekly). Patients were randomized (2:1) to one of the following two treatment arms; all study medications were administered intravenously: • Arm 1: • Four cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: o Carboplatin  AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen -or-  AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen -and- o Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen Reference ID: 5482742 157 • Followed by four additional cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: o Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -and- o Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen • Following surgery, nine cycles of KEYTRUDA 200 mg every 3 weeks were administered. • Arm 2: • Four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: o Carboplatin  AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen -or-  AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen -and- o Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen • Followed by four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: o Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -and- o Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen • Following surgery, nine cycles of placebo every 3 weeks were administered. The main efficacy outcomes were pCR rate and EFS. pCR was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause. An additional efficacy outcome was overall survival (OS). The study population characteristics were: median age of 49 years (range: 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 4.5% Black, and 1.8% American Indian or Alaska Native; 87% ECOG PS of 0 and 13% ECOG PS of 1; 56% were pre-menopausal status and 44% were post-menopausal status; 7% were primary Tumor 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall Stage II and 25% were Stage III. Table 103 and Figure 37 summarize the efficacy results for KEYNOTE-522. At the protocol pre-specified IA4 interim analysis of OS, OS data were not mature with 45% of the required events for the final analysis. Reference ID: 5482742 158 Table 103: Efficacy Results in KEYNOTE-522 Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy/KEYTRUDA n=784 Placebo with chemotherapy/Placebo n=390 pCR (ypT0/Tis ypN0)* Number of patients with pCR 494 217 pCR Rate (%), (95% CI) 63.0 (59.5, 66.4) 55.6 (50.6, 60.6) Treatment difference (%) estimate (95% CI)†,‡ 7.5 (1.6, 13.4) EFS Number of patients with event (%) 123 (16%) 93 (24%) Hazard ratio (95% CI)§ 0.63 (0.48, 0.82) p-Value¶,# 0.00031 * Based on the entire intention-to-treat population n=1174 patients † Based on a pre-specified pCR interim analysis in n=602 patients, the pCR rate difference was statistically significant (p=0.00055 compared to a significance level of 0.003). ‡ Based on Miettinen and Nurminen method stratified by nodal status, tumor size, and choice of carboplatin § Based on stratified Cox regression model ¶ Based on a pre-specified EFS interim analysis (compared to a significance level of 0.0052) # Based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin Reference ID: 5482742 159 Figure 37: Kaplan-Meier Curve for Event-Free Survival in KEYNOTE-522 Locally Recurrent Unresectable or Metastatic TNBC The efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs. gemcitabine and carboplatin), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Patients were randomized (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. Treatment arm [\|\|\| censored] KEYTRUDA + Chemo/KEYTRUDA Placebo + Chemo/Placebo Event-Free Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo/KEYTRUDA: Placebo + Chemo/Placebo: Reference ID: 5482742 160 • Placebo on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. Assessment of tumor status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, tested in the subgroup of patients with CPS ≥10. Additional efficacy outcome measures were ORR and DoR as assessed by BICR. The study population characteristics for patients were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal status. Seventy-five percent of patients had tumor PD-L1 expression CPS ≥1 and 38% had tumor PD-L1 expression CPS ≥10. Table 104 and Figures 38 and 39 summarize the efficacy results for KEYNOTE-355. Table 104: Efficacy Results in KEYNOTE-355 (CPS ≥10) Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy n=220 Placebo every 3 weeks with chemotherapy n=103 OS* Number of patients with event (%) 155 (70%) 84 (82%) Median in months (95% CI) 23 (19.0, 26.3) 16.1 (12.6, 18.8) Hazard ratio† (95% CI) 0.73 (0.55, 0.95) p-Value‡ 0.0093 PFS§ Number of patients with event (%) 136 (62%) 79 (77%) Median in months (95% CI) 9.7 (7.6, 11.3) 5.6 (5.3, 7.5) Hazard ratio† (95% CI) 0.65 (0.49, 0.86) p-Value¶ 0.0012 Objective Response Rate (Confirmed)* ORR (95% CI) 53% (46, 59) 41% (31, 51) Complete response rate 17% 14% Partial response rate 35% 27% Duration of Response* n=116 n=42 Median in months (95% CI) 12.8 (9.9, 25.9) 7.3 (5.5, 15.4) * Based on the pre-specified final analysis † Based on stratified Cox regression model ‡ One-sided p-Value based on stratified log-rank test (compared to a significance level of 0.0113) § Based on a pre-specified interim analysis ¶ One-sided p-Value based on stratified log-rank test (compared to a significance level of 0.00411) Reference ID: 5482742 161 Figure 38: Kaplan-Meier Curve for Overall Survival in KEYNOTE-355 (CPS ≥10) Treatment arm KEYTRUDA + Chemo Placebo + Chemo Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo Placebo + Chemo Reference ID: 5482742 162 Figure 39: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-355 (CPS ≥10) 14.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks The efficacy and safety of KEYTRUDA using a dosage of 400 mg every 6 weeks for the classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma indications for adults was primarily based on the dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma [see Clinical Pharmacology (12.2)]. 16 HOW SUPPLIED/STORAGE AND HANDLING KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution): Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02) Carton containing two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04) Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions • Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include: • Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. Reference ID: 5482742 163 • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.1)]. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus [see Warnings and Precautions (5.1)]. • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.1)]. • Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.1)]. • Other immune-mediated adverse reactions: o Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)]. o Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)]. Infusion-Related Reactions • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion- related reactions [see Warnings and Precautions (5.2)]. Complications of Allogeneic HSCT • Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.3)]. Embryo-Fetal Toxicity • Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)]. • Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)]. Lactation • Advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.2)]. Laboratory Tests • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.1)]. Manufactured by: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA U.S. License No. 0002 For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Reference ID: 5482742 164 Copyright © 2014-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk3475-iv-XXXXrXXX Reference ID: 5482742	custom-source	2025-02-12T15:46:58.199981	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125514s164lbl.pdf', 'application_number': 125514, 'submission_type': 'SUPPL ', 'submission_number': 164}
80,290	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS safely and effectively. See full prescribing information for NAPROSYN, EC-NAPROSYN and ANAPROX DS. NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen delayed-release tablets), ANAPROX DS (naproxen sodium tablets), for oral use Initial U.S. Approval: 1976 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ---------------------RECENT MAJOR CHANGES------------------------- Warnings and Precautions (5.9) 11/2024 ---------------------INDICATIONS AND USAGE-------------------------- NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are non-steroidal anti- inflammatory drugs indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • polyarticular juvenile idiopathic arthritis NAPROSYN Tablets and ANAPROX DS are also indicatedfor: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea ------------------DOSAGE AND ADMINISTRATION-------------------- Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2.1) Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis NAPROSYN Tablets 250 mg (one-half tablet) 500 mg twice daily ANAPROX DS 275 mg (one-half tablet) 550 mg twice daily EC-NAPROSYN 375 mg or 500 mg twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. The dose may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for up to 6 months. Polyarticular Juvenile Idiopathic Arthritis NAPROSYN Tablets may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate. Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms. Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis Recommended starting dose 550 mg of naproxen sodium as ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Acute Gout Recommended starting dose 750 mg of NAPROSYN Tablets followed by 250 mg every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption. ----------------DOSAGE FORMS AND STRENGTHS-------------------- NAPROSYN (naproxen) tablets: 500 mg EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg and 500 mg ANAPROX DS (naproxen sodium) tablets: 550 mg (contains 50 mg of sodium) --------------------------CONTRAINDICATIONS--------------------------- • Known hypersensitivity to naproxen or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ---------------------WARNINGS AND PRECAUTIONS------------------- Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4,7) Heart Failure and Edema: Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: NAPROSYN Tablets, EC NAPROSYN and ANAPROX DS are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS at first appearance of skin rash or other signs of hypersensitivity. (5.9) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). Fetal Toxicity: Limit use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12,7) ---------------------------ADVERSE REACTIONS-------------------------- Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Canton Laboratories LLC.at1-844-302-5227 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------DRUG INTERACTIONS-------------------------- Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NAPROSYN Tablets, EC NAPROSYN or ANAPROX DS with drugs that interfere with hemostasis. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and analgesic doses of aspirin is not generally recommended. (7) ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) ACE Inhibitors and ARBs: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) Digoxin: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) ---------------------USE IN SPECIFIC POPULATIONS------------------ Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in women who have difficulties conceiving. (8.3) Renal Impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min). (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482791 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Rheumatoid Arthritis, Osteoarthritis andAnkylosing Spondylitis 2.3 Polyarticular Juvenile Idiopathic Arthritis 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis 2.5 Acute Gout 2.6 Non-Interchangeability with Other Formulations of Naproxen 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Long-Term Use and Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482791 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions(5.1)].  NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • Polyarticular Juvenile Idiopathic Arthritis NAPROSYN Tablets and ANAPROX DS are also indicated for: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS and other treatment options before deciding to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS, the dose and frequency should be adjusted to suit an individual patient’s needs. Reference ID: 5482791 To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. Naproxen-containing products such as NAPROSYN, EC-NAPROSYN and ANAPROX DS, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. 2.2 Rheumatoid Arthritis, Osteoarthritis and AnkylosingSpondylitis The recommended dosages of NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN are shown in Table 1. Table 1: Recommended dosages for NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN NAPROSYN 250 mg (one half tablet) 500 mg twice daily ANAPROX DS 275 mg (one half tablet) 550 mg (naproxen 500 mg with 50 mg sodium) twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. 2.3 Polyarticular Juvenile Idiopathic Arthritis Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for dose flexibility in children. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen [see Clinical Pharmacology (12)]. The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms. 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of ANAPROX DS (naproxen sodium) tablets is 550 mg followed by 550 mg every 12 hours or 275 mg (one half of a 550 mg tablet) every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg (two and one-half tablets) of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN Tablets may also be used. The recommended starting dose of NAPROSYN Tablets is 500 mg followed by 250 mg (one half of a 500 mg NAPROSYN tablet) every 6-8 hours as required. The total daily dose should not exceed 1250 mg of naproxen. EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products [see Clinical Pharmacology (12)]. 2.5 Acute Gout The recommended starting dose is 750 mg (one and one-half tablets) of NAPROSYN Tablets followed by 250 mg (one-half tablet) every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg (one and one- half tablets) followed by 275 mg (one-half tablet) every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption. Reference ID: 5482791 2.6 Non-Interchangeability with Other Formulations of Naproxen Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations. 3 DOSAGE FORMS AND STRENGTHS NAPROSYN (naproxen) tablets: 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. EC-NAPROSYN (naproxen) delayed-release tablets: 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. ANAPROX DS (naproxen sodium) tablets: 550 mg: dark blue, oblong-shaped, engraved with NPS 550 on one side and scored on both sides. 4 CONTRAINDICATIONS NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7,5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated Reference ID: 5482791 patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Reference ID: 5482791 Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Reference ID: 5482791 Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life- threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours. Discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. Reference ID: 5482791 5.13 Masking of Inflammation and Fever The pharmacological activity of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Long-Term Use and Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short- term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen. In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Reference ID: 5482791 Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis, vomiting Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, fixed drug eruption (FDE), photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reference ID: 5482791 Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with naproxen Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Reference ID: 5482791 Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low- dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen (see 12.2 Pharmacodynamics). There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are not substitutes for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin Reference ID: 5482791 Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPROSYN Tablets, EC NAPROSYN, or ANAPROX DS is not recommended. Probenecid Reference ID: 5482791 Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Intervention: Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post- Reference ID: 5482791 implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti- inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended Reference ID: 5482791 human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies [see Dosage and Administration (2)]. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. 8.5 Geriatric Use The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti- inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.2)]. Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose [see Clinical Pharmacology (12.3)]. Reference ID: 5482791 naproxen (A=·COOH} C14H14o3 mol wt 230.26 naproxen sodium (A=-COONa) C14H13NaO3 mol wt 252.23 8.7 Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2)].Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen) delayed-release tablets and ANAPROX DS (naproxen sodium) tablets are nonsteroidal anti-inflammatory drugs available as follows: NAPROSYN tablets are available as yellow tablets containing 500 mg of naproxen for oral administration. EC-NAPROSYN delayed-release tablets are available as enteric-coated white tablets containing 375 mg of naproxen or 500 mg of naproxen for oral administration. ANAPROX DS tablets are available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and (S)-6- methoxy α-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen and naproxen sodium have the following structures, respectively: Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. The inactive ingredients in NAPROSYN tablets include: croscarmellose sodium, iron oxides, povidone and magnesium stearate. The inactive ingredients in EC-NAPROSYN delayed release tablets include: croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The imprinting on the tablets is black ink. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. The inactive ingredients in ANAPROX DS tablets include: magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Reference ID: 5482791 Opadry YS-1-4216. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. ANAPROX DS (naproxen sodium) has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate- release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions (7)]. 12.3 Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption NAPROSYN Tablets/ANAPROX DS: After administration of NAPROSYN Tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX DS, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX DS. EC-NAPROSYN: EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN Tablets were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: Reference ID: 5482791 EC-NAPROSYN NAPROSYN* 500 mg bid 500 mg bid Cmax (µg/mL) Tmax (hours) AUC0–12 hr (µg·hr/mL) 94.9 (18%) 4 (39%) 845 (20%) 97.4 (13%) 1.9 (61%) 767 (15%) *Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly [see Drug Interactions (7)]. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations (8.2)]. Elimination Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate [see Warnings and Precautions (5.6)]. Specific Populations Pediatric: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension [see Dosage and Administration (2)] were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. Geriatric: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. Reference ID: 5482791 Hepatic Impairment: Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Renal Impairment: Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renalimpairment. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Naproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area). 14 CLINICAL STUDIES Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and polyarticular juvenile idiopathic arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum Reference ID: 5482791 episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX DS (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg twice a day, n=385) and NAPROSYN (375 or 500 mg twice a day, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC-NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. 16 HOW SUPPLIED/STORAGE AND HANDLING NAPROSYN (naproxen) tablets 500 mg: yellow, capsule-shaped tablets, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-316-01 100’s (bottle) Store at 15°C to 30°C (59°F to 86°F) in well-closed containers; dispense in light-resistant containers. EC-NAPROSYN (naproxen) delayed-release tablets 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-415-01 100’s (bottle) 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-416-01 100’s (bottle) Store at 15°C to 30°C (59°F to 86°F) in well-closed containers; dispense in light-resistant containers. ANAPROX DS (naproxen sodium) Tablets 550 mg: dark blue, oblong-shaped tablets, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. Supplied as: NDC 69437-203-01 100’s (bottle) Store at 15°C to 30°C (59° F to 86° F) in well-closed containers. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and periodically during the course of ongoing therapy. Reference ID: 5482791 Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, may be associated with a reversible delay in ovulation (see Use in Specific Populations (8.3). Fetal Toxicity Inform pregnant women to avoid use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for: Atnahs Pharma, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Canton Laboratories, LLC., Alpharetta, GA 30004-5945, United States Reference ID: 5482791 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and mayincrease: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Reference ID: 5482791 Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and • diarrhea sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Atnahs Pharma, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Canton Laboratories, LLC, Alpharetta, GA 30004-5945, United States For more information, call 1-844-302-5227. This Medication Guide has been approved by the U.S. Food andDrug Administration. Revised: May 2024 Reference ID: 5482791	custom-source	2025-02-12T15:46:58.214404	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017581s117,018164s067,020067s026lbl.pdf', 'application_number': 17581, 'submission_type': 'SUPPL ', 'submission_number': 117}
80,292	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS safely and effectively. See full prescribing information for NAPROSYN, EC-NAPROSYN and ANAPROX DS. NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen delayed-release tablets), ANAPROX DS (naproxen sodium tablets), for oral use Initial U.S. Approval: 1976 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ---------------------RECENT MAJOR CHANGES------------------------- Warnings and Precautions (5.9) 11/2024 ---------------------INDICATIONS AND USAGE-------------------------- NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are non-steroidal anti- inflammatory drugs indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • polyarticular juvenile idiopathic arthritis NAPROSYN Tablets and ANAPROX DS are also indicatedfor: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea ------------------DOSAGE AND ADMINISTRATION-------------------- Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2.1) Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis NAPROSYN Tablets 250 mg (one-half tablet) 500 mg twice daily ANAPROX DS 275 mg (one-half tablet) 550 mg twice daily EC-NAPROSYN 375 mg or 500 mg twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. The dose may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for up to 6 months. Polyarticular Juvenile Idiopathic Arthritis NAPROSYN Tablets may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate. Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms. Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis Recommended starting dose 550 mg of naproxen sodium as ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Acute Gout Recommended starting dose 750 mg of NAPROSYN Tablets followed by 250 mg every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption. ----------------DOSAGE FORMS AND STRENGTHS-------------------- NAPROSYN (naproxen) tablets: 500 mg EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg and 500 mg ANAPROX DS (naproxen sodium) tablets: 550 mg (contains 50 mg of sodium) --------------------------CONTRAINDICATIONS--------------------------- • Known hypersensitivity to naproxen or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ---------------------WARNINGS AND PRECAUTIONS------------------- Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4,7) Heart Failure and Edema: Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: NAPROSYN Tablets, EC NAPROSYN and ANAPROX DS are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS at first appearance of skin rash or other signs of hypersensitivity. (5.9) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). Fetal Toxicity: Limit use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12,7) ---------------------------ADVERSE REACTIONS-------------------------- Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Canton Laboratories LLC.at1-844-302-5227 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------DRUG INTERACTIONS-------------------------- Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NAPROSYN Tablets, EC NAPROSYN or ANAPROX DS with drugs that interfere with hemostasis. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and analgesic doses of aspirin is not generally recommended. (7) ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) ACE Inhibitors and ARBs: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) Digoxin: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) ---------------------USE IN SPECIFIC POPULATIONS------------------ Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in women who have difficulties conceiving. (8.3) Renal Impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min). (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482791 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Rheumatoid Arthritis, Osteoarthritis andAnkylosing Spondylitis 2.3 Polyarticular Juvenile Idiopathic Arthritis 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis 2.5 Acute Gout 2.6 Non-Interchangeability with Other Formulations of Naproxen 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Long-Term Use and Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482791 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions(5.1)].  NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • Polyarticular Juvenile Idiopathic Arthritis NAPROSYN Tablets and ANAPROX DS are also indicated for: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS and other treatment options before deciding to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS, the dose and frequency should be adjusted to suit an individual patient’s needs. Reference ID: 5482791 To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. Naproxen-containing products such as NAPROSYN, EC-NAPROSYN and ANAPROX DS, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. 2.2 Rheumatoid Arthritis, Osteoarthritis and AnkylosingSpondylitis The recommended dosages of NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN are shown in Table 1. Table 1: Recommended dosages for NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN NAPROSYN 250 mg (one half tablet) 500 mg twice daily ANAPROX DS 275 mg (one half tablet) 550 mg (naproxen 500 mg with 50 mg sodium) twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. 2.3 Polyarticular Juvenile Idiopathic Arthritis Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for dose flexibility in children. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen [see Clinical Pharmacology (12)]. The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms. 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of ANAPROX DS (naproxen sodium) tablets is 550 mg followed by 550 mg every 12 hours or 275 mg (one half of a 550 mg tablet) every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg (two and one-half tablets) of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN Tablets may also be used. The recommended starting dose of NAPROSYN Tablets is 500 mg followed by 250 mg (one half of a 500 mg NAPROSYN tablet) every 6-8 hours as required. The total daily dose should not exceed 1250 mg of naproxen. EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products [see Clinical Pharmacology (12)]. 2.5 Acute Gout The recommended starting dose is 750 mg (one and one-half tablets) of NAPROSYN Tablets followed by 250 mg (one-half tablet) every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg (one and one- half tablets) followed by 275 mg (one-half tablet) every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption. Reference ID: 5482791 2.6 Non-Interchangeability with Other Formulations of Naproxen Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations. 3 DOSAGE FORMS AND STRENGTHS NAPROSYN (naproxen) tablets: 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. EC-NAPROSYN (naproxen) delayed-release tablets: 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. ANAPROX DS (naproxen sodium) tablets: 550 mg: dark blue, oblong-shaped, engraved with NPS 550 on one side and scored on both sides. 4 CONTRAINDICATIONS NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7,5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated Reference ID: 5482791 patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Reference ID: 5482791 Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Reference ID: 5482791 Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life- threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours. Discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. Reference ID: 5482791 5.13 Masking of Inflammation and Fever The pharmacological activity of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Long-Term Use and Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short- term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen. In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Reference ID: 5482791 Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis, vomiting Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, fixed drug eruption (FDE), photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reference ID: 5482791 Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with naproxen Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Reference ID: 5482791 Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low- dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen (see 12.2 Pharmacodynamics). There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are not substitutes for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin Reference ID: 5482791 Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPROSYN Tablets, EC NAPROSYN, or ANAPROX DS is not recommended. Probenecid Reference ID: 5482791 Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Intervention: Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post- Reference ID: 5482791 implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti- inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended Reference ID: 5482791 human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies [see Dosage and Administration (2)]. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. 8.5 Geriatric Use The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti- inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.2)]. Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose [see Clinical Pharmacology (12.3)]. Reference ID: 5482791 naproxen (A=·COOH} C14H14o3 mol wt 230.26 naproxen sodium (A=-COONa) C14H13NaO3 mol wt 252.23 8.7 Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2)].Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen) delayed-release tablets and ANAPROX DS (naproxen sodium) tablets are nonsteroidal anti-inflammatory drugs available as follows: NAPROSYN tablets are available as yellow tablets containing 500 mg of naproxen for oral administration. EC-NAPROSYN delayed-release tablets are available as enteric-coated white tablets containing 375 mg of naproxen or 500 mg of naproxen for oral administration. ANAPROX DS tablets are available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and (S)-6- methoxy α-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen and naproxen sodium have the following structures, respectively: Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. The inactive ingredients in NAPROSYN tablets include: croscarmellose sodium, iron oxides, povidone and magnesium stearate. The inactive ingredients in EC-NAPROSYN delayed release tablets include: croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The imprinting on the tablets is black ink. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. The inactive ingredients in ANAPROX DS tablets include: magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Reference ID: 5482791 Opadry YS-1-4216. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. ANAPROX DS (naproxen sodium) has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate- release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions (7)]. 12.3 Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption NAPROSYN Tablets/ANAPROX DS: After administration of NAPROSYN Tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX DS, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX DS. EC-NAPROSYN: EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN Tablets were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: Reference ID: 5482791 EC-NAPROSYN NAPROSYN* 500 mg bid 500 mg bid Cmax (µg/mL) Tmax (hours) AUC0–12 hr (µg·hr/mL) 94.9 (18%) 4 (39%) 845 (20%) 97.4 (13%) 1.9 (61%) 767 (15%) *Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly [see Drug Interactions (7)]. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations (8.2)]. Elimination Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate [see Warnings and Precautions (5.6)]. Specific Populations Pediatric: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension [see Dosage and Administration (2)] were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. Geriatric: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. Reference ID: 5482791 Hepatic Impairment: Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Renal Impairment: Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renalimpairment. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Naproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area). 14 CLINICAL STUDIES Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and polyarticular juvenile idiopathic arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum Reference ID: 5482791 episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX DS (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg twice a day, n=385) and NAPROSYN (375 or 500 mg twice a day, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC-NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. 16 HOW SUPPLIED/STORAGE AND HANDLING NAPROSYN (naproxen) tablets 500 mg: yellow, capsule-shaped tablets, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-316-01 100’s (bottle) Store at 15°C to 30°C (59°F to 86°F) in well-closed containers; dispense in light-resistant containers. EC-NAPROSYN (naproxen) delayed-release tablets 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-415-01 100’s (bottle) 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-416-01 100’s (bottle) Store at 15°C to 30°C (59°F to 86°F) in well-closed containers; dispense in light-resistant containers. ANAPROX DS (naproxen sodium) Tablets 550 mg: dark blue, oblong-shaped tablets, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. Supplied as: NDC 69437-203-01 100’s (bottle) Store at 15°C to 30°C (59° F to 86° F) in well-closed containers. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and periodically during the course of ongoing therapy. Reference ID: 5482791 Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, may be associated with a reversible delay in ovulation (see Use in Specific Populations (8.3). Fetal Toxicity Inform pregnant women to avoid use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for: Atnahs Pharma, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Canton Laboratories, LLC., Alpharetta, GA 30004-5945, United States Reference ID: 5482791 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and mayincrease: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Reference ID: 5482791 Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and • diarrhea sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Atnahs Pharma, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Canton Laboratories, LLC, Alpharetta, GA 30004-5945, United States For more information, call 1-844-302-5227. This Medication Guide has been approved by the U.S. Food andDrug Administration. Revised: May 2024 Reference ID: 5482791	custom-source	2025-02-12T15:46:58.311755	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017581s117,018164s067,020067s026lbl.pdf', 'application_number': 18164, 'submission_type': 'SUPPL ', 'submission_number': 67}
80,294	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS safely and effectively. See full prescribing information for NAPROSYN, EC-NAPROSYN and ANAPROX DS. NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen delayed-release tablets), ANAPROX DS (naproxen sodium tablets), for oral use Initial U.S. Approval: 1976 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ---------------------RECENT MAJOR CHANGES------------------------- Warnings and Precautions (5.9) 11/2024 ---------------------INDICATIONS AND USAGE-------------------------- NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are non-steroidal anti- inflammatory drugs indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • polyarticular juvenile idiopathic arthritis NAPROSYN Tablets and ANAPROX DS are also indicatedfor: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea ------------------DOSAGE AND ADMINISTRATION-------------------- Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2.1) Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis NAPROSYN Tablets 250 mg (one-half tablet) 500 mg twice daily ANAPROX DS 275 mg (one-half tablet) 550 mg twice daily EC-NAPROSYN 375 mg or 500 mg twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. The dose may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for up to 6 months. Polyarticular Juvenile Idiopathic Arthritis NAPROSYN Tablets may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate. Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms. Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis Recommended starting dose 550 mg of naproxen sodium as ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Acute Gout Recommended starting dose 750 mg of NAPROSYN Tablets followed by 250 mg every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption. ----------------DOSAGE FORMS AND STRENGTHS-------------------- NAPROSYN (naproxen) tablets: 500 mg EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg and 500 mg ANAPROX DS (naproxen sodium) tablets: 550 mg (contains 50 mg of sodium) --------------------------CONTRAINDICATIONS--------------------------- • Known hypersensitivity to naproxen or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ---------------------WARNINGS AND PRECAUTIONS------------------- Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4,7) Heart Failure and Edema: Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: NAPROSYN Tablets, EC NAPROSYN and ANAPROX DS are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS at first appearance of skin rash or other signs of hypersensitivity. (5.9) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). Fetal Toxicity: Limit use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12,7) ---------------------------ADVERSE REACTIONS-------------------------- Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Canton Laboratories LLC.at1-844-302-5227 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------DRUG INTERACTIONS-------------------------- Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NAPROSYN Tablets, EC NAPROSYN or ANAPROX DS with drugs that interfere with hemostasis. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and analgesic doses of aspirin is not generally recommended. (7) ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) ACE Inhibitors and ARBs: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) Digoxin: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) ---------------------USE IN SPECIFIC POPULATIONS------------------ Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in women who have difficulties conceiving. (8.3) Renal Impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min). (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482791 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Rheumatoid Arthritis, Osteoarthritis andAnkylosing Spondylitis 2.3 Polyarticular Juvenile Idiopathic Arthritis 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis 2.5 Acute Gout 2.6 Non-Interchangeability with Other Formulations of Naproxen 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Long-Term Use and Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482791 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions(5.1)].  NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • Polyarticular Juvenile Idiopathic Arthritis NAPROSYN Tablets and ANAPROX DS are also indicated for: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS and other treatment options before deciding to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS, the dose and frequency should be adjusted to suit an individual patient’s needs. Reference ID: 5482791 To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. Naproxen-containing products such as NAPROSYN, EC-NAPROSYN and ANAPROX DS, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. 2.2 Rheumatoid Arthritis, Osteoarthritis and AnkylosingSpondylitis The recommended dosages of NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN are shown in Table 1. Table 1: Recommended dosages for NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN NAPROSYN 250 mg (one half tablet) 500 mg twice daily ANAPROX DS 275 mg (one half tablet) 550 mg (naproxen 500 mg with 50 mg sodium) twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. 2.3 Polyarticular Juvenile Idiopathic Arthritis Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for dose flexibility in children. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen [see Clinical Pharmacology (12)]. The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms. 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of ANAPROX DS (naproxen sodium) tablets is 550 mg followed by 550 mg every 12 hours or 275 mg (one half of a 550 mg tablet) every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg (two and one-half tablets) of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN Tablets may also be used. The recommended starting dose of NAPROSYN Tablets is 500 mg followed by 250 mg (one half of a 500 mg NAPROSYN tablet) every 6-8 hours as required. The total daily dose should not exceed 1250 mg of naproxen. EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products [see Clinical Pharmacology (12)]. 2.5 Acute Gout The recommended starting dose is 750 mg (one and one-half tablets) of NAPROSYN Tablets followed by 250 mg (one-half tablet) every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg (one and one- half tablets) followed by 275 mg (one-half tablet) every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption. Reference ID: 5482791 2.6 Non-Interchangeability with Other Formulations of Naproxen Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations. 3 DOSAGE FORMS AND STRENGTHS NAPROSYN (naproxen) tablets: 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. EC-NAPROSYN (naproxen) delayed-release tablets: 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. ANAPROX DS (naproxen sodium) tablets: 550 mg: dark blue, oblong-shaped, engraved with NPS 550 on one side and scored on both sides. 4 CONTRAINDICATIONS NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7,5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated Reference ID: 5482791 patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Reference ID: 5482791 Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Reference ID: 5482791 Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life- threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours. Discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. Reference ID: 5482791 5.13 Masking of Inflammation and Fever The pharmacological activity of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Long-Term Use and Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short- term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen. In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Reference ID: 5482791 Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis, vomiting Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, fixed drug eruption (FDE), photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reference ID: 5482791 Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with naproxen Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Reference ID: 5482791 Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low- dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen (see 12.2 Pharmacodynamics). There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are not substitutes for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin Reference ID: 5482791 Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPROSYN Tablets, EC NAPROSYN, or ANAPROX DS is not recommended. Probenecid Reference ID: 5482791 Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Intervention: Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post- Reference ID: 5482791 implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti- inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended Reference ID: 5482791 human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies [see Dosage and Administration (2)]. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. 8.5 Geriatric Use The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti- inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.2)]. Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose [see Clinical Pharmacology (12.3)]. Reference ID: 5482791 naproxen (A=·COOH} C14H14o3 mol wt 230.26 naproxen sodium (A=-COONa) C14H13NaO3 mol wt 252.23 8.7 Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2)].Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen) delayed-release tablets and ANAPROX DS (naproxen sodium) tablets are nonsteroidal anti-inflammatory drugs available as follows: NAPROSYN tablets are available as yellow tablets containing 500 mg of naproxen for oral administration. EC-NAPROSYN delayed-release tablets are available as enteric-coated white tablets containing 375 mg of naproxen or 500 mg of naproxen for oral administration. ANAPROX DS tablets are available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and (S)-6- methoxy α-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen and naproxen sodium have the following structures, respectively: Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. The inactive ingredients in NAPROSYN tablets include: croscarmellose sodium, iron oxides, povidone and magnesium stearate. The inactive ingredients in EC-NAPROSYN delayed release tablets include: croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The imprinting on the tablets is black ink. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. The inactive ingredients in ANAPROX DS tablets include: magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Reference ID: 5482791 Opadry YS-1-4216. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. ANAPROX DS (naproxen sodium) has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate- release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions (7)]. 12.3 Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption NAPROSYN Tablets/ANAPROX DS: After administration of NAPROSYN Tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX DS, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX DS. EC-NAPROSYN: EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN Tablets were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: Reference ID: 5482791 EC-NAPROSYN NAPROSYN* 500 mg bid 500 mg bid Cmax (µg/mL) Tmax (hours) AUC0–12 hr (µg·hr/mL) 94.9 (18%) 4 (39%) 845 (20%) 97.4 (13%) 1.9 (61%) 767 (15%) *Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly [see Drug Interactions (7)]. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations (8.2)]. Elimination Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate [see Warnings and Precautions (5.6)]. Specific Populations Pediatric: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension [see Dosage and Administration (2)] were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. Geriatric: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. Reference ID: 5482791 Hepatic Impairment: Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Renal Impairment: Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renalimpairment. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Naproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area). 14 CLINICAL STUDIES Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and polyarticular juvenile idiopathic arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum Reference ID: 5482791 episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX DS (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg twice a day, n=385) and NAPROSYN (375 or 500 mg twice a day, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC-NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. 16 HOW SUPPLIED/STORAGE AND HANDLING NAPROSYN (naproxen) tablets 500 mg: yellow, capsule-shaped tablets, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-316-01 100’s (bottle) Store at 15°C to 30°C (59°F to 86°F) in well-closed containers; dispense in light-resistant containers. EC-NAPROSYN (naproxen) delayed-release tablets 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-415-01 100’s (bottle) 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. Supplied as: NDC 69437-416-01 100’s (bottle) Store at 15°C to 30°C (59°F to 86°F) in well-closed containers; dispense in light-resistant containers. ANAPROX DS (naproxen sodium) Tablets 550 mg: dark blue, oblong-shaped tablets, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. Supplied as: NDC 69437-203-01 100’s (bottle) Store at 15°C to 30°C (59° F to 86° F) in well-closed containers. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and periodically during the course of ongoing therapy. Reference ID: 5482791 Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPROSYN Tablets, EC NAPROSYN, and ANAPROX DS, may be associated with a reversible delay in ovulation (see Use in Specific Populations (8.3). Fetal Toxicity Inform pregnant women to avoid use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for: Atnahs Pharma, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Canton Laboratories, LLC., Alpharetta, GA 30004-5945, United States Reference ID: 5482791 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and mayincrease: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Reference ID: 5482791 Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and • diarrhea sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Atnahs Pharma, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Canton Laboratories, LLC, Alpharetta, GA 30004-5945, United States For more information, call 1-844-302-5227. This Medication Guide has been approved by the U.S. Food andDrug Administration. Revised: May 2024 Reference ID: 5482791	custom-source	2025-02-12T15:46:58.636884	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017581s117,018164s067,020067s026lbl.pdf', 'application_number': 20067, 'submission_type': 'SUPPL ', 'submission_number': 26}
80,296	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOCIN® SUPPOSITORIES safely and effectively. See full prescribing information for INDOCIN. INDOCIN (indomethacin) Suppositories, for rectal use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE INDOCIN is a nonsteroidal anti-inflammatory drug indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • INDOCIN suppositories 50 mg can be substituted for indomethacin capsules, USP; however, there will be significant differences between the two dosage regimens in indomethacin blood levels (12.3) • The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is indomethacin capsules, USP 25 mg two or three times a day (2.3) • The dosage for acute painful shoulder (bursitis and/or tendinitis) is indomethacin capsules, USP 75-150 mg daily in 3 or 4 divided doses (2.4) • The dosage for acute gouty arthritis is indomethacin capsules, USP 50 mg three times a day (2.5) • INDOCIN Suppositories are not for oral or intravaginal use DOSAGE FORMS AND STRENGTHS INDOCIN (indomethacin) Suppositories: 50 mg (3) CONTRAINDICATIONS • Known hypersensitivity to indomethacin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) • In patients with a history of proctitis or recent rectal bleeding (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of INDOCIN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of INDOCIN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue INDOCIN at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including INDOCIN, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Iroko Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking INDOCIN with drugs that interfere with hemostasis. Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with INDOCIN may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with INDOCIN in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with INDOCIN can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of INDOCIN in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482792 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Suppository Dosing Instructions 2.3 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.4 Acute painful shoulder (bursitis and/or tendinitis) 2.5 Acute Gouty Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Central Nervous System Effects 5.16 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482792 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE INDOCIN Suppository is indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of INDOCIN and other treatment options before deciding to use INDOCIN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. SUPPOSITORIES: INDOCIN Suppositories are available as 50 mg suppositories for rectal use only. INDOCIN Suppositories are not for oral or intravaginal use. Reference ID: 5482792 2.2 Suppository Dosing Instructions THIS SECTION PREDOMINANTLY MAKES REFERENCE TO INDOMETHACIN CAPSULE, USP ORAL DOSAGE FOR GUIDANCE IN USING SUPPOSITORIES. INDOCIN suppositories 50 mg can be substituted for indomethacin capsules, USP; however, there will be significant differences between the two dosage regimens in indomethacin blood levels [see Clinical Pharmacology (12.3)]. Oral dosage recommendations for active stages of the following: 2.3 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin capsules, USP 25 mg twice a day. or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime, either orally or by rectal suppositories, may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used with greater care in the elderly. [see Use in Specific Populations (8.5)] 2.4 Acute painful shoulder (bursitis and/or tendinitis) Indomethacin capsules, USP 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days. 2.5 Acute Gouty Arthritis Indomethacin capsules, USP 50 mg three times a day. Until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. Reference ID: 5482792 3 DOSAGE FORMS AND STRENGTHS INDOCIN Suppositories: 50 mg of indomethacin. White and opaque. 4 CONTRAINDICATIONS INDOCIN is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] • In patients with a history of proctitis or recent rectal bleeding 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Reference ID: 5482792 Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of INDOCIN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If INDOCIN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue INDOCIN until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. Reference ID: 5482792 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including INDOCIN, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If INDOCIN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of Reference ID: 5482792 an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of INDOCIN in patients with advanced renal disease. The renal effects of INDOCIN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of INDOCIN [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If INDOCIN is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, INDOCIN is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When INDOCIN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 5482792 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of INDOCIN at the first appearance of skin rash or any other sign of hypersensitivity. INDOCIN is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as INDOCIN. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue INDOCIN and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDS, including INDOCIN, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including INDOCIN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including INDOCIN, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit INDOCIN use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if INDOCIN treatment extends beyond 48 hours. Discontinue INDOCIN if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with INDOCIN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Reference ID: 5482792 NSAIDs, including INDOCIN, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of INDOCIN in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Central Nervous System Effects INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue INDOCIN if severe CNS adverse reactions develop. INDOCIN may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with INDOCIN. 5.16 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN. Be alert to the possible association between the changes noted and INDOCIN. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. INDOCIN is not indicated for long-term treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates Reference ID: 5482792 observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving INDOCIN Capsules than in the group taking INDOCIN Suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with INDOCIN Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for INDOCIN Capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between INDOCIN and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with INDOCIN Capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the suppositories. Table 1 Summary of Adverse Reactions for INDOCIN Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL Incidence greater than 1% Incidence less than 1% nausea * with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness * vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES Reference ID: 5482792 tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with INDOCIN blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC Incidence greater than 1% Incidence less than 1% None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Reference ID: 5482792 Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2 Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: • Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of INDOCIN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. INDOCIN is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Reference ID: 5482792 Intervention: • During concomitant use of INDOCIN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of INDOCIN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together. Both INDOCIN and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of INDOCIN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of INDOCIN and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of INDOCIN and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of INDOCIN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of INDOCIN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of INDOCIN and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Reference ID: 5482792 Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of INDOCIN and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of INDOCIN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of INDOCIN and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of INDOCIN use between about 20 and 30 weeks of gestation, and avoid INDOCIN use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDS, including INDOCIN, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with Reference ID: 5482792 cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including INDOCIN, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If INDOCIN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There Reference ID: 5482792 have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INDOCIN and any potential adverse effects on the breastfed infant from the INDOCIN or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight- adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including INDOCIN, may delay or prevent rupture of ovarian follicles, which has been associated with Reference ID: 5482792 reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including INDOCIN, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with INDOCIN Capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of INDOCIN Capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly. Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. Reference ID: 5482792 There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). 11 DESCRIPTION INDOCIN (indomethacin) Suppositories is a nonsteroidal anti-inflammatory drug, available as a suppository containing 50 mg of indomethacin administered for rectal use. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following chemical structure. Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The inactive ingredients in INDOCIN Suppositories include: butylated hydroxyanisole, butylated hydroxytoluene, edetic acid, glycerin, polyethylene glycol 3350, polyethylene glycol 8000 and sodium chloride. INDOCIN Suppositories, 50 mg each, are white, opaque, rectal suppositories. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of INDOCIN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482792 12.3 Pharmacokinetics Absorption Following single oral doses of INDOCIN Capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered INDOCIN Capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. The rate of absorption is more rapid from the rectal suppository than from INDOCIN Capsules. Ordinarily, therefore, the total amount absorbed from the suppository would be expected to be at least equivalent to the capsule. In controlled clinical trials, however, the amount of indomethacin absorbed was found to be somewhat less (80-90%) than that absorbed from INDOCIN Capsules. This is probably because some subjects did not retain the material from the suppository for the one hour necessary to assure complete absorption. Since the suppository dissolves rather quickly rather than melting slowly, it is seldom recovered in recognizable form if the patient retains the suppository for more than a few minutes. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of INDOCIN has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Reference ID: 5482792 Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying disease. INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may enable the reduction of steroid Reference ID: 5482792 dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING INDOCIN (indomethacin) Suppositories, 50 mg each, are white, opaque, rectal suppositories. NDC 69344-102-33, boxes of 30. Storage Store below 30°C (86°F). Avoid transient temperatures above 40°C (104°F). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with INDOCIN and periodically during the course of ongoing therapy. INDOCIN Suppositories are for rectal use only. Advise patients not to use INDOCIN Suppositories orally or intra-vaginally. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop INDOCIN and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking INDOCIN immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Reference ID: 5482792 Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of INDOCIN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with INDOCIN is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of INDOCIN with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for and Distributed by: Zyla Life Sciences US, Inc. Wayne, PA 19087 Reference ID: 5482792 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) Reference ID: 5482792 • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: •shortness of breath or trouble breathing •slurred speech •chest pain •swelling of the face or throat •weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: •nausea • vomit blood •more tired or weaker than usual • there is blood in your bowel movement or •diarrhea it is black and sticky like tar •itching • unusual weight gain •your skin or eyes look yellow • skin rash or blisters with fever •indigestion or stomach pain • swelling of the arms, legs, hands and •flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for and Distributed by: Zyla Life Sciences US, Inc. Wayne, PA 19087 For more information, go to www.zyla com or call 1-877-757-0676 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: 04/2021 Reference ID: 5482792	custom-source	2025-02-12T15:46:59.068797	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017814s045lbl.pdf', 'application_number': 17814, 'submission_type': 'SUPPL ', 'submission_number': 45}
80,321	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NAPROSYN SUSPENSION safely and effectively. See full prescribing information for NAPROSYN SUSPENSION. NAPROSYN (naproxen) suspension, for oral use Initial U.S. Approval: 1976 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • NAPROSYN Suspension is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ------------------------RECENT MAJOR CHANGES---------------------------- Warnings and Precautions (5.9) 11/2024 ---------------------INDICATIONSANDUSAGE--------------------------- NAPROSYN Suspension is a non-steroidal anti-inflammatory drug indicatedfor: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • polyarticular juvenile idiopathic arthritis • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea ------------------DOSAGE AND ADMINISTRATION--------------------- Use the lowest effective dose for shortest duration consistent with individual patient treatment goals. (2) Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis NAPROSYN Suspension 250 mg (10 mL) or 375 mg (15 mL) or 500 mg (20 mL) twice daily twice daily twice daily The dose may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for up to 6 months. Polyarticular Juvenile Idiopathic Arthritis Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. The following table may be used as a guide for dosing of naproxen suspension: Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg twice daily 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg twice daily 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg twice daily 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of NAPROSYN Suspension is 500 mg (20 mL), followed by 250 mg (10 mL) every 6 to 8 hours as required. Acute Gout The recommended starting dose is 750 mg (30 mL) of NAPROSYN Suspension followed by 250 mg (10 mL) every 8 hours until the attack has subsided. ----------------DOSAGE FORMS AND STRENGTHS--------------------- NAPROSYN (naproxen) Suspension: 125 mg/5 mL (contains 39 mg sodium) --------------------------CONTRAINDICATIONS---------------------------- • Known hypersensitivity to naproxen or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ---------------------WARNINGS AND PRECAUTIONS------------------- Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3 ) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4, 7) Heart Failure and Edema: Avoid use of NAPROSYN Suspension in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPROSYN Suspension in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: NAPROSYN Suspension is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue NAPROSYN Suspension at first appearance of skin rash or other signs of hypersensitivity. (5.9) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). Fetal Toxicity: Limit use of NSAIDs, including NAPROSYN Suspension, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12, 7) ---------------------------ADVERSE REACTIONS--------------------------- Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Athena Bioscience, LLC at 1-844-302-5227or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------------DRUG INTERACTIONS--------------------------- Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NAPROSYN Suspension with drugs that interfere with hemostasis. Concomitant use of NAPROSYN Suspension and analgesic doses of aspirin is not generally recommended. (7) ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with NAPROSYN Suspension may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) ACE Inhibitors and ARBs: Concomitant use with NAPROSYN Suspension in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) Digoxin: Concomitant use with NAPROSYN Suspension can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) ---------------------USE IN SPECIFIC POPULATIONS------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NAPROSYN Suspension in women who have difficulties conceiving. (8.3) Renal Impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min). (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482796 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis 2.3 Polyarticular Juvenile Idiopathic Arthritis 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis 2.5 Acute Gout 2.6 Non-Interchangeability with Other Formulations of Naproxen 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Long-Term Use and Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482796 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].  NAPROSYN Suspension is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patientsand patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE NAPROSYN (naproxen) Suspension is indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • polyarticular juvenile idiopathic arthritis • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient’s needs. Always use a calibrated measuring device when administering NAPROSYN suspension to ensure the dose is measured and administered accurately. A household teaspoon or tablespoon is not an adequate measuring device, especially when one-half of a teaspoonful is to be measured. Given the variability of the household spoon measure, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care Reference ID: 5482796 providers should recommend an appropriate measuring device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage. Naproxen-containing products such as NAPROSYN suspension, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. 2.2 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis The recommended dosage of NAPROSYN suspension is shown in Table 1. Table 1: Recommended dosages of NAPROSYN Suspension NAPROSYN Suspension 250 mg (10 mL) or 375 mg (15 mL) or 500 mg (20 mL) twice daily twice daily twice daily NAPROSYN Suspension should be shaken gently before use. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. 2.3 Polyarticular Juvenile Idiopathic Arthritis The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen [see Clinical Pharmacology (12.3)]. The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (i.e., 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg twice daily 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg twice daily 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg twice daily 7.5 mL (1 1/2 tsp) twice daily 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of NAPROSYN Suspension is 500 mg (20 mL), followed by 250 mg (10 mL) every 6 to 8 hours as required. The total daily dose should not exceed 1250 mg (50 mL). 2.5 Acute Gout The recommended starting dose is 750 mg (30 mL) of NAPROSYN Suspension followed by 250 mg (10 mL) every 8 hours until the attack has subsided. 2.6 Non-Interchangeability with Other Formulations of Naproxen Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations. 3 DOSAGE FORMS AND STRENGTHS NAPROSYN suspension: 125 mg/5 mL (contains 39 mg sodium): Available in 1 pint (473 mL) light-resistant bottles. Reference ID: 5482796 4 CONTRAINDICATIONS NAPROSYN Suspension is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of NAPROSYN Suspension in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Suspension is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDS. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for Reference ID: 5482796 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10- fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NAPROSYN Suspension until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Suspension immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including NAPROSYN Suspension, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., Reference ID: 5482796 diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of NAPROSYN Suspension in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Suspension is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Each 5 mL of NAPROSYN Suspension contains 39 mg of sodium. This should be considered in patients whose overall intake of sodium must be severely restricted. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NAPROSYN Suspension in patients with advanced renal disease. The renal effects of NAPROSYN Suspension may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Suspension. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Suspension [see Drug Interactions (7)]. Avoid the use of NAPROSYN Suspension in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Suspension is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin- sensitive patients, NAPROSYN Suspension is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPROSYN Suspension is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 5482796 5.9 Serious Skin Reactions NSAIDs, including naproxen can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens- Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPROSYN Suspension at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Suspension is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPROSYN Suspension. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NAPROSYN Suspension and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including NAPROSYN Suspension, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including NAPROSYN Suspension, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPROSYN Suspension, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NAPROSYN Suspension use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPROSYN Suspension treatment extends beyond 48 hours. Discontinue NAPROSYN Suspension if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPROSYN Suspension has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPROSYN Suspension, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. Reference ID: 5482796 5.13 Masking of Inflammation and Fever The pharmacological activity of NAPROSYN Suspension in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Long-Term Use and Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen. In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations Reference ID: 5482796 General: dyspnea, thirst *Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, fixed drug eruption, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Reference ID: 5482796 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with Naproxen. Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NAPROSYN Suspension with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Clinical Pharmacology (12.2)]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non- NSAID analgesics where appropriate. Concomitant use of NAPROSYN Suspension and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. Reference ID: 5482796 NAPROSYN suspension is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of NAPROSYN Suspension and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPROSYN Suspension and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Suspension with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin Intervention: During concomitant use of NAPROSYN Suspension and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Suspension and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPROSYN Suspension and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPROSYN Suspension and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPROSYN Suspension and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Reference ID: 5482796 Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPROSYN Suspension and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPROSYN Suspension and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Suspension is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPROSYN Suspension is not recommended. Probenecid Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPROSYN Suspension and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin [see Warnings and Precautions (5.2)]. Intervention: Patients simultaneously receiving NAPROSYN Suspension and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Reference ID: 5482796 Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di- nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPROSYN Suspension, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NAPROSYN Suspension use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Suspension use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPROSYN Suspension, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPROSYN Suspension, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: Reference ID: 5482796 If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NAPROSYN Suspension treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPROSYN Suspension, and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of NAPROSYN Suspension during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30 weeks of gestation, or third trimester) should be avoided. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration equivalent toapproximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPROSYN Suspension and any potential adverse effects on the breastfed infant from the NAPROSYN Suspension or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Reference ID: 5482796 Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Suspension, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Suspension, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. 8.5 Geriatric Use The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.6)]. Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Reference ID: 5482796 JOOrt CHp nap,o:11en Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening [see Warnings and Precautions (5.1 , 5.2)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION NAPROSYN Suspension (naproxen) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen for oral administration. Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical name is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid. The molecular weight is 230.26 Its molecular formula is C14H14O3, and it has the following chemical structure. Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. The inactive ingredients in NAPROSYN Suspension include sucrose, magnesium aluminum silicate, sorbitol solution and sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was Reference ID: 5482796 administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions (7)]. 12.3 Pharmacokinetics Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The elimination half-life of naproxen ranges from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. Absorption Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. When NAPROSYN Suspension and immediate release naproxen tablets were given to fasted subjects (n=12) in a single-dose, crossover study, there were comparable pharmacokinetic parameters between the two formulations. NAPROSYN Naproxen Tablets Suspension 500 mg Cmax (µg/mL) 64.3 71.1 Tmax (hours) 2.6 2.3 T1/2 (hours) 16.8 16.3 AUC0–t (µg·hr/mL) 1249 1218 Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin- bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations (8.2)]. Elimination Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate [see Warnings and Precautions (5.6)]. Specific Populations Pediatric In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension [see Dosage and Administration (2)] were found to be similar to those found in normal Reference ID: 5482796 adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of NAPROSYN suspension or tablets in pediatric patients. Geriatric Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. Hepatic Impairment Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Renal Impairment Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Drug Interaction Studies Aspirin When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Naproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area). 14 CLINICAL STUDIES Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg Reference ID: 5482796 twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and polyarticular juvenile idiopathic arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of NAPROSYN has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. 16 HOW SUPPLIED/STORAGE AND HANDLING NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium): Available in 1 pint (473 mL) light-resistant bottles NDC – 69437-028-28 Storage Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature] Avoid excessive heat above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use. 17 PATIENT COUNSELING INFORMATION Advise the patient and caregiver to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers should be informed of the following information before initiating therapy with NAPROSYN Suspension and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings Reference ID: 5482796 and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPROSYN Suspension and seek immediate medical therapy [see Warnings and Precautions (5.3 )]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking NAPROSYN Suspension immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPROSYN Suspension, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of NAPROSYN Suspension and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NAPROSYN Suspension is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPROSYN Suspension with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPROSYN Suspension until they talk to their healthcare provider [see Drug Interactions (7)]. Dosing Instructions Instruct patients on how to measure and take the correct dose of NAPROSYN Suspension and to always use a calibrated measuring device when administering NAPROSYN Suspension to ensure the dose is measured and administered accurately [see Dosage and Administration (2.1)]. If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors. Manufactured for: Atnahs Pharma US Limited, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Athena Bioscience, LLC, Athens, GA 30601, United States Reference ID: 5482796 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o olderage o longer use of NSAIDs o poorhealth o smoking o advanced liverdisease o drinking alcohol o bleedingproblems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. How should I take NAPROSYN Suspension? Use ONLY a calibrated measuring device to measure your dose of NAPROSYN Suspension. DO NOT use a household teaspoon or tablespoon. Your pharmacist can provide you with the proper device to correctly measure your dose. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure Reference ID: 5482796 • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and • diarrhea sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Atnahs Pharma US Limited, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom Distributed by: Athena Bioscience, LLC, Athens, GA 30601, United States For more information call 1-844-302-5227. This Medication Guide has been approved by the U.S. Food andDrug Administration. Issued or Revised: April 2021 Reference ID: 5482796	custom-source	2025-02-12T15:46:59.800091	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018965s028lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 28}
80,300	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOMETHACIN CAPSULES safely and effectively. See full prescribing information for INDOMETHACIN CAPSULES. INDOMETHACIN capsules, for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) --------------------------RECENT MAJOR CHANGES---------------------------- Warnings and Precautions (5.9)………………………………………..11/2024 ---------------------------INDICATIONS AND USAGE---------------------------- Indomethacin capsules are a nonsteroidal anti-inflammatory drug indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis (1) ------------------DOSAGE AND ADMINISTRATION--------------------------- • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis, is indomethacin capsules 25 mg two or three times a day (2.2) • The dosage for acute painful shoulder (bursitis and/or tendinitis) is: 75 mg to 150 mg daily in 3 or 4 divided doses (2.3) • The dosage for acute gouty arthritis is indomethacin capsules 50 mg three times a day until pain is tolerable (2.4) ----------------DOSAGE FORMS AND STRENGTHS--------------------------- Indomethacin capsules: 25 mg (3) -------------------------CONTRAINDICATIONS---------------------------------- • Known hypersensitivity to indomethacin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ------------------WARNINGS AND PRECAUTIONS---------------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of indomethacin capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of indomethacin capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: Indomethacin capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue indomethacin capsules at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including indomethacin capsules, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia and nausea (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1 877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------DRUG INTERACTIONS------------------------------- • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking indomethacin capsules with drugs that interfere with hemostasis. Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with indomethacin capsules may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with indomethacin capsules in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with indomethacin capsules can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) -------------------USE IN SPECIFIC POPULATIONS--------------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin capsules in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482795 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Central Nervous System Effects 5.16 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482795 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE Indomethacin capsules are indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease. • Moderate to severe ankylosing spondylitis. • Moderate to severe osteoarthritis. • Acute painful shoulder (bursitis and/or tendinitis). • Acute gouty arthritis. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Dosage Recommendations for Active Stages of the Following: Reference ID: 5482795 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin capsules 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 mg to 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, indomethacin capsules should be used with greater care in the elderly [see Use in Specific Populations (8.5)]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) Indomethacin capsules 75 mg to 150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 to 14 days. 2.4. Acute gouty arthritis Indomethacin capsules 50 mg three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS Indomethacin Capsules, USP are available containing 25 mg of indomethacin, USP: • The 25 mg capsule is a hard-shell gelatin capsule with a light green opaque cap and a light green opaque body axially printed with MYLAN over 143 in black ink on both the cap and body. The capsule is filled with a white powder blend. 4 CONTRAINDICATIONS Indomethacin capsules are contraindicated in the following patients: Reference ID: 5482795 • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death Reference ID: 5482795 declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short- term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue indomethacin capsules until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Reference ID: 5482795 Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin capsules immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including indomethacin capsules, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo- treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, Reference ID: 5482795 those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of indomethacin capsules in patients with advanced renal disease. The renal effects of indomethacin capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin capsules [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin capsules are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be Reference ID: 5482795 fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of indomethacin at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin capsules. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy may be present even though rash is not evident. If such signs or symptoms are present, discontinue indomethacin capsules and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including indomethacin capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs, including indomethacin capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including indomethacin capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit indomethacin capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring for amniotic fluid if indomethacin capsules treatment extends beyond 48 hours. Discontinue indomethacin capsules if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with indomethacin capsules have any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Reference ID: 5482795 NSAIDs, including indomethacin capsules, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of indomethacin capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Central Nervous System Effects Indomethacin capsules may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue indomethacin capsules if severe CNS adverse reactions develop. Indomethacin capsules may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin capsules. 5.16 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin capsules. Be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. Indomethacin capsules are not indicated for long-term treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] Reference ID: 5482795 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking indomethacin suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin capsules and these adverse reactions, some of which have been reported only rarely. Table 1 Summary of Adverse Reactions for Indomethacin Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo anxiety (includes nervousness) muscle weakness involuntary muscle movements light-headedness syncope paresthesia Reference ID: 5482795 Incidence greater than 1% Incidence less than 1% somnolence depression and fatigue (including malaise and listlessness) insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin capsules blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY None pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson Syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress dyspnea asthma Reference ID: 5482795 Incidence greater than Incidence less than 1% 1% rapid fall in blood pressure purpura resembling a shock-like state angiitis angioedema pulmonary edema fever GENITOURINARY None hematuria BUN elevation vaginal bleeding renal insufficiency, including proteinuria renal failure nephrotic syndrome interstitial nephritis MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal Relationship Unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak. Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti- inflammatory agents, including indomethacin, sometimes with fatal outcome. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Reference ID: 5482795 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2: Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: • Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of indomethacin capsules and ACE inhibitors, ARBs, or beta blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of indomethacin capsules and ACE- inhibitors or ARBs in patients who are elderly, volume-depleted, or Reference ID: 5482795 have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [see Warning and Precautions (5.6)]. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Reference ID: 5482795 Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Reference ID: 5482795 Indomethacin capsules reduce basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of indomethacin capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin capsules use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including indomethacin capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. In animal reproduction studies, retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth Reference ID: 5482795 defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If indomethacin capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin capsules and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of indomethacin capsules during labor or delivery. In animal studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Reference ID: 5482795 Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight- adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 5482795 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger have not been established. Indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If a decision is made to use indomethacin for pediatric patients 2 years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1 to 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 to 200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Indomethacin may cause confusion or, rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly. Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times Reference ID: 5482795 r--O-c, N the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222 1222). 11 DESCRIPTION Indomethacin Capsules, USP for oral administration are provided in one dosage strength which contain 25 mg of indomethacin, USP. Indomethacin is a nonsteroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid with the following structural formula: C19H16ClNO4 M.W. 357.79 The molecular formula is C19H16ClNO4 and the molecular weight is 357.79. Indomethacin, USP is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. Each capsule for oral administration contains 25 mg of indomethacin and the following inactive ingredients: colloidal silicon dioxide, gelatin, FD&C Green No. 3, magnesium stearate, microcrystalline cellulose, powdered cellulose, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and D&C Yellow No. 10. The imprinting ink contains the following: black iron oxide, D&C Yellow No.10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, pharmaceutical glaze and propylene glycol. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. Reference ID: 5482795 The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of indomethacin capsules have not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with hepatic impairment. Reference ID: 5482795 Renal Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times and 0.07 times the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES Indomethacin capsules have been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Indomethacin capsules afford relief of symptoms; it does not alter the progressive course of the underlying disease. Reference ID: 5482795 Indomethacin capsules suppress inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin capsules for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin capsules may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING Indomethacin Capsules, USP are available containing 25 mg of indomethacin, USP: The 25 mg capsule is a hard-shell gelatin capsule with a light green opaque cap and a light green opaque body axially printed with MYLAN over 143 in black ink on both the cap and body. The capsule is filled with a white powder blend. They are available as follows: NDC 0378-0143-01 bottles of 100 capsules NDC 0378-0143-10 bottles of 1000 capsules Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant Reference ID: 5482795 use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking indomethacin capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin capsules, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Reference ID: 5482795 Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 5482795 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your Reference ID: 5482795 healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. Reference ID: 5482795 [fil]Mylan® General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). This Medication Guide has been approved by the U.S. Food and Drug Administration. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Revised: 04/2021 Reference ID: 5482795	custom-source	2025-02-12T15:46:59.886646	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018858s049lbl.pdf', 'application_number': 18858, 'submission_type': 'SUPPL ', 'submission_number': 49}
80,298	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOCIN® ORAL SUSPENSION safely and effectively. See full prescribing information for INDOCIN. INDOCIN (indomethacin) Oral Suspension, for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) -----------------------------------RECENT MAJOR---------------------------------- Warnings and Precautions (5.9) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- INDOCIN is a nonsteroidal anti-inflammatory drug indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis (1) -----------------------DOSAGE AND ADMINISTRATION----------------------- Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is INDOCIN 25 mg (5 mL) two or three times a day (2.2) • The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75-150 mg (15-30 mL) daily in 3 or 4 divided doses (2.3) • The dosage for acute gouty arthritis is INDOCIN 50 mg (10 mL) three times a day (2.4) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- INDOCIN (indomethacin) Oral Suspension: 25 mg of indocmethacin per 5mL (3) -------------------------------CONTRAINDICATIONS------------------------------ • Known hypersensitivity to indomethacin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ------------------------WARNINGS AND PRECAUTIONS----------------------- Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of INDOCIN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of INDOCIN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue INDOCIN at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including INDOCIN, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Zyla Life Sciences US Inc., at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking INDOCIN with drugs that interfere with hemostasis. Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended (7) • ACE Iinhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with INDOCIN may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with INDOCIN in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with INDOCIN can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) ------------------------USE IN SPECIFIC POPULATIONS---------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of INDOCIN in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Issued or Revised 11/2024 Reference ID: 5482794 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever Toxicity 5.14 Laboratory Monitoring 5.15 Central Nervous System Effects 5.16 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482794 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE INDOCIN Oral Suspension is indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of INDOCIN and other treatment options before deciding to use INDOCIN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Reference ID: 5482794 Dosage recommendations for active stages of the following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis INDOCIN 25 mg (5 mL) twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg (5 mL) or by 50 mg (10 mL), if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 200 mg (30 - 40 mL) is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg (20 mL), of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg (40 mL). In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg (5 mL) or, if required, by 50 mg (10 mL) daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used with greater care in the elderly [see Use in Specific Populations (8.5)]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) INDOCIN 75-150 mg (15-30 mL) daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days. 2.4 Acute Gouty Arthritis INDOCIN 50 mg (10 mL) three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS INDOCIN (indomethacin) Oral Suspension 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. 4 CONTRAINDICATIONS INDOCIN is contraindicated in the following patients: Reference ID: 5482794 • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, Reference ID: 5482794 the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of INDOCIN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If INDOCIN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue INDOCIN until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Reference ID: 5482794 Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including INDOCIN, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If INDOCIN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Reference ID: 5482794 No information is available from controlled clinical studies regarding the use of INDOCIN in patients with advanced renal disease. The renal effects of INDOCIN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of INDOCIN [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If INDOCIN is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, INDOCIN is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When INDOCIN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Reference ID: 5482794 INDOCIN at the first appearance of skin rash or any other sign of hypersensitivity. INDOCIN is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as INDOCIN. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue INDOCIN and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDS, including INDOCIN, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including INDOCIN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including INDOCIN, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit INDOCIN use to the lowest effective dose and shortest duration possssible. Consider ultrasound monitoring of amniotic fluid if INDOCIN treatment extends beyond 48 hours. Discontinue INDOCIN if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with INDOCIN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Reference ID: 5482794 NSAIDs, including INDOCIN, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of INDOCIN in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Central Nervous System Effects INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue INDOCIN if severe CNS adverse reactions develop. INDOCIN may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with INDOCIN. 5.16 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN. Be alert to the possible association between the changes noted and INDOCIN. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. INDOCIN is not indicated for long-term treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] Reference ID: 5482794 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving INDOCIN Capsules than in the group taking INDOCIN Suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with INDOCIN Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for INDOCIN Capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between INDOCIN and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with INDOCIN Capsules may also occur with use of the suspension. Table 1 Summary of Adverse Reactions for INDOCIN Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness * vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion Reference ID: 5482794 Incidence greater than 1% Incidence less than 1% dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with INDOCIN blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia Reference ID: 5482794 I Incidence greater than 1% Incidence less than 1% * Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2 Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: • Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of INDOCIN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Reference ID: 5482794 Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an INDOCIN and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the INDOCIN alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. INDOCIN is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of INDOCIN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of INDOCIN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together. Both INDOCIN and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of INDOCIN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of INDOCIN with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of INDOCIN and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the Reference ID: 5482794 renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of INDOCIN and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of INDOCIN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of INDOCIN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of INDOCIN and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [ see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of INDOCIN and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of INDOCIN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of INDOCIN and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. Reference ID: 5482794 False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of INDOCIN use between about 20 and 30 weeks of gestation, and avoid INDOCIN use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDS, including INDOCIN, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg (40 mL)). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [See Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Reference ID: 5482794 --- Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including INDOCIN, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If INDOCIN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reference ID: 5482794 Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INDOCIN and any potential adverse effects on the breastfed infant from the INDOCIN or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight- adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including INDOCIN, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including INDOCIN, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 5482794 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with INDOCIN Capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of INDOCIN Capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly. Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large Reference ID: 5482794 co-0- • ~ c1 1- ~NYCH:i CH O~CIH2COOIH overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). 11 DESCRIPTION INDOCIN (indomethacin) Oral Suspension is a nonsteroidal anti-inflammatory drug, available as an oral suspension contain 25 mg of indomethacin per 5mL, alcohol 1%, and sorbic acid 0.1% added as a preservative for oral administration. The chemical name is -(4 chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following chemical structure. Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. Indomethacin has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The suspension has a pH of 4.0-5.0. The inactive ingredients in INDOCIN include: antifoam AF emulsion, flavors, purified water, sodium hydroxide or hydrochloric acid to adjust pH, sorbitol solution, and tragacanth. INDOCIN Oral Suspension, 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of INDOCIN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Following single oral doses of INDOCIN Capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about Reference ID: 5482794 2 hours. Orally administered INDOCIN Capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of INDOCIN Oral Suspension was found to be bioequivalent to a 50 mg INDOCIN Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of INDOCIN has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. Reference ID: 5482794 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying disease. INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING INDOCIN (indomethacin) Oral Suspension, 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. It is supplied as follows: NDC 69344-101-01 in bottles of 237 mL Storage Store below 30°C (86°F). Avoid temperatures above 50°C (122°F). Do not freeze. Reference ID: 5482794 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with INDOCIN and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop INDOCIN and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking INDOCIN immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of INDOCIN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with INDOCIN is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Reference ID: 5482794 Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of INDOCIN with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured by: Patheon Inc. Whitby, Ontario L1N 5Z5, Canada Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 ©2019 Zyla Life Sciences US Inc. All rights reserved. LBL# 801.02 Reference ID: 5482794 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant.Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure Reference ID: 5482794 • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured by: Patheon Inc.111 Consumers Dr. Whitby ON L1N 5Z5 Canada Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 For more information, go to www.zyla.com or call 1-800-518-1084 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 Reference ID: 5482794	custom-source	2025-02-12T15:46:59.917545	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018332s043lbl.pdf', 'application_number': 18332, 'submission_type': 'SUPPL ', 'submission_number': 43}
80,323	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NAPRELAN® safely and effectively. See full prescribing information for NAPRELAN®. NAPRELAN (naproxen sodium) Controlled-Release Tablets, for oral use Initial U.S. Approval: 1976 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • NAPRELAN® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ---------- RECENT MAJOR CHANGES ---------- Warnings and Precautions (5.9) 11/2024 ---------- INDICATIONS AND USAGE ---------- NAPRELAN is a nonsteroidal anti-inflammatory drug indicated for the treatment of: • rheumatoid arthritis (RA)(1) • osteoarthritis (OA)(1) • ankylosing spondylitis (AS)(1) • tendinitis, bursitis (1) • acute gout (1) • primary dysmenorrhea (PD) (1) • the relief of mild to moderate pain (1) ------ DOSAGE AND ADMINISTRATION ----- • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2) • RA, OA, and AS: The dosage is two 375 mg or 500 mg tablets once daily, or one 750 mg tablet once daily. • Management of Pain, PD, and Acute Tendinitis and Bursitis: The dosage is two 500 mg tablets once daily. For patients requiring greater analgesic benefit, two 750 mg tablets or three 500 mg tablets may be used for a limited period. Thereafter, the total daily dose should not exceed two 500 mg tablets • For the treatment of Acute Gout: The dosage is two to three 500 mg tablets once daily on the first day, followed by two 500 mg tablets once daily, until the attack has subsided. ---- DOSAGE FORMS AND STRENGTHS ---- NAPRELAN (naproxen sodium) Controlled-Release Tablets: 375 mg, 500 mg, and 750 mg (3) ------------- CONTRAINDICATIONS ------------ • Known hypersensitivity to naproxen or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ------- WARNINGS AND PRECAUTIONS ----- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of NAPRELAN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPRELAN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: NAPRELAN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue NAPRELAN at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). • Fetal Toxicity: Limit use of NSAIDs, including NAPRELAN, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1). • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) --------------- ADVERSE REACTIONS -------------- The most frequent adverse events were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------DRUG INTERACTIONS-------------- • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NAPRELAN with drugs that interfere with hemostasis. Concomitant use of NAPRELAN and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with NAPRELAN may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with NAPRELAN in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with NAPRELAN can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) --------- USE IN SPECIFIC POPULATIONS ------ Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NAPRELAN in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482801 ________________________________________________________________________________________________________ _______________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis 2.3 Management of Pain, Primary Dysmenorrhea, and Acute Tendinitis and Bursitis 2.4 Acute Gout 2.5 Dosage Adjustments in Patients with Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482801 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • NAPRELAN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE NAPRELAN Tablets are indicated for the treatment of: • rheumatoid arthritis (RA) • osteoarthritis (OA) • ankylosing spondylitis (AS) • tendinitis, bursitis • acute gout • primary dysmenorrhea (PD) • the relief of mild to moderate pain [see Warnings and Precautions (5)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of NAPRELAN and other treatment options before deciding to use NAPRELAN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with NAPRELAN, the dose and frequency should be adjusted to suit an individual patient’s needs. 2.2 Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis The recommended starting dose of NAPRELAN Tablets in adults is two NAPRELAN 375 mg tablets (750 mg) once daily, one NAPRELAN 750 mg (750 mg) once daily, or two NAPRELAN 500 mg tablets (1,000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg twice daily (morning and evening) may have their total daily dose replaced with NAPRELAN Tablets as a single daily dose. During long-term administration, the dose of NAPRELAN Tablets may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses of NAPRELAN Tablets well, the dose may be increased to two NAPRELAN 750 mg tablets (1,500 mg), or three NAPRELAN 500 mg tablets (1,500 mg) once daily for limited periods when a higher level of anti-inflammatory/analgesic activity is required. When treating patients, especially at the higher dose levels, the physician should observe sufficient increased clinical benefit to offset the potential increased risk [see Clinical Pharmacology (12.3)]. The lowest effective dose should be sought and used in every patient. Symptomatic improvement in arthritis usually begins within one week; however, treatment for two weeks may be required to achieve a therapeutic benefit. Reference ID: 5482801 2.3 Management of Pain, Primary Dysmenorrhea, and Acute Tendinitis and Bursitis The recommended starting dose is two NAPRELAN 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two NAPRELAN 750 mg tablets (1,500 mg) or three NAPRELAN 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two NAPRELAN 500 mg tablets (1,000 mg). 2.4 Acute Gout The recommended dose on the first day is two to three NAPRELAN 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two NAPRELAN 500 mg tablets (1,000 mg) once daily, until the attack has subsided. 2.5 Dosage Adjustments in Patients with Hepatic Impairment A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients [see Warnings and Precautions (5.3)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly it is prudent to use the lowest effective dose. 3 DOSAGE FORMS AND STRENGTHS NAPRELAN (naproxen sodium) Controlled-Release Tablets are available as follows: NAPRELAN 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse. Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen. NAPRELAN 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse. Each tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen. NAPRELAN 750: white, capsule-shaped tablet with “N” on one side and “750” on the reverse. Each tablet contains 825 mg naproxen sodium equivalent to 750 mg naproxen. 4 CONTRAINDICATIONS NAPRELAN is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Reference ID: 5482801 Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of NAPRELAN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPRELAN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NAPRELAN until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPRELAN immediately, and perform a clinical evaluation of the patient. Reference ID: 5482801 5.4 Hypertension NSAIDs, including NAPRELAN, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective- treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of NAPRELAN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPRELAN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NAPRELAN in patients with advanced renal disease. The renal effects of NAPRELAN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPRELAN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPRELAN [see Drug Interactions (7)]. Avoid the use of NAPRELAN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPRELAN is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPRELAN is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPRELAN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 5482801 5.9 Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPRELAN at the first appearance of skin rash or any other sign of hypersensitivity. NAPRELAN is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPRELAN. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NAPRELAN and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including NAPRELAN, in pregnant women at about 30 weeks gestation and later. NSAIDs, including NAPRELAN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPRELAN, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NAPRELAN use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPRELAN treatment extends beyond 48 hours. Discontinue NAPRELAN if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPRELAN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPRELAN, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of NAPRELAN in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Reference ID: 5482801 -- ---- 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors. The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship between drug usage and these adverse events. In those reactions listed as “Probable Causal Relationship” there is at least one case for each adverse reaction where there is evidence to suggest that there is a causal relationship between drug usage and the reported event. The adverse reactions reported were based on the results from two double- blind controlled clinical trials of three months duration with an additional nine month open-label extension. A total of 542 patients received NAPRELAN Tablets either in the double-blind period or in the nine month open-label extension. Of these 542 patients, 232 received NAPRELAN Tablets, 167 were initially treated with Naprosyn® and 143 were initially treated with placebo. Adverse reactions reported by patients who received NAPRELAN Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with NAPRELAN Tablets are italicized. The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). The incidence of other adverse events occurring in 3% to 9% of the patients are marked with an asterisk. Those reactions occurring in less than 3% of the patients are unmarked. Incidence greater than 1% (probable causal relationship) Body as a Whole—Pain (back), pain, infection, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%). Gastrointestinal—Nausea, diarrhea, constipation, abdominal pain, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn, stomatitis. Hematologic—Anemia, ecchymosis. Respiratory—Pharyngitis, rhinitis, sinusitis, bronchitis, cough increased. Renal—Urinary tract infection, cystitis. Dermatologic—Skin rash, skin eruptions, ecchymoses, purpura. Metabolic and Nutrition—Peripheral edema, hyperglycemia. Central Nervous System—Dizziness, paresthesia, insomnia, drowsiness, lightheadedness. Reference ID: 5482801 Cardiovascular—Hypertension, edema, dyspnea, palpitations. Musculoskeletal—Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder. Special Senses—Tinnitus*, hearing disturbances, visual disturbances. General—Thirst. Incidence less than 1% (probable causal relationship) Body as a Whole—Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis, edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic. Gastrointestinal—Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess, cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis, jaundice, pancreatitis, necrosis. Renal—Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder, pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia, metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal, urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis. Hematologic—Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC, thrombocytopenia, agranulocytosis, granulocytopenia. Central Nervous System—Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo, amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural, paralysis, dream abnormalities, inability to concentrate, muscle weakness. Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia, dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus, urticaria, neoplasm skin, photosensitive dermatitis, photosensitivity reactions resembling porphyria cutaneous tarda, epidermolysis bullosa. Special Senses—Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation disorder, otitis media, pain eye. Cardiovascular—Angina pectoris, coronary artery disease, myocardial infarction, deep thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG, heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart failure. Respiratory—Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia, respiratory distress, respiratory disorder, eosinophilic pneumonitis. Musculoskeletal—Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain, ptosis, spasm general, bursitis. Metabolic and Nutrition—Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis, BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT increase, SGPT increase, weight decrease. General—Anaphylactoid reactions, angioneurotic edema, menstrual disorders, hypoglycemia, pyrexia (chills and fevers). Incidence less than 1% (causal relationship unknown) Other adverse reactions listed in the naproxen package label, but not reported by those who received NAPRELAN Tablets are shown in italics. These observations are being listed as alerting information to the physician. Hematologic—Aplastic anemia, hemolytic anemia. Central Nervous System—Aseptic meningitis, cognitive dysfunction. Dermatologic—Epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome. Gastrointestinal—Non-peptic GI ulceration, ulcerative stomatitis. Cardiovascular—Vasculitis. 6.2 Postmarketing Experience Reference ID: 5482801 The following adverse reactions have been identified during postapproval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with Naproxen Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NAPRELAN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220 mg/day or 220 mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Clinical Pharmacology (12.2)]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardio protection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of NAPRELAN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. NAPRELAN is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). Reference ID: 5482801 • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of NAPRELAN and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPRELAN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPRELAN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of NAPRELAN and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPRELAN and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPRELAN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPRELAN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPRELAN and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Reference ID: 5482801 Warnings and Precautions (5.2)]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPRELAN and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPRELAN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPRELAN is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPRELAN is not recommended. Probenecid Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPRELAN and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Intervention: Patients simultaneously receiving NAPRELAN and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Reference ID: 5482801 Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with NAPRELAN be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid are determined. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPRELAN, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NAPRELAN use between about 20 and 30 weeks of gestation, and avoid NAPRELAN use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPRELAN, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbit, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1,500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre and post- implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPRELAN, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment Reference ID: 5482801 If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NAPRELAN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPRELAN and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of NAPRELAN during labor or delivery. In animal studies, NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition, increase incidence of dystocia and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester should be avoided. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre- and post-implantation loss. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPRELAN and any potential adverse effects on the breastfed infant from the NAPRELAN or from the underlying maternal condition. Reference ID: 5482801 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPRELAN, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPRELAN, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of NAPRELAN in pediatric populations has not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1,5.2,5.3,5.6,5.14)]. Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. A few patients have experienced seizures, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION NAPRELAN (naproxen sodium) Controlled-Release Tablets is a nonsteroidal anti- inflammatory drug, available as controlled-release tablets in 375 mg, 500 mg, and 750 mg strengths for oral administration. The chemical name is 2-naphthaleneacetic acid, 6-methoxy-α-methyl-sodium salt, (S)-. The molecular weight is 252.24. Its molecular formula is C14H13NaO3, and it has the following chemical structure. Reference ID: 5482801 CIH O a CH3 I CHOOONa Nap roxen sodium Molecular Formula: C14H1sNa03 Molecular w·eight: 252.24 Naproxen sodium is an odorless crystalline powder, white to creamy in color. It is soluble in methanol and water. NAPRELAN Tablets contain 412.5 mg, 550 mg, or 825 mg of naproxen sodium, equivalent to 375 mg, 500 mg, and 750 mg of naproxen, and 37.5 mg, 50 mg, and 75 mg sodium respectively. Each NAPRELAN Tablet also contains the following inactive ingredients: ammoniomethacrylate copolymer Type A, ammoniomethacrylate copolymer Type B, citric acid, crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose, povidone, and talc. The tablet coating contains hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of NAPRELAN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen sodium is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen sodium concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen sodium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions (7)]. 12.3 Pharmacokinetics Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed, resulting in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose in NAPRELAN Tablets is present in the dosage form as an immediate release component. The remaining naproxen sodium is coated as microparticles to provide sustained release properties. After oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-life of naproxen from both immediate release naproxen sodium and NAPRELAN Tablets is approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of naproxen accumulation in the blood is consistent with this. Reference ID: 5482801 (mcg I ml) 125 100 75 50 25 0 8 -+- naproxen 500 mg q 12h ..... Naprelan® 1000mg q24h naproxen +/- 2SD - - Napre lan®+/ -2S □ 12 16 24 Ti me (hours) Plasma Naproxen Concentrations Mean of 24 Subjects (+/-2SD) (Steady State, Day 5) Pharmacokinetic Parameters at Steady State Day 5 (Mean of 24 Subjects) Parameter (units) naproxen 500 mg Q12h/5 days (1000 mg) NAPRELAN 2 x 500 mg tablets (1000 mg) Q24h/5 days Mean SD Range Mean SD Range AUC 0-24 (mcgxh/mL) 1446 168 1167-1858 1448 145 1173-1774 Cmax (mcg/mL) 95 13 71-117 94 13 74-127 Cavg (mcg/mL) 60 7 49-77 60 6 49-74 Cmin (mcg/mL) 36 9 13-51 33 7 23-48 Tmax (hrs) 3 1 1-4 5 2 2-10 Absorption Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. Based on the pharmacokinetic profile, the absorption phase of NAPRELAN Tablets occurs in the first 4 to 6 hours after administration. This coincides with disintegration of the tablet in the stomach, the transit of the sustained release microparticles through the small intestine and into the proximal large intestine. An in vivo imaging study has been performed in healthy volunteers that confirms rapid disintegration of the tablet matrix and dispersion of the microparticles. The absorption rate from the sustained release particulate component of NAPRELAN Tablets is slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption processes that maintains plasma levels and allows for once daily dosing. Food Effects No significant food effects were observed when twenty-four subjects were given a single dose of NAPRELAN Tablets 500 mg either after an overnight fast or 30 minutes after a meal. In common with conventional naproxen and naproxen sodium formulations, food causes a slight decrease in the rate of naproxen absorption following NAPRELAN Tablets administration. Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. Reference ID: 5482801 However the concentration of unbound naproxen continues to increase proportionally to dose. NAPRELAN Tablets exhibit similar dose proportional characteristics. Elimination Metabolism Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes. Excretion The elimination half-life of NAPRELAN Tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2 to 3 doses of NAPRELAN Tablets. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66 to 92%). A small amount (<5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide closely with the rate of clearance from the plasma. In patients with renal failure, metabolites may accumulate. Specific Populations Pediatric: No pediatric studies have been performed with NAPRELAN Tablets, thus safety of NAPRELAN Tablets in pediatric populations has not been established. Hepatic Impairment: Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose. Renal Impairment: Naproxen pharmacokinetics have not been determined in subjects with renal insufficiency. Given that naproxen is metabolized and conjugates are primarily excreted by the kidneys, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30mL/min) [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1,500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Studies to evaluate the mutagenic potential of Naprosyn Suspension have not been completed. Impairment of Fertility Studies to evaluate the impact of naproxen on male or female fertility have not been completed. 14 CLINICAL STUDIES Rheumatoid Arthritis The use of NAPRELAN Tablets for the management of the signs and symptoms of rheumatoid arthritis was assessed in a 12 week double-blind, randomized, placebo, and active-controlled study in 348 patients. Two Reference ID: 5482801 NAPRELAN 500 mg tablets (1,000 mg) once daily and naproxen 500 mg tablets twice daily (1,000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study. Osteoarthritis The use of NAPRELAN Tablets for the management of the signs and symptoms of osteoarthritis of the knee was assessed in a 12 week double-blind, placebo, and active-controlled study in 347 patients. Two NAPRELAN 500 mg tablets (1,000 mg) once daily and naproxen 500 mg tablets twice daily (1,000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study. Analgesia The onset of the analgesic effect of NAPRELAN Tablets was seen within 30 minutes in a pharmacokinetic/pharmacodynamic study of patients with pain following oral surgery. In controlled clinical trials, naproxen has been used in combination with gold, D-penicillamine, methotrexate, and corticosteroids. Its use in combination with salicylate is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs the combination may result in higher frequency of adverse events than demonstrated for either product alone. Special Studies In a double-blind randomized, parallel group study, 19 subjects received either two NAPRELAN 500 mg tablets (1,000 mg) once daily or naproxen 500 mg tablets (1,000 mg) twice daily for 7 days. Mucosal biopsy scores and endoscopic scores were lower in the subjects who received NAPRELAN Tablets. In another double-blind, randomized, crossover study, 23 subjects received two NAPRELAN 500 mg tablets (1,000 mg) once daily, naproxen 500 mg tablets (1,000 mg) twice daily and aspirin 650 mg four times daily (2,600 mg) for 7 days each. There were significantly fewer duodenal erosions seen with NAPRELAN Tablets than with either naproxen or aspirin. There were significantly fewer gastric erosions with both NAPRELAN Tablets and naproxen than with aspirin. The clinical significance of these findings is unknown. 16 HOW SUPPLIED/STORAGE AND HANDLING NAPRELAN (naproxen sodium) 375 mg, 500 mg, and 750 mg are controlled-release tablets supplied as: NAPRELAN 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse; in bottles of 100; NDC 24979-249-01. Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen. NAPRELAN 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse; in bottles of 75; NDC 24979-250-68. Each tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen. NAPRELAN 750: white, capsule-shaped tablet with “N” on one side and “750” on the reverse; in bottles of 30; NDC 24979-2514-06. Each tablet contains 825 mg naproxen sodium equivalent to 750 mg naproxen. Storage Store at room temperature, 20°C to 25°C (68°F to 77°F), excursions permitted 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. PHARMACIST: Dispense in a well-closed container. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPRELAN and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation NAPRELAN, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to report symptoms of Reference ID: 5482801 ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPRELAN and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS NAPRELAN, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Advise patients to stop taking NAPRELAN immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPRELAN, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of NAPRELAN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NAPRELAN is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPRELAN with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPRELAN until they talk to their healthcare provider [see Drug Interactions (7)]. All trademarks are the property of their respective owners. Distributed by: TWi Pharmaceuticals USA, Inc. Paramus, NJ 07652 PKG03116 Rev. 11/2024 Reference ID: 5482801 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other Reference ID: 5482801 NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?" • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • more tired or weaker than usual • diarrhea Reference ID: 5482801 • itching • your skin or eyes look yellow • indigestion or stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: TWi Pharmaceuticals USA, Inc. Paramus, NJ 07652 For more information, call 1-844-518-2989 This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 04/2021 PKG03117 Reference ID: 5482801	custom-source	2025-02-12T15:47:00.331521	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020353s041lbl.pdf', 'application_number': 20353, 'submission_type': 'SUPPL ', 'submission_number': 41}
80,329	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RAPIBLYK safely and effectively. See full prescribing information for RAPIBLYK. RAPIBLYK (landiolol) for injection, for intravenous use Initial U.S. Approval: 2024 -----------------------------INDICATIONS AND USAGE------------------------- RAPIBLYK is a beta adrenergic blocker indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter. (1) ------------------------DOSAGE AND ADMINISTRATION--------------------- • Administer as an intravenous infusion in a monitored setting. (2.1) • Titrate according to ventricular rate. (2.1) • If normal cardiac function, start at 9 mcg/kg/min; adjust dose in 10-minute intervals as needed in increments of 9 mcg/kg/min to a maximum of 36 mcg/kg/min. (2.1) • If impaired cardiac function, start at 1 mcg/kg/min; adjust dose in 15 minute intervals as needed in increments of 1 mcg/kg/min to a maximum of 36 mcg/kg/min. (2.1). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- For injection: 280 mg of landiolol (equivalent to 300 mg of landiolol HCl) as a lyophilized powder in a single-dose vial. (3) -------------------------------CONTRAINDICATIONS----------------------------- • Severe sinus bradycardia (4) • Sick sinus syndrome (4) • Heart block greater than first degree (4) • Decompensated heart failure (4) • Cardiogenic shock (4) • Pulmonary hypertension (4) • Known hypersensitivity to landiolol (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Risk of hypotension, bradycardia, and cardiac failure: Monitor for signs and symptoms of cardiovascular adverse effects. Reduce or discontinue use (5.1, 5.2, 5.3) • Risk of exacerbating reactive airway disease (5.5) • Diabetes mellitus: May mask symptoms of hypoglycemia and alter glucose levels; monitor (5.6) • Monitor for signs of myocardial ischemia when abruptly discontinuing in patients with coronary artery disease (5.10) -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reaction (9.9%) is hypotension (6.1). To report SUSPECTED ADVERSE REACTIONS, contact AOP Orphan Pharmaceuticals at drugsafety.us@aop-health.com or FDA at 1-800 FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Negative Inotropes and Chronotropes: Avoid (7.1) • Sympathomimetics, Positive Inotropes and Vasoconstrictors: Avoid (7.2) • Catecholamine Depleting Drugs: Monitor blood pressure and heart rate (7.3). Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Transitioning from RAPIBLYK Injection Therapy to Alternative Medications 2.3 Instructions for Preparation 2.4 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension 5.2 Bradycardia 5.3 Cardiac Failure 5.4 Reactive Airways Disease 5.5 Use in Patients with Diabetes Mellitus and Hypoglycemia 5.6 Infusion Site Reactions 5.7 Use in Patients with Prinzmetal’s Angina 5.8 Use in Patients with Pheochromocytoma 5.9 Use in Patients with Peripheral Circulatory Disorders 5.10 Abrupt Discontinuation of RAPIBLYK Injection 5.11 Hyperkalemia 5.12 Use in Patients with Metabolic Acidosis 5.13 Use in Patients with Hyperthyroidism 5.14 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Negative Inotropes and Chronotropes 7.2 Sympathomimetics, Positive Inotropes and Vasoconstrictors 7.3 Catecholamine Depleting Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Pediatric Use 8.4 Geriatric Use 8.5 Hepatic Impairment 10 OVERDOSAGE 10.1 Signs and Symptoms of Overdose 10.2 Treatment Recommendations 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage * Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5484332 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE RAPIBLYK is indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage Administer RAPIBLYK as a continuous intravenous infusion, titrating as needed for heart rate control. There are limited data beyond 24 hours of use. Table 1: Dosing Normal cardiac function Impaired cardiac function Starting dose 9 mcg/kg/min 1 mcg/kg/min Titration interval 10 min 15 min Titration step 9 mcg/kg/min 1 mcg/kg/min Maximum dose 36 mcg/kg/min 36 mcg/kg/min 9 mcg/kg/min landiolol is equivalent to 9.6 mcg/kg/min landiolol hydrochloride. 2.2 Transitioning from RAPIBLYK Injection Therapy to Alternative Medications When transitioning to alternative medications consider the pharmacodynamics of the medication to which the patient is being transitioned and monitor clinical response. If switched to an oral beta-blocker, the dosage of RAPIBLYK can be reduced as follows: • Ten minutes after administration of the oral beta-blocker, reduce the infusion rate of RAPIBLYK by 50%. • If satisfactory control is maintained for at least one hour, discontinue RAPIBLYK. 2.3 Instructions for Preparation • Use appropriate aseptic technique for reconstitution. • Reconstitute each 280 mg vial of RAPIBLYK with 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Gently swirl to dissolve contents. • Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be a clear, colorless solution. • Use immediately. The reconstituted RAPIBLYK solution storage conditions are described in Table 2. • Discard unused portion. Table 2: Reconstituted RAPIBLYK Solution Storage and Use Conditions Diluent used to Prepare Solution Reconstituted RAPIBLYK Solution Storage and Use Conditions 50 mL of 0.9% Sodium Chloride Injection, USP Use within 4 hours at room temperature (25°C, 77°F) 50 mL of 5% Dextrose Injection, USP Use within 48 hours at room temperature (25°C, 77°F) 2.4 Administration Following reconstitution, the product contains 280 mg landiolol/50 mL = 5.6 mg/mL. Reference ID: 5484332 The infusion rate can be calculated as: Infusion rate (mL/hour) = target dose (mcg/kg/min) × body weight (kg) / 93 3 DOSAGE FORMS AND STRENGTHS For injection: White to almost white lyophilized powder in a single-dose vial containing 280 mg of landiolol (equivalent to 300 mg landiolol HCl). 4 CONTRAINDICATIONS RAPIBLYK is contraindicated in patients with: • Severe sinus bradycardia, sick sinus syndrome, heart block greater than first degree [see Warnings and Precautions (5.2)]. • Decompensated heart failure [see Warnings and Precautions (5.3)]. • Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest. • Pulmonary hypertension: May precipitate cardiorespiratory decompensation. • Hypersensitivity reactions, including anaphylaxis, to landiolol or any of the inactive ingredients 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension Patients with hemodynamic compromise, hypovolemia, or on interacting medications are at increased risk of hypotension. Monitor blood pressure closely, especially if pretreatment blood pressure is low. Reduce or stop RAPIBLYK injection for hypotension then expect the blood pressure effect to wane within 30 minutes. 5.2 Bradycardia Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders are at increased risk of bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest. Monitor heart rate and rhythm in patients receiving RAPIBLYK injection. Reduce or stop RAPIBLYK injection for bradyarrhythmia. 5.3 Cardiac Failure Beta-blockers, like RAPIBLYK, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop RAPIBLYK injection and start supportive therapy [see Overdosage (10)]. 5.4 Reactive Airways Disease Patients with reactive airways disease should, in general, not receive beta-blockers. Because of its relative beta 1 selectivity and titratability, RAPIBLYK injection may be titrated to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta-2 stimulating agent may be administered with appropriate monitoring of ventricular rates. 5.5 Use in Patients with Diabetes Mellitus and Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus, patients who are fasting (i.e., surgery, not eating regularly, or are vomiting), or children. Monitor for signs and symptoms of hypoglycemia in patients receiving RAPIBLYK. Reference ID: 5484332 5.6 Infusion Site Reactions Infusion site reactions such as pain, swelling and erythema have occurred with the use of RAPIBLYK injection. Avoid infusions into small veins or through a butterfly catheter. If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation. 5.7 Use in Patients with Prinzmetal’s Angina Beta-blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction. 5.8 Use in Patients with Pheochromocytoma If RAPIBLYK injection is used in the setting of pheochromocytoma, administer RAPIBLYK in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers without opposing alpha blockade in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure from the attenuation of beta receptor-mediated vasodilation in skeletal muscle. 5.9 Use in Patients with Peripheral Circulatory Disorders RAPIBLYK injection may exacerbate peripheral circulatory disorders, such as Raynaud’s disease or syndrome, and peripheral occlusive vascular disease. 5.10 Abrupt Discontinuation of RAPIBLYK Injection Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta-blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing RAPIBLYK injection. 5.11 Hyperkalemia Beta-blockers, including RAPIBLYK injection, can cause increases in serum potassium and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta- blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with RAPIBLYK injection. 5.12 Use in Patients with Metabolic Acidosis Beta-blockers have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility. 5.13 Use in Patients with Hyperthyroidism Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy. 5.14 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions When using beta-blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)]. Reference ID: 5484332 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Landiolol injection was studied in 19 placebo-controlled clinical trials involving 1,761 patients (in a variety of clinical in-patient settings) with supraventricular tachycardia or at high risk for supraventricular tachycardia. The most important and common adverse reaction is hypotension, which occurred in 9.9% of patients receiving RAPIBLYK vs. 1% in those receiving placebo [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS 7.1 Negative Inotropes and Chronotropes Avoid concomitant use of RAPIBLYK with negative inotropes and medications that slow heart rate or cardiac conduction. Beta-blockers, like RAPIBLYK, can cause depression of myocardial contractility and increase the risk of bradycardia or heart block. Concomitant use of RAPIBLYK with negative inotropes or chronotropes may augment these effects [see Warnings and Precautions (5.2)(5.3)]. 7.2 Sympathomimetics, Positive Inotropes and Vasoconstrictors Beta adrenergic agonists will antagonize the effects of RAPIBLYK and may attenuate the heart rate lowering effects of RAPIBLYK. Positive inotropes and vasoconstrictors may attenuate the heart rate and blood pressure lowering effects of RAPIBLYK. 7.3. Catecholamine Depleting Drugs Observe patients treated with RAPIBLYK plus a catecholamine depletor (e.g., reserpine, monoamine oxidase inhibitors) for hypotension or marked bradycardia, which may cause vertigo, syncope, or postural hypotension. Catecholamine depleting drugs may have an additive effect when given with beta-blockers, which may increase the risk of hypotension or marked bradycardia related vertigo, syncope, or postural hypotension [see Warnings and Precautions (5.1)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available published data on RAPIBLYK use in pregnant women are insufficient to inform a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Landiolol exposure was limited to a single injection at the time of Cesarean delivery in a small clinical trial. Neonatal bradycardia, hypoglycemia, and respiratory depression have been observed with use of beta-blockers in pregnancy near the time of delivery (see Clinical Considerations). Administration of landiolol to pregnant rats showed distribution of landiolol to the placenta and the fetus. In animal reproduction studies, no embryo-fetal toxicity was observed in rats or rabbits during the period of organogenesis at landiolol exposure in rats approximately 2.7 times human exposure at the maximum recommended human dose (MRHD) (see Data). Reference ID: 5484332 The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Landiolol crosses the placenta in rats. Neonates born to mothers who are receiving landiolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Monitor neonates exposed to landiolol during pregnancy and labor for hypotension, hypoglycemia, bradycardia, and respiratory depression and manage accordingly. Data Animal Data Landiolol HCl was administered intravenously to pregnant rats (25, 50, or 100 mg/kg/day from gestation day 7 to 17) and rabbits (25, 50, or 100 mg/kg/day from gestation day 8 to 18). No adverse embryo-fetal effects were observed in rats at the landiolol HCl dose of 25 mg/kg/day, resulting in systemic landiolol exposure (AUC) of approximately 2.7-times the exposure at the MRHD. In rabbits, no adverse embryo-fetal effects were detected at the landiolol HCl dose of 100 mg/kg/day; the resulting systemic landiolol exposure (AUC) at this dose level was not determined. In a prenatal and postnatal development study in rats, landiolol HCl was administered intravenously at 25, 50, or 100 mg/kg/day from gestation day 17 to postpartum/lactation day 20. A decrease in the viability index for the offspring on postpartum day 4 was observed for the high dose group. No effect on pre/post-natal development was observed at 50 mg/kg dose, which represents landiolol exposures approximately 5.4 times the human exposure at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of landiolol and its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, other drugs in this class are detected in human milk. Landiolol was present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk, but the concentration of landiolol in animal milk does not necessarily predict the concentration of drug in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RAPIBLYK and any potential adverse effects on the breast fed infant from RAPIBLYK or from the underlying maternal condition. Clinical Considerations Monitoring for adverse reactions Monitor the breastfed infant for bradycardia and other symptoms of beta blockade, such as lethargy (hypoglycemia). Reference ID: 5484332 Data In a lactation study, administration of 14C-landiolol HCl administered as a single 1 mg/kg intravenous injection to lactating rats on postpartum/lactation day 13 to 14 was excreted in milk corresponding to approximately 70% of the concentration in plasma. 8.3 Pediatric Use The safety and effectiveness of RAPIBLYK injection in pediatric patients have not been established. 8.4 Geriatric Use Clinical studies of RAPIBLYK did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting greater frequency of decreased renal or cardiac function and of concomitant disease or other drug therapy. 8.5 Hepatic Impairment More conservative dose titration is recommended in patients with mild hepatic impairment (Child-Pugh A). The effect of moderate or severe hepatic impairment (Child-Pugh B or C) on landiolol pharmacokinetics is unknown. Avoid use of RAPIBLYK in patients with moderate or severe hepatic impairment (Child-Pugh B or C). [see Pharmacokinetics (12.3)]. 10 OVERDOSAGE 10.1 Signs and Symptoms of Overdose Overdoses of RAPIBLYK injection can cause adverse cardiac and central nervous system effects. These adverse effects may precipitate severe signs, symptoms, sequelae, and complications such as severe cardiac and respiratory failure, including shock and coma, and may be fatal. Continuous monitoring of the patient is required. • Cardiac adverse effects include bradycardia, atrioventricular block (1-, 2-, 3-degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity. • Central nervous system adverse effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma. • In addition, bronchospasm, hyperkalemia, and hypoglycemia (especially in children) may occur. 10.2 Treatment Recommendations Because of its approximately 4-minute elimination half-life, the first step in the management of toxicity should be to discontinue RAPIBLYK infusion. Then, based on the observed clinical effects, consider the following general measures: Bradycardia Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing. Cardiac Failure Consider intravenous administration of a diuretic or digitalis glycoside. In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, milrinone or inamrinone. Reference ID: 5484332 Symptomatic Hypotension Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine. Bronchospasm Consider intravenous administration of a beta agonist or a theophylline derivative. 11 DESCRIPTION RAPIBLYK (landiolol) for injection is a beta-1 adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 4 minutes). Landiolol is: • [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholine-4 carbonylamino)ethylamino]propoxy]phenyl]propionate and has the following structure: O O (S) O O H N N O (S) O N H OH O HCl • The active pharmaceutical ingredient is the hydrochloride salt of landiolol, which has the empirical formula C25H39N3O8 ∙ HCl and a molecular weight of 546.06 g/mol. It has two chiral centers and is used as pure S,S-enantiomer. • Landiolol HCl is a white crystalline powder. It is a relatively hydrophilic compound, which is very soluble in water. RAPIBLYK is supplied as a single presentation of 280 mg landiolol (equivalent to 300 mg landiolol HCl) as a white to almost white sterile lyophilized powder for intravenous injection in a 50 mL vial. Inactive ingredients include 300 mg of mannitol and sodium hydroxide as needed to adjust pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action RAPIBLYK is a selective beta-1-adrenoreceptor antagonist that inhibits the positive chronotropic effects of the catecholamines, epinephrine and norepinephrine, on the heart, where beta-1-receptors are predominantly located. Landiolol does not exhibit any membrane-stabilizing activity or intrinsic sympathomimetic activity at the approved recommend dosage in vitro. 12.2 Pharmacodynamics Landiolol exposure-response relationships and the time course of pharmacodynamic response are not fully characterized. 12.3 Pharmacokinetics Landiolol peak plasma concentration (Cmax) over the approved dosage range in healthy volunteers and patients with atrial fibrillation or atrial flutter is provided in Table 3. Reference ID: 5484332 Table 3: Landiolol peak plasma concentration (Cmax) in healthy volunteers and patients with atrial fibrillation or atrial flutter. Landiolol Dosage Peak Plasma Concentration (Cmax) Healthy Volunteers (mean)a Atrial Fibrillation or Atrial Flutter Patients (range) 9.3 mcg/kg/min 0.2 mcg/mL Not studied 18.6 mcg/kg/min 0.5 mcg/mL Not studied 37.3 mcg/kg/min 1.0 mcg/mL 0.52 to 1.77 mcg/mL a= 2 hour infusion 9.3 mcg/kg/min landiolol is equivalent to 10 mcg/kg/min landiolol hydrochloride. Landiolol pharmacokinetics increases dose-proportionally in the dosage range of 9.3 to 74.6 mcg/kg/min (2 times the maximum approved recommended dosage). Landiolol reached steady-state values approximately 15 minutes after initiation of the infusion. Distribution Landiolol steady state volume of distribution is 0.4 L/kg. Landiolol protein binding is <10%. Elimination Landiolol elimination half-life is 4.5 minutes at steady state. Total body clearance of landiolol is 57 mL/kg/min following a 20-hour continuous landiolol infusion of 37.3 mcg/kg/min. Metabolism Landiolol is primarily metabolized by pseudocholinesterases and carboxylesterases in the plasma to the active metabolite M1. M1 has less than 1/40th of the pharmacological activity of landiolol. M1 AUC0-inf is approximately 12 times greater than landiolol. Excretion Approximately 50 to 75% of the landiolol administered dose (approximately half of this as metabolite M1, and 8% as parent) is recovered in urine at 4 hours and 89 to 99% at 24 hours following a 60 min intravenous infusion. Specific Populations The effect of age and renal impairment on landiolol pharmacokinetics is unknown. Patients with hepatic impairment Landiolol geometric mean AUC increased by 44% and Cmax by 42% in 5 patients with mild hepatic impairment (Child-Pugh A) and 1 patient with moderate hepatic impairment (Child-Pugh B). The effect of moderate hepatic impairment (Child-Pugh B) on landiolol pharmacokinetics has not been fully characterized and the effect of severe hepatic impairment (Child-Pugh C) is unknown. Drug Interaction Studies In Vitro Studies Reference ID: 5484332 CYP 450 enzymes: Landiolol and the metabolite M1 are time-dependent CYP 2D6 inhibitors at exposures approximately 50 times the human exposure at the MRHD, but do not inhibit CYP 1A2, 2C9, 2C19, or 3A4. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies have not been conducted to evaluate the carcinogenic potential of RAPIBLYK. Mutagenesis Landiolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK +/-, and in vivo micronucleus test in rats). Impairment of Fertility No adverse effects on fertility were observed in male and female rats administered a landiolol HCl dose of 100 mg/kg/day, resulting in systemic exposure (AUC) approximately 10-times the exposure at the MRHD. 14 CLINICAL STUDIES In 5 randomized, double-blind, placebo-controlled studies, treatment of 317 adults with supraventricular tachycardia with landiolol decreased heart rate in 40-90% of treated patients within about 10 minutes, compared to 0-11% of patients who received placebo; heart rate decrease was defined as a >20% decrease in heart rate or a heart rate <100 bpm or at least intermittent cessation of the arrhythmia. The infused dose of landiolol in these studies ranged from 9.3 to 74.6 mcg/kg/min (equivalent to 10 to 80 mcg/kg/min landiolol hydrochloride). 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RAPIBLYK is supplied as a white to almost white, preservative-free, lyophilized powder in single dose vials containing 280 mg landiolol for injection (equivalent to 300 mg landiolol HCl). Each vial is supplied in a carton NDC 84381-110-01 16.2 Storage Store unreconstituted product at 20°C to 25°C (68ºF to 77ºF) [see USP Controlled Room Temperature], with excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Manufactured for: AOP Orphan Pharmaceuticals GmbH Leopold-Ungar-Platz 2 1190 Vienna Austria Part number/ Reference ID: 5484332	custom-source	2025-02-12T15:47:00.406853	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217202s000lbl.pdf', 'application_number': 217202, 'submission_type': 'ORIG ', 'submission_number': 1}
80,325	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use COMBOGESIC® safely and effectively. See full prescribing information for COMBOGESIC®. COMBOGESIC® (acetaminophen and ibuprofen) tablets, for oral use. Initial U.S. Approval: 2023 WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK AND GASTROINTESTINAL RISK See full prescribing information for complete boxed warning. • COMBOGESIC contains acetaminophen, which has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4,000 milligrams per day, and often involve more than one acetaminophen containing product (5.1). • Nonsteroidal anti-inflammatory drugs (NSAIDS), like the ibuprofen in COMBOGESIC, cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.2). • COMBOGESIC tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (5.2). • NSAIDS, like the ibuprofen in COMBOGESIC, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.3). ---------------------------RECENT MAJOR CHANGES------------------------ Warnings and Precautions (5.9) 11/2024 ----------------------------INDICATIONSANDUSAGE----------------------------- COMBOGESIC is a combination of acetaminophen and ibuprofen, a non- steroidal anti-inflammatory drug (NSAID), and is indicated in adults for the short-term management of mild to moderate acute pain (1). ----------------------DOSAGEANDADMINISTRATION------------------------- • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2). • Do not administer with other acetaminophen-containing products (2). Three tablets every 6 hours as needed for pain relief, up to a maximum of 12 tablets per day. (2). ---------------------DOSAGE FORMS AND STRENGTHS------------------------ • Film-coated tablet containing 325 mg acetaminophen and 97.5 mg ibuprofen (3). -------------------------------CONTRAINDICATIONS------------------------------ COMBOGESIC is contraindicated in: • patients with known hypersensitivity to acetaminophen, ibuprofen, other NSAIDs, or to any of the excipients in this product (4). • patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (4) • the setting of coronary artery bypass graft (CABG) surgery (4). -----------------------WARNINGSANDPRECAUTIONS-------------------------- • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4). • Heart Failure and Edema: Avoid use of COMBOGESIC in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5). • Renal Toxicity: Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC, has resulted in renal papillary necrosis and other renal injury (5.6). • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7). • Exacerbation of Asthma Related to Aspirin Sensitivity: COMBOGESIC is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8). • Serious Skin Reactions: Discontinue COMBOGESIC at first appearance of skin rash or other signs of hypersensitivity (5.9). • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). • Fetal Toxicity: Limit use of NSAID-containing products, including COMBOGESIC, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAID-containing products, including COMBOGESIC in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11). • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12). ------------------------------ADVERSE REACTIONS----------------------------------- The most common adverse reactions (greater than or equal to 2%) are nausea, vomiting, headache, dizziness, somnolence, post-procedural hemorrhage, and swelling of the face (6). To report SUSPECTED ADVERSE REACTIONS, contact [NAME OF U.S. DISTRIBUTOR] at [PHONE] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS----------------------------------- A number of known or potential interactions between COMBOGESIC and other drugs/drug classes exist. Please refer to the Drug Interactions section (7) for further information. -----------------------USE IN SPECIFIC POPULATIONS------------------------- • Infertility: NSAID-containing products, including COMBOGESIC, are associated with reversible infertility. Consider withdrawal of COMBOGESIC tablets in women who have difficulties conceiving. (8.3) • Renal or hepatic impairment: Not recommended (5.1, 5.6, 8.6, 8.7). See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide. Revised: 11/2024 Reference ID: 5482802 FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, AND GASTROINTESTINAL RISK 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 3 DOSAGE FORMS AND STRENGTHS 8.3 Females and Males of Reproductive Potential 4 CONTRAINDICATIONS 8.4 Pediatric Use 5 WARNINGS AND PRECAUTIONS 8.5 Geriatric Use 5.1 Hepatotoxicity 8.6 Use in Renal Disease 5.2 Cardiovascular Thrombotic Events 8.7 Use in Hepatic Disease 5.3 Gastrointestinal Bleeding, Ulceration, and 10 OVERDOSAGE Perforation 11 DESCRIPTION 5.4 Hypertension 12 CLINICAL PHARMACOLOGY 5.5 Heart Failure and Edema 12.1 Mechanism of Action 5.6 Renal Toxicity and Hyperkalemia 12.2 Pharmacodynamics 5.7 Anaphylaxis and Other Hypersensitivity 12.3 Pharmacokinetics Reactions 13 NONCLINICAL TOXICOLOGY 5.8 Exacerbation of Asthma Related to Aspirin 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Sensitivity 14 CLINICAL STUDIES 5.9 Serious Skin Reactions 16 HOW SUPPLIED/STORAGE AND HANDLING 5.10 Drug Rash with Eosinophilia and Systemic 17 PATIENT COUNSELING INFORMATION Symptoms (DRESS) 5.11 Fetal Toxicity *Sections or subsections omitted from the full prescribing information are not 5.12 Hematological Toxicity listed. 5.13 Ophthalmological Effects 5.14 Aseptic Meningitis 5.15 Masking of Inflammation and Fever 5.16 Laboratory Monitoring Reference ID: 5482802 FULL PRESCRIBING INFORMATION WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, AND GASTROINTESTINAL RISK HEPATOTOXICITY COMBOGESIC contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.1)]. CARDIOVASCULAR RISK COMBOGESIC contains ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. [see Warnings and Precautions (5.2)]. COMBOGESIC is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.2)]. GASTROINTESTINAL RISK NSAIDS cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.3)]. . 1 INDICATIONS AND USAGE COMBOGESIC is indicated in adults for the short-term management of mild to moderate acute pain. 2 DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. • Do not exceed the recommended dose of COMBOGESIC in 24 hours [see (2) below]. • Do not co-administer COMBOGESIC with other acetaminophen- or NSAID-containing products [see Warnings and Precautions (5.1, 5.2, 5.3)]. The recommended dose of COMBOGESIC is 3 tablets every 6 hours as needed for pain relief, up to a maximum of 12 tablets per day. Reference ID: 5482802 3 DOSAGE FORMS AND STRENGTHS Tablets: white, biconvex, capsule-shaped, film-coated tablets, debossed with the letters “CG” on one side and plain on the other side, each containing 325 mg acetaminophen and 97.5 mg ibuprofen. 4 CONTRAINDICATIONS COMBOGESIC is contraindicated in: • patients with a known hypersensitivity (e.g., anaphylactic reactions, serious skin reactions) to acetaminophen, ibuprofen, other NSAIDs, or to any of the excipients in this product [see Warnings and Precautions (5.7, 5.8, 5.9)]. • patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDS [see Warnings and Precautions (5.7 and 5.8)]. • the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Acetaminophen COMBOGESIC contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involved more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Ibuprofen Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including ibuprofen. Reference ID: 5482802 Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue COMBOGESIC immediately, and perform a clinical evaluation of the patient. COMBOGESIC has not been studied in patients with impaired hepatic function. The use of COMBOGESIC in patients with hepatic impairment is not recommended. 5.2 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.3)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Reference ID: 5482802 Avoid the use of COMBOGESIC in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If COMBOGESIC is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.3 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including the ibuprofen in COMBOGESIC tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term therapy is not without risk. Risk Factors for Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless the benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternative therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate additional evaluation and treatment, and discontinue COMBOGESIC until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.4 Hypertension NSAIDs, including the ibuprofen in COMBOGESIC, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Reference ID: 5482802 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo- treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of COMBOGESIC in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If COMBOGESIC is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC, has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylaxis and Other Hypersensitivity Reactions Acetaminophen There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue COMBOGESIC immediately and seek emergency medical care if they experience these symptoms. Do not prescribe COMBOGESIC for patients with acetaminophen allergy [see Contraindications (4)]. Reference ID: 5482802 Ibuprofen NSAIDs, including the ibuprofen in COMBOGESIC, has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma. Instruct patients to discontinue COMBOGESIC immediately and seek emergency medical care if they experience these symptoms. Do not prescribe COMBOGESIC for patients with ibuprofen or NSAID allergy [see Contraindications (4) and Warnings and Precautions (5.8)]. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, COMBOGESIC is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When COMBOGESIC is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions COMBOGESIC contains acetaminophen and ibuprofen. Acetaminophen or NSAIDs, including ibuprofen, may cause serious skin adverse events such as exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of COMBOGESIC at the first appearance of skin rash or any other sign of hypersensitivity. COMBOGESIC is contraindicated in patients with previous serious skin reactions to acetaminophen or NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs, such as the ibuprofen in COMBOGESIC. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue COMBOGESIC and evaluate the patient immediately. Reference ID: 5482802 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAID-containing products, including COMBOGESIC, in pregnant women at about 30 weeks gestation and later. NSAID-containing products, including COMBOGESIC, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAID-containing products, including COMBOGESIC, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If, after careful consideration of alternative treatment options for pain management, NSAID- treatment is necessary between about 20 weeks and 30 weeks gestation, limit COMBOGESIC use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if COMBOGESIC treatment extends beyond 48 hours. Discontinue COMBOGESIC if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with COMBOGESIC has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including the ibuprofen in COMBOGESIC, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Ophthalmological Effects Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported in patients receiving ibuprofen. If a patient develops such complaints while receiving COMBOGESIC, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing. 5.14 Aseptic Meningitis Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not Reference ID: 5482802 have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on COMBOGESIC, the possibility of its being related to ibuprofen should be considered. 5.15 Masking of Inflammation and Fever The pharmacological activity of COMBOGESIC in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.16 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.1, 5.3, 5.6)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions to ibuprofen or acetaminophen are described elsewhere in other sections of the labelling. • Hepatotoxicity [see Warnings and Precautions (5.1)] • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.2)] • Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylaxis and Other Hypersensitivity Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] The most common adverse reactions (incidence of ≥ 2% for patients receiving COMBOGESIC®) are: nausea, vomiting, headache, dizziness, somnolence, post-procedural hemorrhage, and swelling of the face (Table 1). 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to the rates reported from clinical trials of another drug and may not reflect the rates observed in practice. The clinical trials of COMBOGESIC® have been conducted in patients with postoperative pain following dental and arthroscopic procedures, who received double-blind treatment every 6 hours for 24 or 48 hours. Most commonly (≥2%) reported adverse reactions by organ system during double-blind treatment are listed in the table below. Adverse reactions are closely related to the extent (the level and length) of exposure. The incidences of overall and individual adverse reactions reported during the double-blind treatment period did not suggest an increase of risks associated with short-term (up Reference ID: 5482802 to one or two days) use of the combination drug, COMBOGESIC® in comparison to each individual component, acetaminophen or ibuprofen, and to placebo. Table 1: Most commonly (≥2%) reported adverse reactions by organ system during double-blind treatment COMBOGESIC® N=261 Acetaminophen N=231 Ibuprofen N=231 Placebo N=199 Total number of AEs 145 142 101 133 % of patients with ≥1 AE 30 38 29 37 Gastrointestinal disorders Nausea 15 19 12 23 Vomiting 7 10 3 10 Constipation 1 2 1 1 Dyspepsia 0.4 1 2 1 Injury, poisoning and procedural complications Post Procedural Hemorrhage 2 0.4 1 2 Nervous system disorders Headache 5 6 4 7 Dizziness 3 4 4 5 Somnolence 2 1 0 1 Skin and subcutaneous tissue disorders Swelling face 2 4 4 3 Pruritus 0.4 0.4 0.4 3 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of acetaminophen and ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS Table 2: Clinically Significant Drug Interactions with COMBOGESIC Drugs That Interfere with Hemostasis Clinical Impact: • Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere Reference ID: 5482802 with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of COMBOGESIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.3)]. Intervention: Concomitant use of COMBOGESIC and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.3)]. COMBOGESIC is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of COMBOGESIC and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of COMBOGESIC and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COMBOGESIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.4 and 5.6)]. Digoxin Reference ID: 5482802 Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of COMBOGESIC and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COMBOGESIC and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of COMBOGESIC and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NSAIDS and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of COMBIOGESIC and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.3)]. Intervention: The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NSAIDS and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of COMBOGESIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Reference ID: 5482802 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Ibuprofen Use of NSAID-containing products, including COMBOGESIC, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of COMBOGESIC use between about 20 and 30 weeks of gestation and avoid COMBOGESIC use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus: Use of NSAID-containing products, including COMBOGESIC, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Use of NSAID-containing products, including COMBOGESIC, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimester of pregnancy are inconclusive. In published animal reproduction studies, there were no clear developmental effects at doses up to 2.7-times the maximum human daily dose (MHDD) in the rabbit and 1.5-times in the MHDD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 2.2-times the MHDD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Acetaminophen Prolonged experience with acetaminophen in pregnant women over several decades, based on published observational epidemiological studies and case reports, did not identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data). Reproductive and developmental studies in rats and mice from the published literature have identified adverse events at clinically relevant doses of acetaminophen. Fetotoxicity, increases in bone variations in the fetuses, and necrosis in the fetus liver and kidney have been noted in studies in rats. In mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm Reference ID: 5482802 in their offspring and reduced birth weight in the next generation. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAID-containing products, including COMBOGESIC, in women at about 30 weeks gestation and later in pregnancy, because NSAID-containing products, including COMBOGESIC, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If, after consideration of alternative treatments for pain management, an NSAID-containing product, including COMBOGESIC, is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If COMBOGESIC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue COMBOGESIC and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of COMBOGESIC during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Ibuprofen: Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of Reference ID: 5482802 neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Acetaminophen: The results from a large population-based prospective cohort, including data from 26,424 women with live born singletons who were exposed to oral acetaminophen during the first trimester, indicate no increased risk for congenital malformations, compared to a control group of unexposed children. The rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study showed that 11,610 children with prenatal exposure to acetaminophen during the first trimester had no increased risk of major birth defects compared to 4,500 children in the control group. Other epidemiological data showed similar results. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including recall bias. Animal Data Ibuprofen: In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.12, 0.33, or 0.99 times the maximum human daily dose of 1170 mg of ibuprofen based on a body surface area comparison) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.06, 0.17, 0.50, 1.5-times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above. In a published study, rats were orally dosed with 300 mg/kg ibuprofen (2.5-times the maximum human daily dose of 1170 mg based on a body surface area comparison) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity. One incidence each of a membranous ventricular septal defect and gastroschisis was noted fetuses from rabbits treated with 500 mg/kg (8.3-times the maximum human daily dose) from Gestation Day 9 to 11. Reference ID: 5482802 Acetaminophen: Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.87-times the maximum human daily dose (MHDD = 3.9 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose- related increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses of 1.2-times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral acetaminophen at doses 0.3-times the MHDD, based on a body surface area comparison. In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.45, 0.89, and 1.8 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. 8.2 Lactation Risk Summary The components of COMBOGESIC, ibuprofen and acetaminophen, are present in human milk. Limited published literature reports that, orally administered ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose. There are no reports of adverse effects of ibuprofen on the breastfed infant and no effects on milk production. Limited published studies report that orally administered acetaminophen passes rapidly into human milk with similar levels in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral administration of 1 gram acetaminophen. There is one well-documented report of a rash in a breast fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COMBOGESIC and any potential adverse effects on the breastfed infant from COMBOGESIC or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Ibuprofen Based on the mechanism of action, the use of prostaglandin mediated NSAID-containing products, Reference ID: 5482802 including COMBOGESIC, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAID containing products, including COMBOGESIC in women who have difficulties conceiving or who are undergoing investigation of infertility. Acetaminophen Based on animal data, use of acetaminophen may cause reduced fertility in males and females of reproductive potential. It is not known whether these effects on fertility are reversible. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are approximately 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, and reduced fertility. In female animals given the same doses, reduced implantation sites were reported. Additional published animal studies indicate that acetaminophen exposure in utero adversely impacts reproductive capacity of both male and female offspring at clinically relevant exposures [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of COMBOGESIC in pediatric patients have not been established. COMBOGESIC is not approved for patients under 18 years of age. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)]. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Use in Renal Disease COMBOGESIC has not been studied in patients with impaired renal function. The use of COMBOGESIC in patients with renal impairment is not recommended [see Warnings and Precautions (5.6)]. 8.7 Use in Hepatic Disease COMBOGESIC has not been studied in patients with impaired hepatic function. The use of COMBOGESIC in patients with hepatic impairment is not recommended [see Warnings and Precautions (5.1)]. Reference ID: 5482802 10 OVERDOSAGE COMBOGESIC is a combination product. The clinical presentation of overdose may include the signs and symptoms of acetaminophen toxicity, ibuprofen toxicity, or both. Acetaminophen The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects also may occur. Plasma acetaminophen levels >300 mcg/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are <150 mcg/mL or <37.5 mcg/mL at 12 hours after ingestion. If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram Rumack-Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the acetaminophen level is below the lower line. Ibuprofen Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.6, 5.14)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may benefit the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients if clinically appropriate. 11 DESCRIPTION COMBOGESIC tablets are a combination of acetaminophen, an analgesic and antipyretic, and ibuprofen, a non-steroidal anti-inflammatory drug (NSAID). Reference ID: 5482802 HO OH 0 The chemical name for acetaminophen is N-acetyl-p-aminophenol. The molecular formula is C8H9NO2 and the structural formula is: The molecular weight of acetaminophen is 151.17. Acetaminophen is a white, odorless, crystalline powder, possessing a slightly bitter taste. Acetaminophen is soluble in boiling water and 1N sodium hydroxide, and is freely soluble in alcohol. The chemical name for ibuprofen is (±)-2-(p-isobutylphenyl) propionic acid. The molecular formula is C13H18O2 and the structural formula is: The molecular weight of ibuprofen is 206.29. Ibuprofen is a white powder with a melting point of 74-77°C and is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. COMBOGESIC tablets contain 325 mg acetaminophen and 97.5 mg ibuprofen and are white in color. The inactive ingredients in the tablet are croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, medium chain triglycerides, microcrystalline cellulose, polydextrose, povidone-30, sodium lauryl sulfate, talc, titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Analgesia COMBOGESIC contains acetaminophen and ibuprofen. Acetaminophen is a non-opiate, non-salicylate analgesic. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to primarily involve central actions. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). Its mechanism of action for analgesia, like that of other NSAIDs, is not completely understood, but involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins Reference ID: 5482802 are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics Hematological Effects NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. 12.3 Pharmacokinetics Absorption Peak plasma concentration following the administration of three COMBOGESIC tablets occurs at approximately 45 minutes and 1 hour 15 minutes after administration for acetaminophen and ibuprofen, respectively, under fasting condition. In the same study, the peak plasma concentration (Cmax) and the extent of absorption (AUC0-inf) are 14.88 mcg/mL and 47.44 mcg.h/mL for acetaminophen and 25.58 mcg/mL and 95.62 mcg.h/mL for ibuprofen, respectively. The Cmax and AUC0-inf values for both acetaminophen and ibuprofen increase dose proportionally to increases in COMBOGESIC doses from one, to two, to three tablets. A single-dose pharmacokinetic study of COMBOGESIC in volunteers showed no drug interactions between acetaminophen and ibuprofen. Food effects When COMBOGESIC was administered with food, the time to peak plasma concentration was delayed by approximately 30 minutes for acetaminophen and was approximately the same when compared to fasting conditions for ibuprofen. The peak plasma concentration of acetaminophen was reduced by approximately 30%, but the extent of absorption was not affected. Peak plasma concentration and the extent of absorption were not affected for ibuprofen. Distribution Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (~20%) of acetaminophen is bound to plasma protein. Elimination The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Ibuprofen is rapidly metabolized and eliminated in the urine. The elimination half-life of ibuprofen is in the range of 1.9 to 2.2 hours. Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: a) conjugation with glucuronide; b) conjugation with sulfate; and Reference ID: 5482802 c) oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates. Excretion Less than 9% of acetaminophen is excreted unchanged in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. Studies have shown that following ingestion of ibuprofen 45% to 79% of the dose was recovered in the urine within 24 hours as metabolite A (25%), (+)-2-[p-(2hydroxymethyl-propyl) phenyl]propionic acid and metabolite B (37%), (+)-2-[p-(2carboxypropyl)phenyl]propionic acid; the percentages of free and conjugated ibuprofen were approximately 1% and 14%, respectively. Specific Populations Pediatric Patients The pharmacokinetics of COMBOGESIC has not been studied in pediatric patients below 18 years of age. Hepatic Impairment The pharmacokinetics of COMBOGESIC in patients with impaired hepatic function has not been studied [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)]. Renal Impairment The pharmacokinetics of COMBOGESIC in patients with renal impairment has not been studied. [see Warnings and Precautions (5.6) and Use in Specific Populations (8.6)]. Drug Interaction Studies Aspirin: When ibuprofen is administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen is not altered. The clinical significance of this interaction is not known [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Studies to evaluate the potential effects of COMBOGESIC on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted. Carcinogenesis Acetaminophen Reference ID: 5482802 Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 3.9 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats (0.7 times) or mice (1.3-1.5 times the MHDD, based on a body surface area comparison). Ibuprofen Adequate long-term animal studies have not been conducted to evaluate the carcinogenic potential of ibuprofen. Mutagenesis Acetaminophen Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast, acetaminophen tested positive in the in vitro mouse lymphoma assay and the in vitro chromosomal aberration assay using human lymphocytes. In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1500 mg/kg/day to the rat model (3.7-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.9-times the MHDD, based on a body surface area comparison), suggesting a threshold effect. Ibuprofen In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Impairment of Fertility Acetaminophen In studies of acetaminophen conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 1.8 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.8 times the MHDD (based on a body surface area comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. Reference ID: 5482802 In a published mouse study, oral administration of 50 mg/kg acetaminophen to pregnant mice from Gestation Day 7 to delivery (0.062 times the MHDD) reduced the number of primordial follicles in female offspring and reduced the percentage of full term pregnancies and number of pups born to these females exposed to acetaminophen in utero. In a published study, pregnant rats oral administration of 350 mg/kg acetaminophen (0.87 times the MHDD) from Gestation Day 13 to 21 (dams), reduced the number of germ cells in the fetal ovary and decreased ovary weight and reduced number of pups per litter in F1 females as well as reduced ovary weights in F2 females. Ibuprofen In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.17-times the MHDD based on body surface area comparison) did not impact male or female fertility or litter size. In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.023-times the MHDD based on a body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males but decreased ovulation was reported in females. 14 CLINICAL STUDIES In a Phase 3 efficacy study in 110 patients (aged from 16 to 55 years, approximately two-thirds female, and more than 80% Caucasian) with post-procedural pain following surgical extraction of impacted wisdom teeth, three tablets of COMBOGESIC provided greater pain reduction than placebo or comparable doses of acetaminophen or ibuprofen alone. The treatment differences were measured by the primary end point. The treatment differences in the time-adjusted Summed Pain Intensity Difference over the first 48 hours (SPID 0-48), are statistically significant as summarized in the table below. Table 3: Summary of Time-adjusted SPID (0-48 Hours) by Treatment Group Ibuprofen Acetaminophen Placebo COMBOGESIC 97.5 mg 325 mg N=112 N=111 N=75 N=110 Mean 23.18 17.71 14.86 31.56 SE 1.89 1.89 2.26 1.94 95% CI (Lower) 19.47 14.00 10.43 27.76 95% (Upper) 26.89 21.43 19.30 35.37 P-value COMBOGESIC <0.001 <0.001 <0.001 - The observed treatment differences over the first six hours are illustrated by the separation of pain curves as shown in Figure 1 below. Reference ID: 5482802 40 35 30 E 25 E (lJ u C ~ 20 ~ ci ~ 15 ·.;; C 2 C 10 C "' a. 5 0 -5 ........... •······)(······························,c ......... . 4 Time (h) •••·· " X . -- -- - coMBOGESIC (n=ll0) .... ,c ... Ibuprofen (n=112) ---.. - Acetaminophen (n=lll) --+-- Placebo (n=75) 6 Figure 1: Pain Intensity Differences from baseline over the first dose interval of AFT-MX-6 16 HOW SUPPLIED/STORAGE AND HANDLING COMBOGESIC tablets with acetaminophen 325 mg and ibuprofen 97.5 mg are white, biconvex, capsule-shaped film coated tablets, debossed with the letters “CG” on one side and plain on the other side and are available as follows: NDC 72260-129-01 1 bottle containing 250 tablets Store at 20- 25°C (68°F to 77°F) with excursions permitted within USP controlled room temperature of 15 – 30°C (59 - 86°F). Protect from moisture and light. Reference ID: 5482802 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Important Dosage and Administration Information: • Clearly explain to patients the single-dose and 24-hour dose limit and the time interval between doses. Explain that exceeding these recommendations can result in hepatic toxicity and/or gastrointestinal bleeding, ulceration, and perforation [See Dosage and Administration (2), Warnings and Precautions (5.1, 5.3)]. • Inform patients that the concomitant use of COMBOGESIC with other NSAIDs, acetaminophen-containing products, or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of hepatic and gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.1, 5.3), Drug Interactions (7)]. Alert patients that these may be present in “over the counter” medications for treatment of colds, fever, or insomnia. • Alert patients that NSAIDs and acetaminophen may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Hepatotoxicity: Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms). Instruct patients to stop therapy and seek immediate medical assistance if these occur [see Warnings and Precautions (5.1)]. Alcohol: Advise patients not to take COMBOGESIC concomitantly with alcohol-containing beverages [see Warnings and Precautions (5.1)]. Cardiovascular Thrombotic Effects: Inform patients that COMBOGESIC, like other NSAID- containing medications, may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Advise patients to be alert for chest pain, shortness of breath, weakness, and slurring of speech, and to seek medical assistance when observing any sign or symptom indicative of CV effects. [see Warnings and Precautions (5.2)]. Gastrointestinal Bleeding, Ulceration, and Perforation: Inform patients that COMBOGESIC, like other NSAID-containing medications, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to be alert for the signs and symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis, and to seek medical assistance should these symptoms occur. [see Warnings and Precautions (5.3)]. Heart Failure and Edema: Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Weight Gain and Edema: Advise patients to promptly report unexplained weight gain or edema to their physicians [see Warnings and Precautions (5.5)]. Anaphylactic Reactions: Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if Reference ID: 5482802 these occur [see Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS: Advise patients to stop taking COMBOGESIC immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible. [see Warnings and Precautions (5.9, 5.10)]. Female Fertility: Advise females of reproductive potential who desire pregnancy that NSAID containing products, including COMBOGESIC tablets, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity: Inform pregnant women to avoid use of COMBOGESIC and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with COMBOGESIC is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Use of NSAIDS and Low-Dose Aspirin: Inform patients not to use low-dose aspirin concomitantly with COMBOGESIC until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured by: Catalent Greenville Inc., 1240 Sugg Parkway, Greenville, NC 27834 Distributed by: AFT Pharmaceuticals Ltd, 129 Hurstmere Road, Takapuna, Auckland, New Zealand, 0622. Reference ID: 5482802 Medication Guide COMBOGESIC (kom-boh-JEE-zik) (acetaminophen and ibuprofen) tablets COMBOGESIC is a combination prescription medicine that contains acetaminophen and ibuprofen (a nonsteroidal anti-inflammatory drug [NSAID]). What is the most important information I should know about COMBOGESIC? COMBOGESIC may cause serious side effects, including: • Severe liver problems. Acetaminophen, one of the ingredients in COMBOGESIC, has caused severe and life- threatening acute liver failure which caused the need for a liver transplant and has caused death. o Taking COMBOGESIC with other products that contain acetaminophen can lead to serious severe liver problems and death. Do not take COMBOGESIC with other acetaminophen containing products. o You should not take more than 3 COMBOGESIC tablets in one dose or more than 12 COMBOGESIC tablets in one day. o If you take too much COMBOGESIC or acetaminophen, call your healthcare provider or Poison Control Center at 1-800-222-1222, or go to the nearest hospital emergency room right away. • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of medicines containing NSAIDs o with longer use of medicines containing NSAIDs Do not take COMBOGESIC right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking COMBOGESIC after a recent heart attack unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take COMBOGESIC after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems COMBOGESIC should only be taken exactly as prescribed, at the lowest dose possible for your treatment, and for the shortest time needed. What is COMBOGESIC? COMBOGESIC is a combination prescription medicine that contains acetaminophen and ibuprofen (a non-steroidal anti-inflammatory drug [NSAID]) used in adults for the short-term management of mild to moderate acute pain. It is not known if COMBOGESIC is safe and effective for use in children. Reference ID: 5482802 Do not take COMBOGESIC: • If you are allergic to acetaminophen, ibuprofen, other NSAIDs, or to any of the ingredients in COMBOGESIC. See the end of this Medication Guide for a complete list of ingredients in COMBOGESIC. • If you have had an asthma attack, hives, or other allergic reactions after taking aspirin or any other NSAIDs. • Right before or after heart bypass surgery. Before taking COMBOGESIC, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • have heart problems • have bleeding problems • have or have had ulcers • drink alcohol • are pregnant or plan to become pregnant. Taking COMBOGESIC at about 20 weeks of pregnancy or later may harm your unborn baby. o If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. o NSAID containing products, including COMBOGESIC, may cause reversible fertility problems in females, which may temporarily affect your ability to become pregnant during treatment with COMBOGESIC. Talk to your healthcare provider if this is a concern for you. • are breastfeeding or plan to breastfeed. Ibuprofen can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with COMBOGESIC. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. COMBOGESIC and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. How should I take COMBOGESIC? • Take COMBOGESIC exactly as your healthcare provider tells you to take it. • You should not take more than 3 COMBOGESIC tablets in one dose or more than 12 COMBOGESIC tablets each day. ● If you take too much COMBOGESIC, call your healthcare provider or Poison Control Center at 1-800-222-1222, or go to the nearest hospital emergency room right away. What should I avoid while taking COMBOGESIC? • You should avoid drinking alcohol during treatment with COMBOGESIC. Drinking alcohol during treatment with COMBOGESIC may increase your chances of having serious side effects. What are the possible side effects of COMBOGESIC? COMBOGESIC may cause serious side effects, including: See “What is the most important information I should know about COMBOGESIC?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • high potassium level in your blood (hyperkalemia) Reference ID: 5482802 • life-threatening allergic reactions • life-threatening skin reactions • low red blood cells (anemia) • changes in your vision Other side effects of COMBOGESIC include: nausea, vomiting, headache, dizziness, sleepiness, bleeding after medical procedures, swelling of the face. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking COMBOGESIC and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and sticky like tar • diarrhea • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever (including rash with hives, sores in your mouth or eyes, or your skin blisters and peels) • indigestion or stomach pain • swelling of the arms, legs, hands, and feet • flu-like symptoms These are not all the possible side effects of COMBOGESIC. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of COMBOGESIC. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use COMBOGESIC for a condition for which it was not prescribed. Do not give COMBOGESIC to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about COMBOGESIC that is written for health professionals. What are the ingredients in COMBOGESIC? Active ingredients: acetaminophen and ibuprofen Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, medium chain triglycerides, microcrystalline cellulose, polydextrose, povidone-30, sodium lauryl sulfate, Reference ID: 5482802 talc, titanium dioxide. Manufactured by: Catalent Greenville Inc, 1240 Sugg Parkway, Greenville, NC 27834. Ph: +64 800 423 823 Distributed by: AFT Pharmaceuticals Ltd, 129 Hurstmere Road, Takapuna, Auckland, New Zealand, 0622. Ph: +64 800 423 823 For more information, go to www.aftpharm.com or call: +64 800 423 823 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5482802	custom-source	2025-02-12T15:47:00.960215	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/209471s001lbl.pdf', 'application_number': 209471, 'submission_type': 'SUPPL ', 'submission_number': 1}
80,330	------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ATTRUBY safely and effectively. See full prescribing information for ATTRUBY. ATTRUBY™ (acoramidis) tablets, for oral administration, Initial U.S. Approval: 2024 ---------------INDICATIONS AND USAGE-------------------------- ATTRUBY is a transthyretin stabilizer indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular- related hospitalization. (1, 2.1) ----------DOSAGE AND ADMINISTRATION---------------------- The recommended dosage of ATTRUBY is 712 mg orally twice daily. (2.1) -------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 356 mg acoramidis (3) ------------------CONTRAINDICATIONS----------------------------- None. (4) To report SUSPECTED ADVERSE REACTIONS, contact BridgeBio Pharma Inc. at 1-844-550-2246 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Issued: 11/2024 * Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Reference ID: 5484268 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ATTRUBY is indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of ATTRUBY is 712 mg orally twice daily (with or without food). Swallow tablets whole; do not cut, crush, or chew. 3 DOSAGE FORMS AND STRENGTHS ATTRUBY is available as 356 mg acoramidis, white, film-coated, oval tablets, printed with the BridgeBio company logo followed by “ACOR” in black ink on one side. 4 CONTRAINDICATIONS None. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data reflect the exposure of 421 participants with ATTR-CM to ATTRUBY 712 mg (administered as two 356 mg tablets) administered orally twice daily in a randomized, double-blind, placebo-controlled trial of 30 months fixed treatment duration. The median duration of exposure to ATTRUBY in the safety population was 29 months. There was a higher frequency of gastrointestinal (GI) adverse reactions such as diarrhea 11.6% versus 7.6% and upper abdominal pain 5.5% versus 1.4% in the ATTRUBY versus placebo group, respectively. The majority of these GI adverse reactions were categorized as mild and resolved without drug discontinuation. A similar proportion of ATTRUBY-treated and placebo-treated participants discontinued study drug because of an adverse event (9.3% and 8.5%, respectively). Laboratory Tests Increase in Serum Creatinine and Decrease in eGFR Initiation of ATTRUBY causes an increase in serum creatinine and decrease in eGFR which generally occurs within 4 weeks of starting therapy and stabilizes. In a trial of adults with ATTR-CM, a mean increase in serum creatinine of 0.2 and 0.0 mg/dL and a mean decrease in eGFR of 8.2 and 0.7 mL/min/1.73 m2 was observed in the ATTRUBY and placebo groups, respectively, at Day 28. The changes in serum creatinine and eGFR were reversible after treatment discontinuation. Reference ID: 5484268   7 DRUG INTERACTIONS UDP-glucuronosyltransferases (UGT) Inducers and Strong CYP3A Inducers Acoramidis is metabolized by UGT enzyme-mediated glucuronidation. Concomitant use of UGT inducers can potentially decrease acoramidis exposure. While acoramidis is not metabolized by CYP3A, strong CYP3A inducers can also induce UGT enzymes. Avoid concomitant use of ATTRUBY with UGT inducers and strong CYP3A inducers. Sensitive Cytochrome P450 2C9 (CYP2C9) substrates Acoramidis inhibits CYP2C9 and may result in an increase in CYP2C9 substrate concentrations when these drugs are co administered. Consider more frequent monitoring of patients for evidence of increased exposure (for example, signs of exposure related toxicity) when ATTRUBY is co administered with sensitive CYP2C9 substrates. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data with acoramidis use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproductive studies in rats and rabbits, no embryofetal abnormalities were observed at exposures up to 34 times and 13 times the clinical exposure at the maximum recommended human dose, respectively (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Report pregnancies to the BridgeBio reporting line at 1-844-550-2246. Data Animal Data In pregnant rats, oral administration of acoramidis (0, 50, 350, and 1,000 mg/kg/day) throughout organogenesis did not result in any adverse effects on embryofetal development at up to 1,000 mg/kg/day, approximately 34 times the clinical exposure at the maximum recommended human dose (MRHD) based on AUC. In pregnant rabbits, oral administration of acoramidis (0, 25, 75, and 200 mg/kg/day) throughout organogenesis resulted in increased pre-implantation loss at 200 mg/kg/day, a dose that caused maternal toxicity (26% reduced body weight gain). No embryofetal abnormalities were observed at 200 mg/kg/day, approximately 13 times the clinical exposure at the MRHD based on AUC. In a pre- and postnatal developmental toxicity study, pregnant rats received oral administration of acoramidis at doses of 0, 50, 350, or 1,000 mg/kg/day throughout pregnancy and lactation (Gestation Day 6 to Lactation Day 20). Maternal death, body weight reduction, and decreased number of females with live born pups (due to increase in resorbed litters) were observed at 1,000 mg/kg/day, approximately 43 times the clinical exposure at the MRHD based on AUC. Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 1,000 mg/kg/day. No adverse effects on pre- and postnatal development were observed at 350 mg/kg/day, approximately 18 times the clinical exposure at the MRHD based on AUC. Reference ID: 5484268 Me F Me 8.2 Lactation Risk Summary There are no available data on the presence of acoramidis in either human or animal milk or the effects of the drug on the breastfed infant or maternal milk production.The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ATTRUBY and any potential adverse effects on the breastfed child from ATTRUBY or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ATTRUBY have not been established in pediatric patients. 8.5 Geriatric Use No dosage adjustment is required for elderly patients (≥65 years) [see Clinical Pharmacology (12.3)]. Of the total number of participants randomized in the clinical study (n=632), 97% were 65 years and over, with a median age of 78 years. 10 OVERDOSAGE There is no clinical experience with overdose. In case of suspected overdose, treatment should be symptomatic and supportive. 11 DESCRIPTION ATTRUBY contains 356 mg acoramidis equivalent to 400 mg acoramidis HCl. Acoramidis HCl is a transthyretin stabilizer. The chemical name of acoramidis HCl is 3-[3-(3,5-dimethyl 1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid hydrochloride. The molecular formula is C15H18FN2O3Cl, and the molecular weight is 328.77 g/mol. The structural formula is: Acoramidis HCl is a white to tan solid. The solubility of acoramidis is  12 micrograms/mL from pH 1.2 to 6.8 in aqueous media. ATTRUBY is supplied as a white, film-coated, oval tablet, contains 356 mg acoramidis, printed with the BridgeBio company logo followed by “ACOR” in black ink on one side. The inactive ingredients are croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coating and printing ink contain black iron oxide, glyceryl monocaprylocaprate, hypromellose, polyvinyl alcohol, propylene glycol, talc, titanium dioxide, and vinyl alcohol graft copolymer. Reference ID: 5484268 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acoramidis is a selective stabilizer of transthyretin (TTR). Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, the rate-limiting step in amyloidogenesis. 12.2 Pharmacodynamics TTR Stabilization Changes in serum TTR level or in vitro TTR stabilization assays were utilized as pharmacodynamic markers of TTR stabilization. Increases in mean serum TTR levels were observed by Day 28 in ATTR CM patients treated with ATTRUBY. Near-complete in vitro TTR stabilization was observed as early as Day 28 and through completion of a 30-month study of patients with ATTR-CM (wild-type and variant) treated with the recommended dosage [see Clinical Studies (14)]. Free thyroxine ATTRUBY may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone (TSH). A reduction in free thyroxine values has been observed with transthyretin stabilizers probably due to reduced thyroxine binding to or displacement from transthyretin (TTR). NT-proBNP and Troponin I In a clinical study of ATTRUBY in patients with ATTR-CM, at Month 30, the increase in N-terminal prohormone of brain natriuretic peptide [NT-proBNP] and troponin I was lower with ATTRUBY versus placebo. The increase in NT-proBNP at Month 30 for ATTRUBY was about half that of placebo [see Clinical Studies (14)]. Cardiac Electrophysiology At approximately 1.2 times the steady state peak plasma concentrations (Cmax) at the recommended dose, ATTRUBY does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics The systemic exposures (Cmax and AUC) increase in a less than dose proportional manner following single and multiple doses of acoramidis. Over the dose range from 89 mg twice daily to 712 mg twice daily, AUC increases only 130%. Acoramidis steady state is achieved by 4 days with approximately 1.3 fold accumulation at the approved recommended dosage. At steady state, a dose of 712 mg twice daily results in a mean (SD) Cmax of 13700 (6090) ng/mL and AUC0-12h of 47200 (10300) ng.h/mL. Absorption The time to Cmax of acoramidis (Tmax) is approximately 1 hour following oral administration. Effect of Food No clinically significant differences in acoramidis pharmacokinetics were observed following administration of a high-fat meal (800-1000 total calories, ≥ 50% fat). Distribution The apparent steady-state volume of distribution for acoramidis is 654 liters. Acoramidis is 96% bound to human plasma proteins in vitro. Acoramidis primarily binds to TTR. Reference ID: 5484268 Elimination The effective half-life of acoramidis is approximately 6 hours with a steady state apparent clearance of 16 L/hr. Metabolism Acoramidis is primarily metabolized by glucuronidation via UGT1A9, UGT1A1 and UGT2B7. Acoramidis β-D-glucuronide (Acoramidis-AG) is the predominant metabolite of acoramidis (8% of total circulating drug related moieties). Acoramidis-AG is approximately 1/3 as pharmacologically active compared with acoramidis, has a low potential for covalent binding, and does not contribute to pharmacological activity. Excretion After a single oral dose of radiolabeled acoramidis 712 mg to healthy adult subjects, approximately 32% of the dose radioactivity was recovered in feces (15% unchanged), and approximately 68% was recovered in urine (<10% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of acoramidis were observed based on age, race/ethnicity (including Japanese and non-Japanese), sex, or renal impairment. The effect of hepatic impairment (Child Pugh A, B, or C) on acoramidis pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Following the administration of acoramidis (712 mg, BID) in a clinical study in healthy adult volunteers, there was not a clinically significant increase in exposure to the organic anion transporter-1 (OAT1) substrate (adefovir) and to OAT3 substrate (oseltamivir carboxylate). Concomitant diuretic use in patients does not affect steady-state plasma acoramidis concentrations. In Vitro Studies Cytochrome P450 Enzymes: Acoramidis is a time-dependent inhibitor of CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4/5. Acoramidis does not induce CYP1A2, CYP2B6, or CYP3A4. UDP-Glucuronosyl Transferase (UGT): Acoramidis is a substrate of multiple UGT enzymes including UGT1A9, UGT1A1, and UGT2B7. Transporter Systems: Acoramidis is a substrate for OAT1 and breast cancer resistance protein (BCRP). Acoramidis inhibits OAT1 and OAT3, but does not inhibit MATE1, OCT1, OCT2, OATP1B1, OATP1B3, MATE2-K, BCRP, P-gp, or BSEP. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no evidence of increased incidence of neoplasia in a 2-year carcinogenicity study in male rats Reference ID: 5484268 dosed up to 50 mg/kg and in female rats dosed up to 350 mg/kg, which provided exposures approximately equivalent to and 11 times the AUC at the maximum recommended human dose (MRHD), respectively. There was no evidence of an increased incidence of neoplasia in transgenic (Tg.rasH2) mice following repeated daily administration for 26 weeks at daily doses up to 300 mg/kg. Mutagenesis There was no evidence of mutagenicity or clastogenicity for acoramidis in an Ames assay or in vivo rat micronucleus and alkaline comet assay. Impairment of Fertility In a male and female fertility study, rats were orally administered acoramidis at 0, 50, 350, and 1,000 mg/kg/day. Male rats were given acoramidis prior to and during cohabitation for a total of up to 52 days. Female rats were given acoramidis prior to and during cohabitation until implantation of the embryo (Gestational Day 7) for a total of up to 34 days. There were no effects on fertility, reproductive performance, or mating behavior in male or female rats at doses up to 1,000 mg/kg/day, approximately 38-times the AUC at the MRHD. 14 CLINICAL STUDIES The efficacy of ATTRUBY was demonstrated in a multicenter, international, randomized, double-blind, placebo-controlled study in 611 adult patients with wild-type or variant (hereditary or de novo) ATTR-CM (NCT03860935). Participants were randomized (2:1) to receive ATTRUBY 712 mg (n=409) or placebo (n=202) twice daily for 30 months. Treatment assignment was stratified by type of ATTR-CM [variant (ATTRv-CM) or wild- type (ATTRwt-CM)], NT-proBNP level, and estimated glomerular filtration rate (eGFR). The mean age of study participants was 77 years, 90.8% were male, 87.9% were White, 4.7% Black or African American, 2.1% Asian, 5.3% race other, 19% had a history of permanent pacemaker and 58% had a history of atrial fibrillation. No significant imbalance in baseline characteristics was observed between the two treatment groups. Participants were permitted to initiate open-label tafamidis after 12 months in the study. A total of 107 participants received tafamidis: 61 (14.9%) in the ATTRUBY arm and 46 (22.8%) in the placebo arm. The median time to initiation of tafamidis for these 107 participants was 17 months. The primary composite endpoint included all-cause mortality (ACM) and cumulative frequency of cardiovascular-related hospitalizations (CVH) over 30 months, analyzed hierarchically using the stratified Finkelstein-Schoenfeld (F-S) test. The F-S test demonstrated a statistically significant reduction (p=0.018) in ACM and cumulative frequency of CVH in the ATTRUBY arm versus the placebo arm. All-cause mortality was reported in 19% and 26% of participants in the ATTRUBY and placebo groups, respectively. The majority (79%) of the deaths were cardiovascular. CVH was reported in 27% and 43% of participants in the ATTRUBY and placebo groups, respectively. The mean number of CVH events was 0.3 vs 0.6 per year. The majority (59%) of CVH were heart failure hospitalizations reported in 13% and 26% of the participants in the ATTRUBY and placebo groups, respectively. The treatment effect of ATTRUBY on functional capacity and health status was assessed by the 6MWD and the Kansas City Cardiomyopathy Questionnaire-Overall Summary score (KCCQ-OS) respectively. At month 30, the LS mean difference (95% CI) in change from baseline in 6MWD was 40 [21, 58] meters (p < 0.0001) and change from baseline in KCCQ-OS was 10 [6, 14] points (p < 0.0001) (Figure 1 and Figure 2). Reference ID: 5484268 0 g -~ -20 ] -40 § Gi' "'"' u -.!. -60 "" + c- .l! u -80 ~ ::a: "' -100 ..J ATTRUBY ..c ro ..c 0 ~ 0.. Q) ~ - ..!,. C: Q) > w Placebo e 0 8 "' u .s -5 ] E Gi' £"; ~ ~ -10 ] -15 u 1 ---! -20 "' I- ATTRUBY •• •• •• Placebo I ..J 1-- ATTRUBY •••••• Placebo! Baseline 6 9 12 18 24 30 Baseline 3 6 9 12 Month 407 351 347 369 363 392 384 ATTRUBY 408 263 389 390 397 202 175 176 185 185 190 186 Placebo 202 134 192 194 1% 1.0 0.8 0.6 0.4 0.2 0.0 --ATTRUBY --- · Placebo I 0 3 6 9 12 15 18 21 Time since Randomization (Months) Subjects Remaining at Risk (Cumulative Events) ···1-........ 18 24 Month 404 407 199 20 1 24 27 ATTRUBY 409 (0) 389 (20) 370 (39) 355 (54) 337 (72) 319 (90) 308 (101) 298 (111) 284 (125) 270 (1 39) Placebo 202 (0) 191 (11) 172 (30) 159 (43) 152(50) 143 (59) 135 (67) 129 (73) 121 (81 ) 108 (94) -- ----! 30 405 20 1 30 0 (147) 0 (102) Figure 1 - 6MWD Change from Baseline Figure 2 - KCCQ-OS Score Change from Baseline Abbreviations: 6MWD = Six-Minute Walk Distance; KCCQ-OS = Kansas City Cardiomyopathy Questionnaire Overall Summary Score; SE = standard error; LS = least squares. The changes from baseline in 6MWT and KCCQ-OS were analyzed using the mixed model for repeated measures (MMRM) with treatment group, visit, genotype (ATTRv-CM vs ATTRwt-CM), NT-proBNP level (≤ 3000 vs > 3000 pg/mL), eGFR level (≥ 45 vs < 45 mL/min/1.73 m2) and treatment group-by-visit interaction as factors, and baseline value as covariate. A Cox regression analysis indicated a 35.5% decrease in the risk of the composite of ACM or first CV hospitalization (hazard ratio: 0.645 [95% CI: 0.500, 0.832]). A Kaplan-Meier plot of time to first event of ACM or CVH is shown in Figure 3. Figure 3: Time to First All-cause Mortality or Cardiovascular-Related Hospitalization over Month 30, mITT Population Figure 4 shows the treatment effects by prespecified subgroups. Reference ID: 5484268 Subgroup Overall Sex Male Female Age (years) < 78 2'. 78 Race White Non-White Country United States Rest of World ATTR-CM Genotype ATTRv-CM ATTRwt-CM NT-proBNP (pg/mL) '.S 3000 > 3000 eGFR (mL/min/1. 73m2) < 45 2'. 45 ATTR NAC Stage I 1I Ill NYHAClass I, 1I Ill No.(%) of Patients 611 (100.0) 555 (90.8) 56 (9.2) 299 (48.9) 312 (51.1) 537 (87.9) 74 (12.1) 119 (19.5) 492 (80.5) 59 (9. 7) 552 (90.3) 401 (65.6) 210 (34.4) 94 (15.4) 517 (84.6) 361 (59.1) 196 (32.1) 54 (8.8) 512 (83.8) 99 (16.2) Win Ratio <--P lacebo Better ATTRUBY Better f-----9------i ~ -- I ■ I - ~ - -- i--e---t - ~ -- I ■ I ~ ,------e--t -- I ■ I ::: I ■ I -- I I I I 0.25 0.5 2 4 ---> I 8 Win Ratio [95% CI] 1.5 [ 1.1, 2.0] 1.5 [ 1.1, 1.9 ] 2.0 [ 0.9, 4.7] 2.0 [ 1.2, 3.1] 1.1 [ 0.7, 1.8] 1.4 [ 1.1, 1.9 ] 2.2 [ 1.0, 4.8] 1.4 [ 0.8, 2.4] 1.5 [ 1.1, 2.0] 2.4 [ 1.1, 5.0 ] 1.4 [ 1.0, 2.0 ] 1.4 [ 0.9, 2.1] 1.7 [ 1.1, 2.6] 1.0 [ 0.5, 2.0] 1.6 [ 1.2, 2.2] 1.4 [ 0.9, 2.1] 1.8 [ 1.1, 2.8] 1.1 [ 0.5, 2.5] 1.7 [ 1.2, 2.4] 0.7 [ 0.3, 1.6] Figure 4: Win-Ratio Analyses for Hierarchical Combination of All-Cause Mortality and Cardiovascular-Related Hospitalization by Overall and Subgroup, mITT Population Abbreviations: ATTR-CM = transthyretin amyloid cardiomyopathy; ATTRv-CM = variant ATTR-CM; ATTRwt-CM = wild-type ATTR-CM; eGFR = estimated glomerular filtration rate; mITT=modified intent-to-treat; NAC = National Amyloidosis Centre; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association All-Cause Mortality includes heart transplant, CMAD and all-cause death. Cardiovascular-related hospitalizations include cardiovascular hospitalizations and urgent unplanned visits requiring treatment with intravenous diuretic for decompensated heart failure. Non-White includes American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, Other, multiple races and Not reported. ATTR NAC Stage: ATTR Stage I, defined as NT-proBNP ≤ 3000 ng/L and eGFR ≥ 45 mL/min/1.73 m2; Stage III, defined as NT-proBNP > 3000 ng/L and eGFR < 45 mL/min/1.73 m2, the remainder categorized as Stage II. 16 HOW SUPPLIED/STORAGE AND HANDLING ATTRUBY (acoramidis) tablets, 356 mg, are white, film-coated, oval tablets, printed with the BridgeBio company logo followed by “ACOR” in black ink on one side. ATTRUBY tablets are supplied as a carton of 112 tablets: 4 blister cards (each containing 28 tablets)– (NDC 82228-712-28). Reference ID: 5484268 Store ATTRUBY at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in original blister card until use to protect from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Pregnancy Advise patients who are exposed to ATTRUBY during pregnancy to contact the BridgeBio reporting line at 1-844-550-2246. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. For more information about ATTRUBY, go to www.ATTRUBY.com Distributed by: BridgeBio Pharma, Inc. Palo Alto, CA 94304 Reference ID: 5484268 PATIENT INFORMATION ATTRUBYTM (ah-troo-be) (acoramidis) tablets What is ATTRUBY? ATTRUBY is a prescription medicine used to treat adults with a disease that affects the heart muscle called cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM), to reduce death and hospitalization related to heart problems. It is not known if ATTRUBY is safe and effective in children. Before taking ATTRUBY, tell your healthcare provider about all your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if ATTRUBY will harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ATTRUBY. You may also report your pregnancy by calling the BridgeBio reporting line at 1-844-550-2246. • are breastfeeding or plan to breastfeed. It is not known if ATTRUBY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ATTRUBY. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I take ATTRUBY? • Take ATTRUBY exactly as your healthcare provider tells you to. • Take ATTRUBY tablets by mouth 2 times a day, with or without food. • Swallow tablets whole. Do not cut, crush, or chew tablets. What are the possible side effects of ATTRUBY? The most common side effects of ATTRUBY were mild and include: • stomach-area (abdominal) pain • diarrhea These are not all of the possible side effects of ATTRUBY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ATTRUBY? • Store ATTRUBY tablets at room temperature between 68°F to 77°F (20°C to 25°C). • Store in original blister card until use to protect from moisture. Keep ATTRUBY and all medicines out of the reach of children. General information about the safe and effective use of ATTRUBY. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ATTRUBY for a condition for which it was not prescribed. Do not give ATTRUBY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ATTRUBY that is written for health professionals. What are the ingredients in ATTRUBY? Active ingredient: acoramidis Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coating and printing ink contain black iron oxide, glyceryl monocaprylocaprate, hypromellose, polyvinyl alcohol, propylene glycol, talc, titanium dioxide, and vinyl alcohol graft copolymer. Distributed by: BridgeBio Pharma, Inc., Palo Alto, CA 94304 For more information about ATTRUBY, go to www.ATTRUBY.com or call 1-844-550-2246 This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5484268	custom-source	2025-02-12T15:47:01.313106	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216540s000lbl.pdf', 'application_number': 216540, 'submission_type': 'ORIG ', 'submission_number': 1}
80,331	_________________ ______________ ______________ ______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZANAFLEX® safely and effectively. See full prescribing information for ZANAFLEX. ZANAFLEX® (tizanidine) capsules, for oral use ZANAFLEX® (tizanidine) tablets, for oral use Initial U.S. Approval: 1996 __________________RECENT MAJOR CHANGES _________________ Indications and Usage (1) 11/2024 Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 11/2024 Contraindications (4) 11/2024 Warnings and Precautions (5.1, 5.2, 5.4, 5.5) 11/2024 __________________ INDICATIONS AND USAGE Zanaflex is a central alpha-2-adrenergic agonist indicated for the treatment of spasticity. (1) _______________ DOSAGE AND ADMINISTRATION • Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. (2.1) • Recommended starting dose: 2 mg by mouth every 6 to 8 hours, as needed, up to a maximum of 3 doses in 24 hours (2.2) • Dosage can be increased by 2 mg to 4 mg per dose every 1 to 4 days; maximum total daily dosage is 36 mg (2.2) • Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in a change in tolerability and control of symptoms. Consistent administration with respect to food is recommended. If substitution between dosage forms is necessary, take into consideration these pharmacokinetic differences. (2.2, 2.6, 12.3) • Patients with renal impairment (creatinine clearance <25 mL/min) or hepatic impairment: use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased. (2.3, 2.4) • To discontinue Zanaflex, decrease dose slowly to minimize the risk of withdrawal adverse reactions (2.5) DOSAGE FORMS AND STRENGTHS • Capsules: 2 mg, 4 mg, or 6 mg (3) • Tablets: 4 mg (3) ___________________ CONTRAINDICATIONS____________________ • Concomitant use with strong CYP1A2 inhibitors (4, 7.1) • Patients with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex (4, 5.5) _______________ WARNINGS AND PRECAUTIONS _______________ • Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Zanaflex should not be used with other α2-adrenergic agonists (5.1, 7.7) • Risk of liver injury: monitor ALTs; discontinue Zanaflex if liver injury occurs (5.2) • Sedation: Zanaflex may interfere with everyday activities; sedative effects of Zanaflex, alcohol, and other central nervous system (CNS) depressants are additive (5.3, 7.4) • Hallucinations: consider discontinuation of Zanaflex (5.4) ____________________ADVERSE REACTIONS____________________ The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-8007277151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ Moderate or weak CYP1A2 inhibitors: avoid concomitant use; may cause hypotension, bradycardia, or excessive drowsiness; if concomitant use is necessary and adverse reactions occur, reduce Zanaflex dosage or discontinue. (7.2, 12.3) USE IN SPECIFIC POPULATIONS _______________ • Pregnancy: Based on animal data, may cause fetal harm (8.1) • Geriatric use: Zanaflex should be used with caution in elderly patients because clearance is decreased four-fold (8.5) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluation and Testing Before and After Initiating Zanaflex 2.2 Recommended Dosage 2.3 Recommended Dosage in Patients with Renal Impairment 2.4 Recommended Dosage in Patients with Hepatic Impairment 2.5 Discontinuation of Zanaflex 2.6 Switching Between With/Without Food and Different Tizanidine Dosage Forms 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension 5.2 Liver Injury 5.3 Sedation 5.4 Hallucinosis/Psychotic-Like Symptoms 5.5 Hypersensitivity Reactions 5.6 Withdrawal Adverse Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Strong CYP1A2 Inhibitors 7.2 Moderate or Weak CYP1A2 Inhibitors 7.3 Oral Contraceptives 7.4 Alcohol and Other CNS Depressants 7.5 α2-Adrenergic Agonists 7.6 Antihypertensive Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5484759 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Zanaflex is indicated for the treatment of spasticity in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluation and Testing Before and After Initiating Zanaflex Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions (5.2)]. 2.2 Recommended Dosage The recommended starting dose is 2 mg by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased every 1 to 4 days by 2 mg to 4 mg at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied. There are pharmacokinetic differences when administering Zanaflex between the fed or fasted state [see Clinical Pharmacology (12.3)]. Zanaflex may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure. Because of the short duration of therapeutic effect, treatment with Zanaflex should be reserved for those daily activities and times when relief of spasticity is most important. 2.3 Recommended Dosage in Patients with Renal Impairment In patients with creatinine clearance < 25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.4 Recommended Dosage in Patients with Hepatic Impairment In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.5 Discontinuation of Zanaflex When discontinuing Zanaflex, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg to 4 mg per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and Dependence (9.3)]. Reference ID: 5484759 2.6 Switching Between With/Without Food and Different Tizanidine Dosage Forms There are pharmacokinetic differences when: 1) switching between administration of Zanaflex with or without food 2) switching between dosage forms if being administered with food. If these situations occur, monitor patients for therapeutic effect or adverse reactions [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Capsules 2 mg: Light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap 4 mg: White opaque body with a blue opaque cap with “4 MG” printed on the cap 6 mg: Blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the cap Tablets 4 mg white, uncoated tablets with a quadrisecting score on one side and debossed with “A594” on the other side 4 CONTRAINDICATIONS Zanaflex is contraindicated in patients: • taking strong CYP1A2 inhibitors [see Drug Interactions (7.1)]. • with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension Zanaflex is an α2-adrenergic agonist that can produce hypotension [see Adverse Reactions (6.1) and Drug Interactions (7.5)]. Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when Zanaflex is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Zanaflex be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Reference ID: 5484759 Clinical Pharmacology (12.3)]. Therefore, concomitant use of Zanaflex with strong CYP1A2 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1)]. 5.2 Liver Injury Zanaflex may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with Zanaflex [see Adverse Reactions (6.1, 6.2)]. Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. 5.3 Sedation Zanaflex can cause sedation, which may interfere with everyday activity. In the multiple dose studies of Zanaflex, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study [see Adverse Reactions (6.1)]. The CNS depressant effects of Zanaflex with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions (7.4)]. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation. 5.4 Hallucinosis/Psychotic-Like Symptoms Zanaflex use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Zanaflex in patients who develop hallucinations. 5.5 Hypersensitivity Reactions Zanaflex can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Zanaflex is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications (4)]. 5.6 Withdrawal Adverse Reactions Zanaflex can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of Zanaflex (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the Zanaflex dosage should be decreased slowly [see Dosage and Administration (2.5)]. Reference ID: 5484759 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information: • Hypotension [see Warnings and Precautions (5.1)] • Liver Injury [see Warnings and Precautions (5.2)] • Sedation [see Warnings and Precautions (5.3)] • Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Withdrawal Adverse Reactions [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety of Zanaflex has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies (14)]. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day. The most common adverse reactions (>10% of patients treated with Zanaflex) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three- quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related. Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received Zanaflex where the frequency in the Zanaflex group was greater than the placebo group. Reference ID: 5484759 Table 1: Multiple Dose, Placebo-Controlled Studies—Adverse Reactions Reported in >2% of Patients Treated with Zanaflex Tablets and Incidence Greater than Placebo Adverse Reaction Placebo N = 261 % Zanaflex Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Liver test abnormality 2 6 Constipation 1 4 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 includes weakness, fatigue, and/or tiredness In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies (14)], the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness), and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less. Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported Adverse Reaction Placebo N = 48 % Zanaflex Tablet, 8mg, N = 45 % Zanaflex Tablet, 16 mg, N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10 * includes weakness, fatigue, and/or tiredness Reference ID: 5484759 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Zanaflex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Ventricular tachycardia, decreased blood pressure Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2)], hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations [see Warnings and Precautions (5.4)], depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions (5.5)], exfoliative dermatitis, rash 7 DRUG INTERACTIONS 7.1 Strong CYP1A2 Inhibitors Concomitant use of Zanaflex with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)]. 7.2 Moderate or Weak CYP1A2 Inhibitors Concomitant use of Zanaflex with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce Zanaflex dosage or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)]. 7.3 Oral Contraceptives Concomitant use of Zanaflex with oral contraceptives is not recommended. However, if concomitant use is clinically necessary and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)]. Reference ID: 5484759 7.4 Alcohol and Other CNS Depressants Alcohol increases the exposure of tizanidine after administration of Zanaflex. This was associated with an increase in adverse reactions of Zanaflex. Concomitant use of Zanaflex with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3)]. 7.5 α2-Adrenergic Agonists Concomitant use of Zanaflex with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative [see Warnings and Precautions (5.1)]. 7.6 Antihypertensive Medications Concomitant use of Zanaflex with antihypertensive medications may cause additive hypotensive effects [see Warnings and Precautions (5.1)]. Monitor patients who take Zanaflex with antihypertensive medications for hypotension. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of Zanaflex in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of tizanidine (0.3 to 100 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal and postnatal offspring mortality and reductions in body weight at doses of 30 mg/kg/day and above. Maternal toxicity was observed at the highest dose tested. The no-effect dose for embryofetal developmental toxicity in rats (3 mg/kg/day) is similar to the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Reference ID: 5484759 Oral administration of tizanidine (1 to 100 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal and postnatal offspring mortality at all doses. Maternal toxicity was observed at the highest dose tested. Oral administration of tizanidine (10 and 30 mg/kg/day) during the perinatal period of pregnancy (2-6 days prior to delivery) resulted in increased postnatal offspring mortality at both doses. A no-effect dose for embryofetal developmental toxicity in rabbit was not identified. The lowest dose tested (1 mg/kg/day) is less than the MRHD on a mg/m2 basis. In a pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. A no-effect dose for pre- and postnatal developmental toxicity was not identified. The lowest dose tested (3 mg/kg/day) is similar to the MRHD on a mg/m2 basis, respectively. 8.2 Lactation Risk Summary There are no data on the presence of tizanidine in human milk, the effects on the breastfed infant, or the effects on human milk production. Animal studies have reported the presence of tizanidine in the milk of lactating animals. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Zanaflex and any potential adverse effects on the breastfed infant from Zanaflex or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential There are no adequate and well-controlled studies in humans on the effect of Zanaflex on female or male reproductive potential. Oral administration of tizanidine to male and female rats resulted in adverse effects on fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of tizanidine (0, 1, 3, and 10 mg/kg/day) to juvenile rats from postnatal day (PND) 7 through PND 70 resulted in delayed sexual maturation in males at all doses, reduced body weight gain, delayed sexual maturation in females, and bilateral corneal crystals at the mid and high doses. Corneal crystals were still observed at the mid and high doses after a three-week recovery period. Neurobehavioral deficits were observed on a learning and memory task at the high dose. A no-effect dose for adverse effects on postnatal development not identified. 8.5 Geriatric Use Zanaflex is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are Reference ID: 5484759 more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of Zanaflex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Pharmacokinetic data showed that younger subjects cleared tizanidine faster than the elderly subjects [see Clinical Pharmacology (12.3)]. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with Zanaflex. 8.6 Renal Impairment In patients with renal insufficiency (creatinine clearance < 25 mL/min), clearance of tizanidine was reduced [see Clinical Pharmacology (12.3)]. In these patients, dosage reduction is recommended [see Dosage and Administration (2.3)]. Because the risk of adverse reactions to Zanaflex may be greater in patients with impaired renal function, monitor these patients closely for the onset or increase in severity of common adverse reactions [see Adverse Reactions (6.1)]. 8.7 Hepatic Impairment Zanaflex should be used with caution in patients with hepatic impairment. The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. In patients with hepatic impairment, dosage reduction is recommended [see Dosage and Administration (2.4)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Zanaflex contains tizanidine, which is not a controlled substance. 9.2 Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine. 9.3 Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Tizanidine is closely related to clonidine, which is often Reference ID: 5484759 abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used, especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be discontinued, the dose should be decreased slowly to minimize the risk of withdrawal symptoms [see Dosage and Administration (2.5)]. Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m2 basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration. 10 OVERDOSAGE A review of the safety surveillance database revealed cases of intentional and accidental Zanaflex overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs, including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases, a decrease in sensorium was observed including lethargy, somnolence, confusion, and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. Should overdose occur, ensure the adequacy of an airway and monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description (11)]. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center. 11 DESCRIPTION Zanaflex® contains tizanidine hydrochloride as the active ingredient, which is a central alpha2 adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3 benzothiadiazole monohydrochloride. It has a molecular formula of C9H8ClN5S-HCl and a molecular weight of 290.2. Its structural formula is: Reference ID: 5484759 N ~ \ s =-- I N Cl HCI Tizanidine hydrochloride is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine hydrochloride is slightly soluble in water and methanol; solubility in water decreases as the pH increases. Zanaflex capsules are for oral administration and contain 2, 4, or 6 mg tizanidine (equivalent to 2.29 mg, 4.58 mg, and 6.87 mg tizanidine hydrochloride, respectively), and the inactive ingredients colorants, gelatin, hypromellose, silicon dioxide, sugar spheres, and titanium dioxide. Zanaflex tablets are for oral administration and contain 4 mg tizanidine (equivalent to 4.58 mg tizanidine hydrochloride), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, microcrystalline cellulose, and stearic acid. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. 12.2 Pharmacodynamics The CNS depressant effects of tizanidine and alcohol are additive [see Warnings and Precautions (5.3) and Drug Interactions (7.4)]. 12.3 Pharmacokinetics Tizanidine has linear pharmacokinetics over the doses studied in clinical development [1 mg (half the recommended dosage) to 20 mg]. Zanaflex capsules and tablets are bioequivalent to each other under fasting conditions, but not under fed conditions (see Absorption, Effect of Food). Absorption Following oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass hepatic metabolism. Reference ID: 5484759 Effect of Food There are pharmacokinetic differences between Zanaflex capsules and Zanaflex tablets with respect to administration with food. A single dose of either two 4 mg tablets or two 4 mg capsules was administered under fed and fasting conditions in an open-label, four-period, randomized crossover study in 96 volunteers, of whom 81 were eligible for the statistical analysis. Pharmacokinetics under fed conditions were different than under fasting conditions and vary by dosage form. Tablets or Capsules - Fasting • Tmax was 1.0 hours after dosing • T ½ was approximately 2 hours. Tablets - Fed • Mean Cmax was increased by approximately 30% • Median Tmax was increased by 25 minutes, to 1 hour and 25 minutes. • Extent of absorption was increased approximately 30% Capsules - Fed • Mean Cmax was decreased by 20% (consequently, approximately 66% the Cmax for the tablet when administered with food) • Median Tmax was increased 2 to 3 hours • Extent of absorption was increased approximately 10% (consequently, approximately 80% of the amount absorbed from the tablet administered with food) Capsule Content Sprinkled on Applesauce Compared to administration of an intact capsule while fasting: • Cmax and AUC was increased 15%–20% • Tmax was decreased 15 minutes Reference ID: 5484759 6 "' .P "' .E. C 0 4 -~ i I g 3 8 I $ ! C i 2 / C " i:! I " I ~ 1 f n I Ii: • 0 2 l:I-CI A.:2: x•ma._...nn.WIIFlxd 0---0 812:a.illmg~lW:Nts'MIDJ!fbm .. C::2'14ln;l~ClpAi@IW.,foo(I /J,,--,6. 0;2111 •mgllnndtl4CapildN.WlliMIR:ald 12 14 16 18 20 tbn lltlmilhmQ 22 26 Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Zanaflex Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions Distribution Tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 L/kg (CV = 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins. Elimination Metabolism Tizanidine has a half-life of approximately 2.5 hours (CV=33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half- lives range from 20 to 40 hours. Excretion Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. Specific Populations Geriatric Patients No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg Zanaflex showed that younger subjects cleared the drug four times faster than the elderly subjects [see Use in Specific Populations (8.5)]. Patients with Hepatic Impairment The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would Reference ID: 5484759 be expected to have significant effects on pharmacokinetics of tizanidine [see Use in Specific Populations (8.7)]. Patients with Renal Impairment Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect [see Use in Specific Populations (8.6)]. Gender Effects No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data following single and multiple dose administration of 4 mg Zanaflex, however, showed that gender had no effect on the pharmacokinetics of tizanidine. Drug Interactions CYP1A2 Inhibitors The effects of coadministration of fluvoxamine or ciprofloxacin, both strong CYP1A2 inhibitors, on the pharmacokinetics of a single 4 mg dose of Zanaflex was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively, with coadministration of fluvoxamine. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively, with coadministration of ciprofloxacin [see Contraindications (4)]. There have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine [see Drug Interactions (7.2)]. In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. Oral Contraceptives No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and Zanaflex. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg Zanaflex, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Drug Interactions (7.3))]. Acetaminophen Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine. Reference ID: 5484759 Alcohol Alcohol increased the AUC and Cmax of tizanidine by approximately 20% and 15%, respectively [see Drug Interactions (7.4)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was no increase in tumors in either species. Mutagenesis Tizanidine was negative in in vitro (bacterial reverse mutation [Ames], mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay. Impairment of Fertility Oral administration of tizanidine to rats prior to and during mating and continuing during early pregnancy in females resulted in reduced fertility in male and female rats at doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 3 times and similar to the MRHD, respectively, on a mg/m2 basis. 14 CLINICAL STUDIES The efficacy of Zanaflex for the treatment of spasticity was demonstrated in two adequate and well-controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2). Single-Dose Study in Patients with Multiple Sclerosis with Spasticity In Study 1, 140 patients with spasticity caused by multiple sclerosis were randomized to receive single oral doses of 8 mg or 16 mg of Zanaflex, or placebo. Patients and assessors were blinded to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). Response was assessed by physical examination; muscle tone was rated on a 5-point scale (Ashworth score) as follows: • 0 = normal muscle tone Reference ID: 5484759 -5 C, 5 u -4 (/) = 0 -3 ;: .t:: "' <( -2 .!: i: _, C, E C, > 0 a. 0 E ____ -----r-------------------~ ----------------◄ ' ' ' --- ::::~~~~~:~~~-- --------' --------------------------------- T 1 place ------··1 ·----------1----------------------------------------- ! ' Hours Post-Dose • 1 = slight spastic catch • 2 = more marked muscle resistance • 3 = considerable increase in tone, making passive movement difficult • 4 = a muscle immobilized by spasticity Spasm counts were also collected. Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for Zanaflex compared to placebo was detected at 1, 2, and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg and 16 mg Zanaflex groups was indistinguishable from muscle tone in patients who received placebo. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse reactions including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group. Figure 2: Single Dose Study—Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Seven-Week Study in Patients with Spinal Cord Injury with Spasticity In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or Zanaflex. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. Reference ID: 5484759 -6~------------------------------~ j :: ::::::::::::::--r:::::: _______ -+■ __ '-;;:(mccca::':c~:-:·i~'::~cc::-:~:-:~:-:~e:-:'8::'m~g)'::', :5 ■ 1 -3 --------------1-----------~~------------------------------------1 ~ -2 E §? -~ e -------------------------------------------------------------------------1 -----------------------------------+--------------------------------+-----------< E • placebo • - o--l-------e----------l--------=======------+--------l • --------------1 ---------------------------------------------, 2~----~----------~---------~----~ End of Titration (Study Weol< 3) End of Maintenance (Study Week 7) Endpoint (Last Observation Carried Forward) At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the Zanaflex treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome), but also did not lead to any consistent advantage of Zanaflex treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. Figure 3: Seven Week Study—Mean Change in Muscle Tone 0.5–2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Zanaflex Capsules Zanaflex (tizanidine) capsules are two-piece hard gelatin shells containing 2 mg, 4 mg, or 6 mg tizanidine in bottles of 150 capsules available as follows: • The 2 mg capsules have a light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap: NDC 83107-001-15 • The 4 mg capsules have a white opaque body with a blue opaque cap with “4 MG” printed on the cap: NDC 83107-002-15 • The 6 mg capsules have a blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the capsules: NDC 83107-003-15 Zanaflex Tablets Zanaflex (tizanidine) tablets are uncoated containing 4 mg tizanidine in bottles of 150 tablets. The tablets have a quadrisecting score on one side and are debossed with “A594” on the other side: NDC 83107-004-15. Reference ID: 5484759 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure. 17 PATIENT COUNSELING INFORMATION Serious Drug Interactions Advise patients they should not take Zanaflex if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their healthcare providers when they start or stop taking any medication because of the risks associated with interaction between Zanaflex and other medicines [see Contraindications (4) and Drug Interactions (7)]. Zanaflex Dosing and Administration Tell patients to take Zanaflex exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules [see Dosage and Administration (2)]. Inform patients that they should not take more Zanaflex than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue Zanaflex, because rebound hypertension and tachycardia may occur [see Warnings and Precautions (5.6)]. Hypotension Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position [see Warnings and Precautions (5.1)]. Sedation Tell patients that Zanaflex may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions (5.3)]. Tell patients that the sedation may be additive when Zanaflex is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that Zanaflex decreases spasticity and caution should be used. Hypersensitivity Reactions Inform patients of the signs and symptoms of severe allergic reactions and instruct them to discontinue Zanaflex and seek immediate medical care should these signs and symptoms occur [see Warnings and Precautions (5.5)]. Reference ID: 5484759 Zanaflex® capsules is a registered trademark of Legacy Pharma Inc. Zanaflex® tablets is a registered trademark of Legacy Pharma Inc. Manufactured for: Legacy Pharma Inc. Georgetown, Grand Cayman KY1-9012 LEGACY LOGO – TO BE ADDED Reference ID: 5484759	custom-source	2025-02-12T15:47:01.684435	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020397s029,021447s017lbl.pdf', 'application_number': 20397, 'submission_type': 'SUPPL ', 'submission_number': 29}
80,327	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SEGLENTIS safely and effectively. See full prescribing information for SEGLENTIS. SEGLENTIS (celecoxib and tramadol hydrochloride) tablets, for oral use, C-IV Initial U.S. Approval: 2021 WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SEGLENTIS See full prescribing information for complete boxed warning. • SEGLENTIS exposes users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing SEGLENTIS and reassess regularly for these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation and following a dosage increase. (5.2) • Accidental ingestion of SEGLENTIS, especially by children, can result in a fatal overdose of tramadol. (5.2) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.3, 7) • If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4) • Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (5.5) • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. (5.6) • SEGLENTIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.6) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.7) • Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to CYP2D6 polymorphism (5.8) • SEGLENTIS is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4). Avoid the use of SEGLENTIS in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. (5.8) • The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SEGLENTIS requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. (5.9, 7) -------------------------- RECENT MAJOR CHANGES---------------------------- Warnings and Precautions (5.25) 11/2024 -------------------------- INDICATIONS AND USAGE---------------------------- SEGLENTIS contains tramadol hydrochloride, an opioid agonist, and celecoxib, a nonsteroidal anti-inflammatory drug, and is indicated for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate (1). Limitations of Use (1): Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration (5.1), reserve SEGLENTIS for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia. SEGLENTIS should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. ------------------------DOSAGE AND ADMINISTRATION---------------------- • SEGLENTIS should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks (2.1). • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve higher doses of opioids for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using higher doses of opioid clearly outweigh the substantial risks (2.1, 5). • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available (2.1). • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1) • Respiratory depression can occur at any time during opioid therapy, especially upon initiation and following a dosage increase. (2.1, 5.2) • Initiate treatment of SEGLENTIS with two tablets every 12 hours as needed for pain relief and not to exceed 4 tablets over 24 hours. (2.3). • Do not abruptly discontinue SEGLENTIS in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.4, 5.29) • Do not use with other celecoxib- or tramadol-containing products (2.1). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablet: celecoxib 56 mg and tramadol hydrochloride 44 mg (3). -------------------------------CONTRAINDICATIONS------------------------------ • Children younger than 12 years of age (4). • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4). • Significant respiratory depression (4). • In the setting of CABG surgery (4). • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4). • Known or suspected gastrointestinal obstruction, including paralytic ileus (4). • Hypersensitivity to tramadol, celecoxib, any other component of this product, or sulfonamides, or opioids (4). • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4). • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4). ------------------------WARNINGS AND PRECAUTIONS---------------------- Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically Reference ID: 5482803 causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.10) Serotonin Syndrome Risk: Potentially life-threatening condition could result from use of SEGLENTIS, particularly during concomitant use with serotonergic drugs. (5.11). Increased Risk of Seizures: Present within recommended dosage range. Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. (5.12, 7). Risk of Suicide: Do not prescribe for suicidal or addiction-prone patients (5.13). Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid (5.15). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation(5.14). Severe Hypotension with Tramadol: Regularly evaluate during dosage initiation. Avoid use of SEGLENTIS in patients with circulatory shock (5.16). Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of SEGLENTIS in patients with impaired consciousness or coma (5.17). Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.19). Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.20). Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Regularly evaluate blood pressure (5.21, 7). Heart Failure and Edema: Avoid use of SEGLENTIS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.22). Renal Toxicity: Regularly evaluate renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of SEGLENTIS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.23). Exacerbation of Asthma Related to Aspirin Sensitivity: SEGLENTIS is contraindicated in patients with aspirin-sensitive asthma. Regularly evaluate patients with preexisting asthma (without aspirin sensitivity) (5.24). Serious Skin Reactions: Discontinue SEGLENTIS at first appearance of skin rash or other signs of hypersensitivity (5.25). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.26). Fetal Toxicity: Limit use of NSAIDs, including SEGLENTIS, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.27, 8.1). Hematologic Toxicity: Regularly evaluate hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.28, 7) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence > 5% and > placebo) are nausea, vomiting, dizziness, headache, somnolence (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Kowa Pharmaceuticals America, Inc., at toll-free phone 1-888 SEGLENTIS or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with SEGLENTIS because they may reduce analgesic effect of SEGLENTIS or precipitate withdrawal symptoms (7). Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking SEGLENTIS with drugs that interfere with hemostasis. Concomitant use of SEGLENTIS and analgesic doses of aspirin is not generally recommended (7). Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with SEGLENTIS may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7). ACE Inhibitors and ARBs: Concomitant use with SEGLENTIS in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, regularly evaluate for signs of worsening renal function (7). Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7). Digoxin: Concomitant use with SEGLENTIS can increase serum concentration and prolong the half-life of digoxin. Monitor serum digoxin levels (7). --------------------------USE IN SPECIFIC POPULATIONS-------------------- Pregnancy: May cause fetal harm (8.1) Lactation: Breastfeeding not recommended (8.2). Severe Renal Impairment: Use not recommended (8.6). Moderate and Severe Hepatic Impairment: Use not recommended (8.7). Poor Metabolizers of CYP2C9: Due to the inability to start SEGLENTIS at a lower dose, use of SEGLENTIS is not recommended (8.8). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482803 1 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SEGLENTIS 5.31 Masking of Inflammation and Fever 5.32 Hyponatremia 5.33 Hypoglycemia 6 ADVERSE REACTIONS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 2.1 Important Dosage and Administration Instructions 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose 2.3 Recommended Dosage 2.4 Safe Reduction or Discontinuation of SEGLENTIS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 3 DOSAGE FORMS AND STRENGTHS 8.5 Geriatric Use 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse and Misuse 5.2 Life-Threatening Respiratory Depression 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants 5.4 Neonatal Opioid Withdrawal Syndrome 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) 5.6 Cardiovascular Thrombotic Events 8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Poor Metabolizers of CYP2C9 Substrates 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 5.7 Gastrointestinal Bleeding, Ulceration, and Perforation 5.8 Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children 5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 5.10 Opioid-Induced Hyperalgesia and Allodynia 5.11 Serotonin Syndrome Risk 5.12 Increased Risk of Seizures 5.13 Suicide Risk 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 5.14 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients 5.15 Adrenal Insufficiency 5.16 Severe Hypotension 5.17 Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness 5.18 Risk of Use in Patients with Gastrointestinal Conditions 5.19 Anaphylaxis and Other Hypersensitivity Reactions 5.20 Hepatotoxicity 5.21 Hypertension 5.22 Heart Failure and Edema SEGLENTIS study on acute pain after bunionectomy with osteotomy 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 5.23 Renal Toxicity and Hyperkalemia 5.24 Exacerbation of Asthma Related to Aspirin Sensitivity 5.25 Serious Skin Reactions 5.26 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.27 Fetal Toxicity 5.28 Hematological Toxicity 5.29 Withdrawal 5.30 Risks of Driving and Operating Machinery Reference ID: 5482803 FULL PRESCRIBING INFORMATION WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SEGLENTIS ADDICTION, ABUSE, AND MISUSE Because the use of SEGLENTIS exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)]. LIFE-THREATENING RESPIRATORY DEPRESSION Serious, life-threatening, or fatal respiratory depression may occur with use of SEGLENTIS, especially during initiation. To reduce the risk of respiratory depression, proper dosing of SEGLENTIS is essential [see Warnings and Precautions (5.2)]. ACCIDENTAL INGESTION Accidental ingestion of even one dose of SEGLENTIS, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.2)]. RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of SEGLENTIS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) and Drug Interactions (7)]. NEONATAL OPIOID WITHDRAWAL SYNDROME (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)]. OPIOID ANALGESIC RISK EVALUATION AND MITIGATION STRATEGY (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)]. CARDIOVASCULAR THROMBOTIC EVENTS • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use [see Warnings and Precautions (5.6)]. • SEGLENTIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.6)]. GASTROINTESTINAL BLEEDING, ULCERATION, AND PERFORATION NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Reference ID: 5482803 Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events [see Warnings and Precautions (5.7)]. ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE THREATENING RESPIRATORY DEPRESSION IN CHILDREN Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions (5.8)]. SEGLENTIS is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of SEGLENTIS in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see Warnings and Precautions (5.8)]. INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SEGLENTIS requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.9), Drug Interactions (7)]. Reference ID: 5482803 1 INDICATIONS AND USAGE SEGLENTIS is indicated for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1)], reserve SEGLENTIS for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia. SEGLENTIS should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions • Do not exceed the recommended dose of SEGLENTIS. • Do not co-administer SEGLENTIS with other tramadol or celecoxib containing products. • SEGLENTIS should only be prescribed by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve higher doses of opioids for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose of opioid clearly outweigh the substantial risks [see Warnings and Precautions (5.1)]. • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. • Respiratory depression can occur at any time during opioid therapy, especially upon initiation and following a dosage increase [see Warnings and Precautions (5.2)]. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SEGLENTIS [see Warnings and Precautions (5.2)]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual Reference ID: 5482803 state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.3)]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. 2.3 Recommended Dosage The dose of SEGLENTIS is 2 tablets every 12 hours as needed for pain and not to exceed 4 tablets over 24 hours. 2.4 Safe Reduction or Discontinuation of SEGLENTIS Do not abruptly discontinue SEGLENTIS in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking SEGLENTIS, there are a variety of factors that should be considered, including the total daily dose of opioid (including SEGLENTIS) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on SEGLENTIS who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily opioid dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with a reduced dosing schedule of SEGLENTIS to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the Reference ID: 5482803 dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.29), Drug Abuse and Dependence (9.2 and 9.3)]. 3 DOSAGE FORMS AND STRENGTHS SEGLENTIS coated tablets contain 56 mg celecoxib and 44 mg tramadol hydrochloride (equivalent to 39 mg tramadol). The tablets are white to off-white elongated coated tablets debossed with "100" on one side and "CTC" on the other. 4 CONTRAINDICATIONS SEGLENTIS is contraindicated in: • All patients younger than 12 years of age [see Warnings and Precautions (5.8)]. • Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.8)]. SEGLENTIS is also contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2)]. • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.6)]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.14)]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.18)]. • Previous hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to tramadol, opioids, celecoxib, sulfonamides, or any other component of the drug product [see Warnings and Precautions (5.19)]. • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Drug Interactions (7)]. • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [see Warnings and Precautions (5.19, 5.24)]. 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse and Misuse Tramadol Reference ID: 5482803 SEGLENTIS contains tramadol, a Schedule IV controlled substance. As an opioid, SEGLENTIS exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SEGLENTIS. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing SEGLENTIS, and reassess all patients receiving SEGLENTIS for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as SEGLENTIS but use in such patients necessitates intensive counseling about the risks and proper use of SEGLENTIS along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing SEGLENTIS. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Tramadol Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of SEGLENTIS, the risk is greatest during the initiation of therapy. To reduce the risk of respiratory depression, proper dosing of SEGLENTIS is essential [see Dosage and Administration (2)]. Overestimating the SEGLENTIS dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of SEGLENTIS, especially by children, can result in respiratory depression and death due to an overdose of tramadol. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper Reference ID: 5482803 [see Dosage and Administration (2.4)]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SEGLENTIS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Tramadol Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SEGLENTIS with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]. Advise both patients and caregivers about the risks of respiratory depression and sedation when SEGLENTIS is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs Reference ID: 5482803 [see Drug Interactions (7)]. 5.4 Neonatal Opioid Withdrawal Syndrome Tramadol Use of SEGLENTIS for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)]. 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Tramadol To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 5.6 Cardiovascular Thrombotic Events Celecoxib Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events Reference ID: 5482803 began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists’ Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non fatal myocardial infarction, and non-fatal stroke. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use SEGLENTIS for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.7)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of SEGLENTIS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SEGLENTIS is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.7 Gastrointestinal Bleeding, Ulceration, and Perforation Celecoxib NSAIDs, including celecoxib, a component of SEGLENTIS, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can Reference ID: 5482803 occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short- term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA. Strategies to Minimize the GI Risks in NSAID-treated patients • Use the approved dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SEGLENTIS until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.8 Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children Tramadol Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life- threatening respiratory depression and death: • SEGLENTIS is contraindicated for all children younger than 12 years of age because SEGLENTIS contains tramadol [see Contraindications (4)]. • SEGLENTIS is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Reference ID: 5482803 • Avoid the use of SEGLENTIS in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. • As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [see Use in Special Populations (8.4), Overdosage (10)]. Nursing Mothers Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking SEGLENTIS could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with SEGLENTIS [see Use in Specific Populations (8.2)]. CYP2D6 Genetic Variability: Ultra-rapid metabolizer Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as 1/1xN or 1/2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher-than-expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10)]. Therefore, individuals who are ultra-rapid metabolizers should not use SEGLENTIS. 5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes Tramadol The effects of concomitant use or discontinuation of CYP3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from SEGLENTIS are complex. Use of CYP3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SEGLENTIS requires careful consideration of the effects on the parent drug, tramadol, which is a weak serotonin and norepinephrine reuptake inhibitor and μ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in μ-opioid receptor binding [see Drug Interactions (7)]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors Because SEGLENTIS contains tramadol, the concomitant use of SEGLENTIS with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for Reference ID: 5482803 serious adverse events including seizures and serotonin syndrome. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression. Evaluate patients receiving tramadol and any CYP2D6 inhibitor at frequent intervals for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when SEGLENTIS is used in conjunction with inhibitors of CYP2D6 [see Drug Interactions (7)]. Cytochrome P450 3A4 Interaction Because SEGLENTIS contains tramadol, the concomitant use of SEGLENTIS with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression. The concomitant use of SEGLENTIS with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Evaluate patients receiving SEGLENTIS and any CYP3A4 inhibitor or inducer at frequent intervals for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when SEGLENTIS is used in conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)]. 5.10 Opioid-Induced Hyperalgesia and Allodynia Opioid-induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Causes of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.4), Warnings and Precautions (5.29)]. 5.11 Serotonin Syndrome Risk Tramadol Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, a component of SEGLENTIS, particularly during concomitant use with serotonergic Reference ID: 5482803 drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue SEGLENTIS if serotonin syndrome is suspected. 5.12 Increased Risk of Seizures Tramadol Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of SEGLENTIS increases the seizure risk in patients taking: [see Drug Interactions (7)]: • Selective serotonin re-uptake inhibitors (SSRIs) and Serotonin-norepinephrine re-uptake inhibitors (SNRIs) antidepressants or anorectics, • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), • Other opioids, • Monoamine oxidase inhibitors (MAOI) [see Warnings and Precautions (5.11), Drug Interactions (7)] • Neuroleptics, or • Other drugs that reduce the seizure threshold. Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In SEGLENTIS overdose, naloxone administration may increase the risk of seizure. 5.13 Suicide Risk Tramadol • Do not prescribe SEGLENTIS for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed [see Drug Abuse and Dependence (9)]. • Prescribe SEGLENTIS with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers, or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression [see Drug Interactions (7)]. Reference ID: 5482803 • Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration (2), Warnings and Precautions (5.3)]. 5.14 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients Tramadol The use of SEGLENTIS in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease SEGLENTIS-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at the recommended dosage of SEGLENTIS [see Warnings and Precautions (5.2)]. Elderly, Cachectic, or Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, or altered clearance, compared to younger, healthier patients [see Warnings and Precautions (5.2)]. Regularly evaluate such patients closely, particularly when initiating SEGLENTIS and when SEGLENTIS is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.15 Adrenal Insufficiency Tramadol Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.16 Severe Hypotension Tramadol Tramadol, a component of SEGLENTIS, may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating dosage of SEGLENTIS. In patients with circulatory shock, tramadol may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of SEGLENTIS in patients with circulatory shock. Reference ID: 5482803 5.17 Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness Tramadol In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), SEGLENTIS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with SEGLENTIS. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SEGLENTIS in patients with impaired consciousness or coma. 5.18 Risk of Use in Patients with Gastrointestinal Conditions Tramadol SEGLENTIS is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. The tramadol in SEGLENTIS may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.19 Anaphylaxis and Other Hypersensitivity Reactions Tramadol Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol, a component of SEGLENTIS. When these events do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive SEGLENTIS [see Contraindications (4)]. If anaphylaxis or other hypersensitivity occurs, stop administration of SEGLENTIS immediately, discontinue SEGLENTIS permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see Contraindications (4)]. Celecoxib Celecoxib, a component of SEGLENTIS has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see Contraindications (4) and Warnings and Precautions (5.24)]. Seek emergency help if any anaphylactic reaction occurs. 5.20 Hepatotoxicity As tramadol and celecoxib are both extensively metabolized by the liver, the use of SEGLENTIS in patients with moderate and severe hepatic impairment is not recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Celecoxib Reference ID: 5482803 Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including celecoxib. In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SEGLENTIS immediately, and perform a clinical evaluation of the patient. 5.21 Hypertension Celecoxib NSAIDs, including celecoxib, a component in SEGLENTIS, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Regularly evaluate blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.22 Heart Failure and Edema Celecoxib Avoid the use of SEGLENTIS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If SEGLENTIS is used in patients with severe heart failure, regularly evaluate patients for signs of worsening heart failure. The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Fluid retention and edema have been observed in some patients treated with NSAIDs. Use of celecoxib may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. In the CLASS study, the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. Reference ID: 5482803 5.23 Renal Toxicity and Hyperkalemia Celecoxib Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of SEGLENTIS in patients with advanced renal disease. The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating SEGLENTIS. Regularly evaluate renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of SEGLENTIS [see Drug Interactions (7)]. Use of SEGLENTIS in patients with advanced renal disease is not recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.24 Exacerbation of Asthma Related to Aspirin Sensitivity Celecoxib A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, SEGLENTIS is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When SEGLENTIS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.25 Serious Skin Reactions Celecoxib Serious skin reactions have occurred following treatment with celecoxib, a component of SEGLENTIS, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE) which may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE). These serious events may occur without warning and can be fatal. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of SEGLENTIS at the first appearance of skin rash or any other sign of hypersensitivity. SEGLENTIS is Reference ID: 5482803 contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.26 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as SEGLENTIS. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue SEGLENTIS and evaluate the patient immediately. 5.27 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including SEGLENTIS, in pregnant women at about 30 weeks gestation and later. NSAIDs, including SEGLENTIS, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including SEGLENTIS, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit SEGLENTIS use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if SEGLENTIS treatment extends beyond 48 hours. Discontinue SEGLENTIS if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.28 Hematological Toxicity Celecoxib Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with SEGLENTIS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with SEGLENTIS should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. NSAIDs, including SEGLENTIS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors Reference ID: 5482803 (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.29 Withdrawal Tramadol Do not abruptly discontinue SEGLENTIS in a patient physically dependent on opioids. When discontinuing SEGLENTIS in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.4), Drug Abuse and Dependence (9.3)]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including SEGLENTIS. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)]. 5.30 Risks of Driving and Operating Machinery Tramadol SEGLENTIS may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of SEGLENTIS and know how they will react to the medication. 5.31 Masking of Inflammation and Fever Celecoxib The pharmacological activity of SEGLENTIS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.32 Hyponatremia Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, a component of SEGLENTIS, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Regularly evaluate for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with SEGLENTIS, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue SEGLENTIS [see Dosage and Administration (2.4)]. 5.33 Hypoglycemia Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g., diabetes). If hypoglycemia is suspected, regularly evaluate blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration (2.4)]. 6 ADVERSE REACTIONS Reference ID: 5482803 The following serious adverse reactions are discussed, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.6)] • Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.7)] • Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions (5.8)] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.10)] • Serotonin Syndrome [see Warnings and Precautions (5.11)] • Seizures [see Warnings and Precautions (5.12)] • Suicide [see Warnings and Precautions (5.13)] • Adrenal Insufficiency [see Warnings and Precautions (5.15)] • Severe Hypotension [see Warnings and Precautions (5.16)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.18)] • Anaphylaxis and Other Hypersensitivity Reactions [see Warnings and Precautions (5.19)] • Hepatotoxicity [see Warnings and Precautions (5.20)] • Hypertension [see Warnings and Precautions (5.21)] • Heart Failure and Edema [see Warnings and Precautions (5.22)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.23)] • Serious Skin Reactions [see Warnings and Precautions (5.25)] • Hematologic Toxicity [see Warnings and Precautions (5.28)] • Withdrawal [see Warnings and Precautions (5.29)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 550 subjects in 7 clinical studies, from Phase 1 to Phase 3, were exposed to SEGLENTIS during the clinical development program, including 385 subjects exposed to 200 mg of SEGLENTIS, either single or multiple administration. In a placebo-controlled post-bunionectomy acute pain trial, 637 patients received 200 mg of SEGLENTIS every 12 hours or 50 mg tramadol every 6 hours or 100 mg celecoxib every 12 hours or placebo, orally for 48 hours (blinded period) [see Clinical Studies (14)] and followed up to 7 days post-dose. Table 1 lists the adverse reactions reported by > 5% of patients in any treatment group and greater in SEGLENTIS than placebo. Discontinuation due to adverse events occurred in 1.6% of SEGLENTIS-treated patients (3 out of 183), 1.6% of tramadol-treated patients (3 out of 183), no celecoxib-treated patients, and no placebo-treated patients. The adverse reactions that led to Reference ID: 5482803 discontinuation of study drug were nausea (1.1%) and pruritus/rash (0.5%) in the SEGLENTIS group, and vomiting (1.1%) and supraventricular tachycardia (0.5%) in the tramadol group. Table 1: Reported Adverse Reactions in >5% of Patients in Any Treatment Group and greater in SEGLENTIS than Placebo System Organ Class Preferred Term SEGLENTIS (N = 183) n (%) Tramadol (N = 183) n (%) Celecoxib (N = 182) n (%) Placebo (N = 89) n (%) Gastrointestinal disorders Nausea Vomiting 55 (30.1) 29 (15.8) 69 (37.7) 30 (16.4) 30 (16.5) 4 (2.2) 17 (19.1) 2 (2.2) Nervous system disorders Dizziness Headache Somnolence 31 (16.9) 21 (11.5) 15 (8.2) 34 (18.6) 33 (18.0) 10 (5.5) 9 (4.9) 20 (11.0) 4 (2.2) 13 (14.6) 6 (6.7) 3 (3.4) Metabolism and nutritional disorders Decreased appetite 6 (3.3) 11 (6.0) 1 (0.5) 0 Total daily dose: 400 mg of SEGLENTIS (200 mg twice a day); 200 mg of tramadol (50 mg four times a day); 200 mg of celecoxib (100 mg twice a day); or placebo. Note: Acetaminophen 1 g IV and oxycodone hydrochloride 5 mg Immediate Release (IR) tablets were permitted as rescue medication. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of either tramadol or celecoxib-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin Syndrome Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen Deficiency Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)]. QT Prolongation/Torsade De Pointes Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting. Eye Disorders Miosis, mydriasis. Metabolism and Nutrition Disorders Reference ID: 5482803 Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients. Hyponatremia Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions (5.32)]. Hypoglycemia Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions (5.33)]. Opioid-Induced Hyperalgesia and Allodynia Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.10)]. Nervous System Disorders Movement disorder, speech disorder. Psychiatric Disorders Delirium. Cardiovascular Vasculitis, deep venous thrombosis. General Anaphylactoid reaction, angioedema. Liver and Biliary Liver necrosis, hepatitis, jaundice, hepatic failure. Hemic and Lymphatic Agranulocytosis, aplastic anemia, pancytopenia, leucopenia. Metabolic Hypoglycemia, hyponatremia. Nervous Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage. Renal Interstitial nephritis. Skin and Appendages Erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE). Reference ID: 5482803 7 DRUG INTERACTIONS Table 2: Clinically Significant Drug Interactions with SEGLENTIS Inhibitors of CYP2D6 Clinical Impact: The concomitant use of SEGLENTIS and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)]. Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued evaluate patients at frequent intervals for adverse events including respiratory depression and sedation. Examples: Quinidine, fluoxetine, paroxetine, and bupropion. CYP2D6 Substrates Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib, which may enhance the exposure and toxicity of CYP2D6 substrate drugs. Intervention: If concomitant use of a CYP2D6 substrate drug is necessary, evaluate patients at frequent intervals for adverse events of that CYP2D6 substrate drug. Evaluate each patient's medical history when consideration is given to prescribing SEGLENTIS [see Clinical Pharmacology (12.3)]. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of SEGLENTIS and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, evaluate patients at frequent intervals for seizures and serotonin syndrome, and signs of respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, evaluate patients for efficacy maintenance and for signs and symptoms of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). Reference ID: 5482803 CYP3A4 Inducers Clinical Impact: The concomitant use of SEGLENTIS and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol [see Warnings and Precautions (5.9, 5.29)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression. Intervention: If concomitant use is necessary, evaluate patients for efficacy maintenance and for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, evaluate patients at frequent intervals for seizures and serotonin syndrome, and signs of respiratory depression and sedation. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of SEGLENTIS and carbamazepine is not recommended. Examples: Rifampin, carbamazepine, phenytoin. CYP2C9 Inhibitors or inducers Clinical Impact: Celecoxib metabolism is predominantly mediated via CYP2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co- administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of celecoxib. Intervention: If concomitant use with CYP2C9 inhibitor drugs is necessary, evaluate patients for adverse events of celecoxib from SEGLENTIS. If concomitant use with CYP2C9 inducer drugs is necessary, evaluate patients for efficacy maintenance of SEGLENTIS. Evaluate each patient's medical history when consideration is given to prescribing SEGLENTIS. Drugs That Interfere with Hemostasis Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of SEGLENTIS with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.28)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions Reference ID: 5482803 (5.7)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg). Intervention: Concomitant use of SEGLENTIS and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.7)]. SEGLENTIS is not a substitute for low dose aspirin for cardiovascular protection. NSAIDs and Salicylates Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.7)]. Intervention: The concomitant use of SEGLENTIS with other NSAIDs or salicylates is not recommended. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation. Discontinue SEGLENTIS if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.11)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. Intervention: Do not use SEGLENTIS in patients taking MAOIs or within 14 days of stopping such treatment. Examples Phenelzine, tranylcypromine, linezolid. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or Reference ID: 5482803 ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of SEGLENTIS and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of SEGLENTIS and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.23)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of SEGLENTIS and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine. Muscle Relaxants Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with the concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3). Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. During concomitant use of SEGLENTIS with diuretics, evaluate patients at frequent intervals for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.23)]. Digoxin Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of SEGLENTIS and digoxin, regularly evaluate serum digoxin levels. Evaluate patients at frequent intervals for signs of digoxin toxicity and adjust the dosage of digoxin as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when SEGLENTIS is used concomitantly with anticholinergic drugs. Lithium Reference ID: 5482803 Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of SEGLENTIS and lithium, regularly evaluate patients for signs of lithium toxicity. Warfarin Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. Intervention: Regularly evaluate the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. Intervention: During concomitant use of SEGLENTIS and methotrexate, regularly evaluate patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of SEGLENTIS and cyclosporine, regularly evaluate patients for signs of worsening renal function. Pemetrexed Clinical Impact: Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of SEGLENTIS and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, regularly evaluate for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. Intervention: Regularly evaluate patients with concomitant use of SEGLENTIS with corticosteroids for signs of bleeding [see Warnings and Precautions (5.7)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal data, advise pregnant women of the potential risk to fetus. Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions (5.4)). Reference ID: 5482803 Use of NSAIDs, including SEGLENTIS, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SEGLENTIS use between about 20 and 30 weeks of gestation and avoid SEGLENTIS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). There are no available data on use of SEGLENTIS in pregnant women. In an animal reproduction study, oral administration of celecoxib and tramadol co-crystal to pregnant rabbits during the period of organogenesis, resulted in embryo-fetal deaths and an increase of incidence of vertebral defects at approximately 4.7 and 0.11 times the dose of celecoxib and tramadol, respectively, at the maximum recommended human dose (MRHD) of SEGLENTIS at 400 mg/day (224 mg celecoxib/176 mg tramadol) (see Data). Tramadol Available data with tramadol use in pregnant women are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 3.2, 1.4, and 8.2 times the tramadol dose of 176 mg at the MRHD of SEGLENTIS. In a pre- and post-natal development study, tramadol decreased pup body weight and increased pup mortality at 2.7 and 4.3 times the MRHD, respectively. In a published study, tramadol caused structural abnormalities in the brains of fetuses when administered to female Sprague Dawley rats from Gestation Days 10 to 21 at 2.7 times the MRHD (see Data). Celecoxib Premature Closure of Fetal Ductus Arteriosus: Use of NSAIDs, including SEGLENTIS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo- fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 13 times the celecoxib dose of 224 mg at the MRHD of SEGLENTIS. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 4 times the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post- implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Reference ID: 5482803 The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Tramadol: Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing, and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)]. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during postmarketing. Celecoxib: Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SEGLENTIS, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary, including SEGLENTIS, at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If SEGLENTIS treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SEGLENTIS and follow up according to clinical practice (see Data). Labor or Delivery Tramadol: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. SEGLENTIS is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including SEGLENTIS, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during Reference ID: 5482803 --- labor. The effect of SEGLENTIS, if any, on the later growth, development, and functional maturation of the child is unknown. Celecoxib: There are no studies on the effects of SEGLENTIS during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Celecoxib: The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib. Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Treatment of pregnant rabbits during organogenesis with celecoxib and tramadol co-crystal resulted in an increase in the incidence of scoliosis and other vertebral defects (including absent thoracic hemicentrum/a and neural arch(es) and fused thoracic vertebral centra and/or neural arch(es)) at an oral dose of 100 mg/kg/day (56 mg celecoxib/44 mg tramadol/kg/day; approximately 4.7 and 0.11 times the MRHD on the basis of celecoxib and tramadol, respectively, on an AUC basis), which is a dose that also caused maternal toxicity (decreased body weight gain). In addition, there was a slight increase of post-implantation loss in rabbits at 100 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for embryofetal toxicity was 55 mg/kg/day (approximately 3.3 and 0.02 times the Reference ID: 5482803 MRHD of celecoxib and tramadol, respectively, on an AUC basis). Tramadol: Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m2 basis are 3.2, 1.4, and 8.2 times the MRHD of tramadol (176 mg) for mouse, rat, and rabbit, respectively. No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 3.9, 4.3, and 33 times the MRHD of tramadol (176 mg), respectively, on a mg/m2 basis. Tramadol was evaluated in pre-and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (2.7 times the MRHD of tramadol on a mg/m2 basis) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (4.3 times the MRHD of tramadol on a mg/m2 basis). In a published study, oral administration of tramadol at 50 mg/kg (2.7 times the MRHD of tramadol on a mg/m2 basis) to pregnant female rats from Gestation Days 10 to 21 caused structural abnormalities in the brains of the offspring. Celecoxib: Celecoxib at oral doses ≥150 mg/kg/day (approximately 4 times the level of celecoxib of 224 mg at the MRHD of SEGLENTIS based on AUC), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose- dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 13 times the MRHD based on AUC) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 13 times the MRHD based on AUC). Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 15 times the MRHD based on AUC). The effects of SEGLENTIS on labor and delivery in pregnant women are unknown. 8.2 Lactation Risk Summary SEGLENTIS is not recommended for obstetrical preoperative medication or for post-delivery analgesia in lactating women because the safety of tramadol in infants and newborns has not been studied. Tramadol Tramadol and its metabolite, O-desmethyltramadol (M1), are present in human milk. There is no Reference ID: 5482803 information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The M1 metabolite is more potent than tramadol in mu opioid receptor binding [see Clinical Pharmacology (12.1)]. Published studies have reported tramadol and M1 in colostrum with administration of tramadol to breastfeeding mothers in the early post-partum period. Women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of M1 in breast milk that can be dangerous in their breastfed infants. In women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose dependent. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SEGLENTIS (see Data) [see Warnings and Precautions (5.8)]. Celecoxib Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Clinical Considerations If infants are exposed to SEGLENTIS through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. Data Tramadol Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. 8.3 Females and Males of Reproductive Potential Infertility Tramadol Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2)]. Published studies in adult male rodents report that tramadol, at clinically relevant doses, can produce adverse effects on male reproductive hormones and tissues [see Nonclinical Toxicology (13.1)]. Celecoxib Females: Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including celecoxib, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 5482803 8.4 Pediatric Use The safety and effectiveness of SEGLENTIS in pediatric patients have not been established. Tramadol Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions (5.8)]. In some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. Because of the risk of life-threatening respiratory depression and death: • SEGLENTIS is contraindicated for all children younger than age 12 years of age [see Contraindications (4)]. • SEGLENTIS is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of SEGLENTIS in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. 8.5 Geriatric Use In the randomized, double-blind, active- and placebo-controlled, parallel group study comparing SEGLENTIS to tramadol, celecoxib, and placebo in patients with acute post-operative pain following unilateral first metatarsal osteotomy with internal fixation, 9.1% of patients were ≥65 years of age. Age subgroup examination was planned by protocol and it revealed a similar trend in efficacy compared to younger patients and no untoward or unexpected adverse reactions were seen in the elderly patients who received SEGLENTIS. No dose adjustments are required for elderly patients. Tramadol Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.14)]. Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to regularly evaluate renal function. Celecoxib Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, monitor patients for adverse effects [see Warnings and Precautions (5.6, 5.7, 5.20, 5.23, 5.31)]. Because SEGLENTIS is approved at a unique dosage of celecoxib, SEGLENTIS is not recommended in patients that require dosages other than 2 tablets every 12 hours, containing a total daily dose of celecoxib of 224 mg. Of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 Reference ID: 5482803 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see Warnings and Precautions (5.7, 5.23)]. 8.6 Renal Impairment Because SEGLENTIS contains celecoxib, the use of SEGLENTIS in patients with severe renal impairment is not recommended [see Warnings and Precautions (5.23) and Clinical Pharmacology (12.3)]. The pharmacokinetics and tolerability of SEGLENTIS in patients with renal impairment has not been studied. Tramadol Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may take several days for elevated plasma concentrations to develop. 8.7 Hepatic Impairment As tramadol and celecoxib are both extensively metabolized by the liver, the use of SEGLENTIS in patients with moderate and severe hepatic impairment is not recommended [see Warnings and Precautions (5.20), Clinical Pharmacology (12.3)]. The pharmacokinetics and tolerability of SEGLENTIS in patients with impaired hepatic function have not been studied. Tramadol Metabolism of tramadol and M1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. Celecoxib The daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. Because the dose of celecoxib and tramadol cannot be adjusted individually for SEGLENTIS, the use in moderate hepatic impairment is not recommended. The use of celecoxib in patients with severe hepatic impairment is not recommended [see Clinical Pharmacology (12.3)]. 8.8 Poor Metabolizers of CYP2C9 Substrates Celecoxib In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C93/3), based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) celecoxib is administered starting with half the lowest recommended dose [see Clinical Pharmacology (12.5)]. Because SEGLENTIS is not available in lower strengths of celecoxib, SEGLENTIS is not recommended in patients who are known or suspected to be poor CYP2C9 Reference ID: 5482803 metabolizers [see Clinical Pharmacology (12.5)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance SEGLENTIS contains tramadol, a Schedule IV controlled substance. 9.2 Abuse SEGLENTIS contains tramadol, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use, (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of SEGLENTIS increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent use of SEGLENTIS with alcohol and/or other CNS depressants. Abuse and addiction to opioids may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of SEGLENTIS abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use SEGLENTIS in combination with other abused drugs. “Drug seeking” behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. SEGLENTIS, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of SEGLENTIS Abuse of SEGLENTIS poses a risk of overdose and death. The risk is increased with concurrent use Reference ID: 5482803 of SEGLENTIS with alcohol and/or other CNS depressants. SEGLENTIS is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue SEGLENTIS in a patient physically dependent on opioids. Rapid tapering of SEGLENTIS in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing SEGLENTIS, gradually taper the dosage using a patient-specific plan that considers the following: the dose of SEGLENTIS the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.4), Warnings and Precautions (5.29)]. If SEGLENTIS is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation SEGLENTIS is a combination drug composed of tramadol and celecoxib. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, celecoxib toxicity or both. Tramadol Reference ID: 5482803 Acute overdose with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, seizures, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Deaths due to overdose have been reported with abuse and misuse of tramadol [see Warnings and Precautions (5.1); Drug Abuse and Dependence (9.2)]. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. Celecoxib Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.6, 5.7, 5.21, 5.23)]. No overdoses of celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. No information is available regarding the removal of celecoxib by hemodialysis but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Treatment of Overdose Tramadol In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-supporting measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to tramadol overdose, administer an opioid antagonist. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in SEGLENTIS, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. Reference ID: 5482803 I O HO H N HCl Celecoxib Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222 1222). 11 DESCRIPTION SEGLENTIS (celecoxib and tramadol hydrochloride) tablets contains a co-crystal with molecular weight of 681.2, composed of tramadol hydrochloride, an analgesic and opioid agonist, and celecoxib, a nonsteroidal anti-inflammatory drug, in a 1:1 molecular ratio. The chemical name for tramadol hydrochloride is (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3 methoxyphenyl)cyclohexanol hydrochloride (C16H26ClNO2). The structural formula is: O HO H N HCl The molecular weight of tramadol hydrochloride is 299.84 (the molecular weight of tramadol is 263.38). The chemical name for celecoxib is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole (C17H14F3N3O2S). The molecular weight is 381.38 and it has the following chemical structure: SEGLENTIS coated tablets contain 56 mg celecoxib and 44 mg of tramadol hydrochloride (equivalent to 39 mg tramadol) in a co-crystal structure. Tablets are white to off-white in color. Inactive ingredients in the tablet are sodium lauryl sulfate, crospovidone, mannitol, sodium stearyl fumarate, talc, cellulose microcrystalline, copovidone and color mixture (polyvinyl alcohol partially hydrolyzed, titanium dioxide, polyethylene glycol and talc). Reference ID: 5482803 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SEGLENTIS is a co-crystal that contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake, and celecoxib, a nonsteroidal anti-inflammatory drug, in a 1:1 molecular ratio. Tramadol Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound [see Clinical Pharmacology (12.2)]. Celecoxib Celecoxib is an analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2). Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Celecoxib concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics Effects on the Central Nervous System Tramadol produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Tramadol administration may produce a constellation of symptoms including nausea and vomiting, dizziness, and somnolence. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Reference ID: 5482803 Effects on the Cardiovascular System Tramadol produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four- way crossover, placebo-and positive-(moxifloxacin) controlled study in 68 adult male and female healthy subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily dose), the study demonstrated no significant effect on the QTcF interval. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Warnings and Precautions (5.15), Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2)]. Concentration–Adverse Reaction Relationships There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2)]. Platelets In clinical trials using normal volunteers, celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib. Fluid Retention Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal Reference ID: 5482803 nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone. 12.3 Pharmacokinetics Absorption Tramadol is presented in SEGLENTIS as a racemate. After Tramadol immediate-release (IR) administration both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The rate and extent of absorption of tramadol and celecoxib in SEGLENTIS show differences in absorption compared to Tramadol IR Tablets or Celecoxib capsule when those drugs are administered individually and concomitantly in a single four way cross-over study. The PK parameters of tramadol, tramadol-M1 metabolite and celecoxib after single dose oral administration of SEGLENTIS Tablets, Tramadol IR Tablets, Celecoxib Capsule or Tramadol IR Tablets and Celecoxib Capsule administered concomitantly is shown in Table 3. Table 3: The PK parameters of tramadol, tramadol-M1 metabolite and celecoxib after single dose oral administration of SEGLENTIS Tablets, Tramadol IR Tablets, Celecoxib Capsule, or Tramadol IR Tablets and Celecoxib Capsule administered concomitantly in four way cross-over study (male and female participants receiving all treatments in random order). Analyte PK Parameter * 2 x SEGLENTIS Tablets (112 mg celecoxib + 88 mg tramadol) n=33 2 x 50 mg Tramadol IR Tablets n=32 1x 100 mg Celecoxib Capsule n=33 2 x 50 mg Tramadol IR Tablets + 100 mg Celecoxib Capsule n=32 312 (22) Tramadol Cmax (ng/mL) 214 (29) 305 (23) - Tmax (h) $ 3.0 (1.25, 8.0) 2.0 (0.75, 3.0) - 1.9 (1.0, 6.0) AUC0-t (ng·h/mL) 2507 (36) 2709 (35) - 2888 (34) AUC0-∞ (ng·h/mL) 2590 (35) a 2802(32) b - 2990 (32) b T½ (h) 6.5 (15) 6.1 (17) - 6.2 (16) Tramadol-M1 metabolite Cmax (ng/mL) 55 (29) 78 (29) - 78 (29) Tmax (h) $ 4.0 (2.5, 8.0) 2.5 (1.25, 6.0) - 2.5 (1.25, 8.0) AUC0-t (ng·h/mL) 846 (27) 965 (25) - 1010 (25) AUC0-∞ (ng·h/mL) 880 (24) a 1002 (21) b - 1049 (21) b T½ (h) 7.2 (14) 6.7 (14) - 7.0 (15) Celecoxib Cmax (ng/mL) 259 (34) - 318 (47) 165 (46) Tmax (h) $ 1.5 (0.75, 6.0) - 3.0 (1.25, 8.0) 2.5 (1.0, 12.0) AUC0-t (ng·h/mL) 1930 (41) - 2348 (40) 1929 (38) AUC0-∞ (ng·h/mL) 2128 (42) c - 2553 (43) d 2224 (39) e T½ (h) 13 (27) - 11 (46) 14 (29) * Arithmetic Mean (% CV); $ Median (minimum, maximum); a n=32, b n=31, c n=28, d n=27, e n=21 Multiple dose After multiple dose administration of SEGLENTIS tablets twice daily for a total of 15 consecutive doses, the steady-state accumulation ratio of tramadol Cmax and AUCτ (15th dose/ 1st dose) were 2.20-fold and 2.37-fold, respectively. The steady-state accumulation ratio of celecoxib Cmax and AUCτ (15th dose/ 1st dose) were 1.76-fold and 2.15-fold, respectively. Based on pre-dose concentrations, the steady state appears to be achieved for all three analytes, tramadol, M1 metabolite and celecoxib, of SEGLENTIS tablets. Reference ID: 5482803 The absolute oral bioavailability of tramadol and celecoxib from SEGLENTIS have not been determined. Tramadol has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol tablets. Absolute bioavailability studies have not been conducted for celecoxib. Tramadol: In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of enantiomer present. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self- induction. Celecoxib: The coadministration of celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. Food Effect When SEGLENTIS tablets were administered with a high-fat, high-calorie meal, the Cmax and the AUC of tramadol and tramadol-M1 metabolite were not significantly affected. For celecoxib, component of SEGLENTIS tablets, the Tmax was delayed by approximately 2.5 hour and resulted in around a 30% increase in Cmax and AUC, which was approximately similar to the food effect of Celecoxib capsule. SEGLENTIS can be administered without regard to timing of meals. Distribution Tramadol The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Celecoxib In healthy subjects, celecoxib is highly protein bound (~ 97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primary to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells. Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-life of tramadol were 6.5 hours and 9.0 hours after single- dose and multiple-dose administration of SEGLENTIS tablets, respectively. There was no change in the elimination half-life of celecoxib (13 hours) after single or multiple dose administration of SEGLENTIS tablets. Metabolism Tramadol: Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and Reference ID: 5482803 CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denotated M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response [see Warnings and Precautions (5.8); Drug Interactions (7)]. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower. Concomitant therapy with inhibitors of CYP2D6 such as fluoxetine, paroxetine and quinidine could result in significant drug interactions. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of serotonin re-uptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure and serotonin syndrome [see Warnings and Precautions (5.11, 5.12) and Drug Interactions (7)]. Celecoxib: Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid, and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Excretion Tramadol: Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. Celecoxib: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (T1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min. Specific Populations Geriatric Patients Reference ID: 5482803 Tramadol: Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age [see Use in Specific Populations (8.5)]. Celecoxib: At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Pediatric Patients Pharmacokinetics of SEGLENTIS has not been established in pediatric patients. Sex Sex effects on the Pharmacokinetics of SEGLENTIS have not been assessed. The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg IV dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown. Race Race effects on the Pharmacokinetics of SEGLENTIS have not been assessed. Celecoxib: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown. Renal Impairment Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied [see Use in Specific Populations (8.6), Warnings and Precautions (5.23)]. Hepatic Impairment Metabolism of tramadol and M1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1). A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady state celecoxib AUC is increased about 40% and 180%, Reference ID: 5482803 respectively, above that seen in healthy control subjects [see Use in Specific Populations (8.7)]. Drug Interaction Studies In vitro studies indicate that celecoxib is not an inhibitor of CYP2C9, 2C19 or 3A4. In vivo studies have shown the following: Aspirin When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Lithium In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone [see Drug Interactions (7)]. Fluconazole Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole [see Drug Interactions (7)]. Other Drugs The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, [see Drug Interactions (7)], phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found. Tramadol and Celecoxib Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4. The formation of tramadol M1 metabolite is dependent on CYP2D6. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. An in vivo multiple dose PK study of 100 mg tramadol (2x50 mg) and 100 mg celecoxib (1x100 mg) administered concomitantly twice daily for 15 doses demonstrates that steady-state Cmax and AUC of tramadol and its active metabolite M1 are comparable along with comparable PK profiles to the 100 mg tramadol (2x50 mg) administered alone twice daily for 15 doses. The study results indicate that co-administration of celecoxib does not appear to affect the PK of tramadol or M1. 12.5 Pharmacogenomics Poor Metabolizers of CYP2C9 CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C92 and CYP2C93 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C93/3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C91/1 or I/3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 2, 5, 6, 9 and 11. It is estimated that the frequency of the homozygous 3/*3 genotype is 0.3% to 1.0% in various ethnic groups [see Use in Specific Populations (8.8)]. Poor / Extensive Metabolizers of CYP2D6 Reference ID: 5482803 The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There are no animal or laboratory studies with SEGLENTIS (product composed of tramadol and celecoxib) to evaluate carcinogenesis, mutagenesis, or impairment of fertility. Data on the individual components are described below. Carcinogenesis Tramadol A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg in the drinking water (0.8 times the maximum recommended human dose (MRHD) of tramadol at 176 mg on a mg/m2 basis) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No evidence of carcinogenicity was noted in a rat 2-year carcinogenicity study testing oral doses of up to 30 mg/kg in the drinking water (1.7 times the MRHD of tramadol on a mg/m2 basis). Celecoxib Celecoxib was not carcinogenic in Sprague-Dawley rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 4 to 9 times the MRHD based on AUC) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately 2.2 times the MRHD based on AUC) for two years. Mutagenesis Tramadol Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay. Tramadol was not mutagenic in the in vitro bacterial reverse mutation assay using Salmonella and E. coli (Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal aberration assay, or the in vivo micronucleus assay in bone marrow. Celecoxib Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow. Impairment of Fertility Tramadol No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. These dosages are 2.7 and 4.1 times the maximum recommended human dose (MRHD) of tramadol (176 mg) on a mg/m2 basis, respectively [see Use in Specific Populations (8.3)]. Reference ID: 5482803 However, published studies report that treatment of adult male rats with tramadol (40 mg/kg, IP and SC for 30 and 60 days, respectively, 2.2 times the MRHD of tramadol on a mg/m2 basis; or 4.5 to 135 mg/kg, SC for 18 weeks, 0.2 to 7.4 times the MRHD of tramadol on a mg/m2 basis) produced adverse effects on male reproductive hormones and male reproductive tissues. Celecoxib Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day (approximately 24 times the MRHD of celecoxib (224 mg) based on AUC). At ≥50 mg/kg/day (approximately 13 times the MRHD of celecoxib (224 mg) based on AUC) there was increased preimplantation loss. 13.2 Animal Toxicology and/or Pharmacology Celecoxib An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown. 14 CLINICAL STUDIES SEGLENTIS study on acute pain after bunionectomy with osteotomy The efficacy and safety of SEGLENTIS was evaluated in one randomized, double-blind, parallel group study comparing SEGLENTIS to tramadol, celecoxib, and placebo (NCT03108482). The study enrolled 637 patients 18 years of age or older (age ranged between 18 and 77) with acute post operative pain (>5 and <9 on a 0-10 Numeric Pain Rating Scale [NPRS]) following unilateral first metatarsal osteotomy with internal fixation. Patients were randomized at a ratio of 2:2:2:1 to SEGLENTIS 200 mg every 12 hours, tramadol 50 mg every 6 hours, celecoxib 100 mg every 12 hours, or placebo in a double-blind, double-dummy study. Use of rescue medication (acetaminophen and oxycodone HCl) was permitted during the study. Patients had a mean baseline pain intensity of 6.7 on the NPRS. The primary efficacy endpoint was time-weighted summed pain intensity difference over 48 hours (SPID48). Patients in the SEGLENTIS group had statistically significantly better mean SPID48 scores than any of the other groups after bunionectomy. Pain intensity difference from baseline over 48 hours mean values by treatment group are shown in Figure 1. Figure 1: Pain Intensity Difference by Evaluation Time Point from Baseline to 48 hours – Post Operative Bunionectomy with Osteotomy (Full Analysis Set Population) Reference ID: 5482803 1.0 0.5 0.0 -0.5 -1 .0 (I) -1 .5 :::, ro > -2.0 C "' ~ -2.5 -3.0 -3.5 -4.0 -4.5 -5.0 0 6 12 18 TRADENAME 24 Tirre Post-Dose (h) Treatment Trarnadol 30 36 42 48 Celecoxib Placebo 16 HOW SUPPLIED/STORAGE AND HANDLING SEGLENTIS (celecoxib and tramadol hydrochloride) tablets are coated tablets containing celecoxib 56 mg and tramadol hydrochloride 44 mg. The tablets are white to off-white elongated coated tablets debossed with "100 on one side and "CTC" on the other side and are available as follows: Bottles of 35 tablets: NDC 66869-564-35 Bottles of 90 tablets: NDC 66869-564-90 Bottles of 90 tablets (Bottle only): NDC 66869-564-09 Dispense in a tight container. Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store SEGLENTIS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving SEGLENTIS unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. Reference ID: 5482803 Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or Drug Enforcement Administration (DEA)-registered collectors are available, instruct patients to dispose of SEGLENTIS by following these four steps: • Mix SEGLENTIS (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds; • Place the mixture in a container such as a sealed plastic bag; • Throw the container in the household trash; • Remove all personal information on the prescription label of the empty bottle. Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of SEGLENTIS, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share SEGLENTIS with others and to take steps to protect SEGLENTIS from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting SEGLENTIS or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)]. Instruct patients to take steps to store SEGLENTIS securely and to dispose of unused SEGLENTIS in accordance with the local state guidelines and/or regulations. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if SEGLENTIS is used with benzodiazepines, CNS depressants, including alcohol, or some illicit drugs and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.9); Drug Interactions (7)]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SEGLENTIS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Reference ID: 5482803 Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver know what to do. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.6)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.7)]. Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise caregivers that SEGLENTIS is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to 18 years of age receiving SEGLENTIS to watch for signs of respiratory depression [see Warnings and Precautions (5.8)]. Opioid-Induced Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain. Inform patients and caregivers not to exceed the recommended dose of SEGLENTIS [see Warnings and Precautions (5.10), Adverse Reactions (6.2)]. Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.11), Drug Interactions (7)]. Seizures Inform patients that SEGLENTIS may cause seizures with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol [see Warnings and Precautions (5.12)]. Reference ID: 5482803 MAOI Interaction Inform patients not to take SEGLENTIS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking SEGLENTIS [see Drug Interactions (7)]. Important Administration Instructions • Instruct patients how to properly take SEGLENTIS [see Dosage and Administration (2)]. • Advise patients not to modify the dose of SEGLENTIS without consulting with a physician or other healthcare professional. • If patients have been receiving treatment with SEGLENTIS for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication [see Dosage and Administration (2.4)]. Maximum single-dose and 24-hour dose Advise patients not to exceed the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures, and death [see Dosage and Administration (2); Warnings and Precautions (5.2)]. Driving or Operating Heavy Machinery Advise patients that SEGLENTIS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.30)]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.15)]. Hypotension Inform patients that SEGLENTIS may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.16)]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in SEGLENTIS. Advise patients how to recognize such a reaction and when to seek medical attention. Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.19); Adverse Reactions (6)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, Reference ID: 5482803 pruritus, diarrhea jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop SEGLENTIS and seek immediate medical therapy [see Warnings and Precautions (5.20), Use in Specific Populations (8.6)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.22)]. Serious Skin Reactions, including DRESS Advise patients to stop taking SEGLENTIS immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.25, 5.26)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of SEGLENTIS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with SEGLENTIS until they talk to their healthcare provider [see Drug Interactions (7)]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of SEGLENTIS for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life- threatening if not recognized and treated and that the patient should inform their healthcare provider if they have used opioids at any time during their pregnancy, especially near the time of birth [see Warnings and Precautions (5.4); Use in Specific Populations (8.1)]. Embryo-Fetal Toxicity Advise female patients of reproductive potential that SEGLENTIS may cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Inform pregnant women to avoid use of SEGLENTIS and other NSAIDS starting at 30 weeks of gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with SEGLENTIS is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.27) and Use in Specific Populations (8.1)]. Lactation Advise women that breastfeeding is not recommended during treatment with SEGLENTIS [see Warnings and Precautions (5.4); Use in Specific Populations (8.2)]. Infertility Advise patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)]. Advise females of reproductive potential who desire pregnancy that NSAIDs, including the celecoxib Reference ID: 5482803 contained in SEGLENTIS, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Manufactured and Packaged by: Towa Pharmaceutical Europe, S.L. Martorelles, 08107 Barcelona Spain Distributed by: Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117 USA FPI-SEG-US-00011 11/2024 SEGLENTIS® is a registered trademark of Esteve Pharmaceuticals, S.A. and is used under license. © Kowa Pharmaceuticals America, Inc. (2021) Reference ID: 5482803 Medication Guide SEGLENTIS [“Seg-LEN-tis”] (celecoxib and tramadol hydrochloride) tablets, CIV SEGLENTIS is: • A strong prescription pain medicine that contains the opioid (narcotic) tramadol and the Nonsteroidal Anti-inflammatory Drug (NSAID) celecoxib. • SEGLENTIS is used for the management of acute pain in adults, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about SEGLENTIS: • Get emergency help or call 911 right away if you take too much SEGLENTIS (overdose). When you first start taking SEGLENTIS, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. • Taking SEGLENTIS with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Never give anyone else your SEGLENTIS. They could die from taking it. Selling or giving away SEGLENTIS is against the law. • Store SEGLENTIS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. • Celecoxib can cause serious side effects, including: o Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: • with increasing doses of NSAIDs • with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft” (CABG). Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. o Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: • anytime during use • without warning symptoms • that may cause death The risk of getting an ulcer or bleeding increases with: • past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs • taking medicines called “corticosteroids”, “antiplatelet drugs” “anticoagulants”, “SSRIs” or “SNRIs” • increasing doses of NSAIDs • longer use of NSAIDs • smoking • drinking alcohol • older age • poor health • advanced liver disease • bleeding problems Important Information Guiding Use in Pediatric Patients: • Do not give SEGLENTIS to a child younger than 12 years of age. • Do not give SEGLENTIS to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. • Avoid giving SEGLENTIS to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems. Do not take SEGLENTIS if you have: • Severe asthma, trouble breathing, or other lung problems. • A bowel blockage or narrowing of the stomach or intestines. • An allergy to tramadol, opioids, celecoxib, sulfonamides, or any of the inactive ingredients in SEGLENTIS. • Had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • Taken a Monoamine Oxidase Inhibitor, MAOI (medicine used for depression) within the last 14 days or are currently taking one. Do not take SEGLENTIS right before or after heart bypass surgery. Reference ID: 5482803 Before taking SEGLENTIS, tell your healthcare provider about all of your medical conditions, including if you have a history of: • Head injury, seizures • Liver, kidney, thyroid problems • Problems urinating • Pancreas or gallbladder problems • Abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems • High blood pressure • Asthma Tell your healthcare provider if you: • Are pregnant or plan to become pregnant: Use of SEGLENTIS for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. Taking SEGLENTIS at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take SEGLENTIS for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take SEGLENTIS and other NSAIDs after about 30 weeks of pregnancy. Tell your healthcare provider if you become pregnant or think that you may be pregnant. • Are breastfeeding: Not recommended; may harm your baby. • Notice your pain getting worse. If your pain gets worse after you take SEGLENTIS, do not take more of SEGLENTIS without first talking to your doctor. Talk to your doctor if the pain you have increases, if you feel more sensitive to pain, or if you have new pain after taking SEGLENTIS. • Are living in a household where there are small children or someone who has abused street or prescription drugs. • Are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking SEGLENTIS with certain other medicines can cause serious side effects that could lead to death. Do not start taking any new medicine without talking to your healthcare provider first. When taking SEGLENTIS: • Do not change your dose. Take SEGLENTIS exactly as prescribed by your healthcare provider. Use SEGLENTIS at the lowest dosage possible for the shortest time needed. • For acute (short-term) pain, you may only need to take SEGLENTIS for a few days. You may have some SEGLENTIS left over that you did not use. See disposal information at the bottom of this section for directions on how to safely dispose of SEGLENTIS. • The maximum dosage is 2 tablets every 12 hours. Do not take more than your prescribed dose and do not take more than 4 tablets per day. If you miss a dose, take your next dose at your usual time. • Call your healthcare provider if the dose you are taking does not control your pain. • If you have been taking SEGLENTIS regularly, do not stop taking SEGLENTIS without talking to your healthcare provider. • Dispose of expired, unwanted, or unused SEGLENTIS immediately by taking your drug to an authorized Drug Enforcement Administration (DEA)-registered collector or drug take-back program. If one is not available, you can dispose of SEGLENTIS by mixing the product with dirt, cat litter, or used coffee grounds, placing the mixture in a sealed plastic bag, and throwing the bag in your trash. While taking SEGLENTIS DO NOT: • Drive or operate heavy machinery, until you know how SEGLENTIS affects you. SEGLENTIS can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with SEGLENTIS may cause you to overdose and die. The possible side effects of SEGLENTIS: • Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. • NSAIDs can cause serious side effects, including: new or worse high blood pressure, heart failure, liver problems including liver failure, kidney problems including kidney failure, low red blood cells (anemia), life-threatening skin reactions, life- threatening allergic reactions. Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency medical help or call 911 right away if you have: • Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. Stop taking SEGLENTIS and call your healthcare provider right away if you get any of the following symptoms: • Nausea, more tired or weaker than usual, diarrhea, itching, your skin or eyes look yellow, indigestion or stomach pain, flu- like symptoms, vomit blood, there is blood in your bowel movement or it is black and sticky like tar, unusual weight gain, skin rash or blisters with fever, swelling of the arms, legs, hands and feet. SEGLENTIS may cause fertility problems in males and females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of SEGLENTIS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Reference ID: 5482803 Distributed by: Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117 USA. For more information, go to www.seglentisrx.com or call 1-888-SEGLENTIS. MG-SEG-US-00002 11/2023 SEGLENTIS® is a registered trademark of Esteve Pharmaceuticals, S.A. and is used under license. © Kowa Pharmaceuticals America, Inc. (2021) This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2023 Reference ID: 5482803	custom-source	2025-02-12T15:47:01.914608	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213426s003lbl.pdf', 'application_number': 213426, 'submission_type': 'SUPPL ', 'submission_number': 3}
80,332	_________________ ______________ ______________ ______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZANAFLEX® safely and effectively. See full prescribing information for ZANAFLEX. ZANAFLEX® (tizanidine) capsules, for oral use ZANAFLEX® (tizanidine) tablets, for oral use Initial U.S. Approval: 1996 __________________RECENT MAJOR CHANGES _________________ Indications and Usage (1) 11/2024 Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 11/2024 Contraindications (4) 11/2024 Warnings and Precautions (5.1, 5.2, 5.4, 5.5) 11/2024 __________________ INDICATIONS AND USAGE Zanaflex is a central alpha-2-adrenergic agonist indicated for the treatment of spasticity. (1) _______________ DOSAGE AND ADMINISTRATION • Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. (2.1) • Recommended starting dose: 2 mg by mouth every 6 to 8 hours, as needed, up to a maximum of 3 doses in 24 hours (2.2) • Dosage can be increased by 2 mg to 4 mg per dose every 1 to 4 days; maximum total daily dosage is 36 mg (2.2) • Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in a change in tolerability and control of symptoms. Consistent administration with respect to food is recommended. If substitution between dosage forms is necessary, take into consideration these pharmacokinetic differences. (2.2, 2.6, 12.3) • Patients with renal impairment (creatinine clearance <25 mL/min) or hepatic impairment: use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased. (2.3, 2.4) • To discontinue Zanaflex, decrease dose slowly to minimize the risk of withdrawal adverse reactions (2.5) DOSAGE FORMS AND STRENGTHS • Capsules: 2 mg, 4 mg, or 6 mg (3) • Tablets: 4 mg (3) ___________________ CONTRAINDICATIONS____________________ • Concomitant use with strong CYP1A2 inhibitors (4, 7.1) • Patients with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex (4, 5.5) _______________ WARNINGS AND PRECAUTIONS _______________ • Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Zanaflex should not be used with other α2-adrenergic agonists (5.1, 7.7) • Risk of liver injury: monitor ALTs; discontinue Zanaflex if liver injury occurs (5.2) • Sedation: Zanaflex may interfere with everyday activities; sedative effects of Zanaflex, alcohol, and other central nervous system (CNS) depressants are additive (5.3, 7.4) • Hallucinations: consider discontinuation of Zanaflex (5.4) ____________________ADVERSE REACTIONS____________________ The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-8007277151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ Moderate or weak CYP1A2 inhibitors: avoid concomitant use; may cause hypotension, bradycardia, or excessive drowsiness; if concomitant use is necessary and adverse reactions occur, reduce Zanaflex dosage or discontinue. (7.2, 12.3) USE IN SPECIFIC POPULATIONS _______________ • Pregnancy: Based on animal data, may cause fetal harm (8.1) • Geriatric use: Zanaflex should be used with caution in elderly patients because clearance is decreased four-fold (8.5) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluation and Testing Before and After Initiating Zanaflex 2.2 Recommended Dosage 2.3 Recommended Dosage in Patients with Renal Impairment 2.4 Recommended Dosage in Patients with Hepatic Impairment 2.5 Discontinuation of Zanaflex 2.6 Switching Between With/Without Food and Different Tizanidine Dosage Forms 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension 5.2 Liver Injury 5.3 Sedation 5.4 Hallucinosis/Psychotic-Like Symptoms 5.5 Hypersensitivity Reactions 5.6 Withdrawal Adverse Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Strong CYP1A2 Inhibitors 7.2 Moderate or Weak CYP1A2 Inhibitors 7.3 Oral Contraceptives 7.4 Alcohol and Other CNS Depressants 7.5 α2-Adrenergic Agonists 7.6 Antihypertensive Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5484759 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Zanaflex is indicated for the treatment of spasticity in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluation and Testing Before and After Initiating Zanaflex Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions (5.2)]. 2.2 Recommended Dosage The recommended starting dose is 2 mg by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased every 1 to 4 days by 2 mg to 4 mg at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied. There are pharmacokinetic differences when administering Zanaflex between the fed or fasted state [see Clinical Pharmacology (12.3)]. Zanaflex may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure. Because of the short duration of therapeutic effect, treatment with Zanaflex should be reserved for those daily activities and times when relief of spasticity is most important. 2.3 Recommended Dosage in Patients with Renal Impairment In patients with creatinine clearance < 25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.4 Recommended Dosage in Patients with Hepatic Impairment In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.5 Discontinuation of Zanaflex When discontinuing Zanaflex, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg to 4 mg per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and Dependence (9.3)]. Reference ID: 5484759 2.6 Switching Between With/Without Food and Different Tizanidine Dosage Forms There are pharmacokinetic differences when: 1) switching between administration of Zanaflex with or without food 2) switching between dosage forms if being administered with food. If these situations occur, monitor patients for therapeutic effect or adverse reactions [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Capsules 2 mg: Light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap 4 mg: White opaque body with a blue opaque cap with “4 MG” printed on the cap 6 mg: Blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the cap Tablets 4 mg white, uncoated tablets with a quadrisecting score on one side and debossed with “A594” on the other side 4 CONTRAINDICATIONS Zanaflex is contraindicated in patients: • taking strong CYP1A2 inhibitors [see Drug Interactions (7.1)]. • with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension Zanaflex is an α2-adrenergic agonist that can produce hypotension [see Adverse Reactions (6.1) and Drug Interactions (7.5)]. Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when Zanaflex is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Zanaflex be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Reference ID: 5484759 Clinical Pharmacology (12.3)]. Therefore, concomitant use of Zanaflex with strong CYP1A2 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1)]. 5.2 Liver Injury Zanaflex may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with Zanaflex [see Adverse Reactions (6.1, 6.2)]. Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. 5.3 Sedation Zanaflex can cause sedation, which may interfere with everyday activity. In the multiple dose studies of Zanaflex, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study [see Adverse Reactions (6.1)]. The CNS depressant effects of Zanaflex with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions (7.4)]. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation. 5.4 Hallucinosis/Psychotic-Like Symptoms Zanaflex use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Zanaflex in patients who develop hallucinations. 5.5 Hypersensitivity Reactions Zanaflex can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Zanaflex is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications (4)]. 5.6 Withdrawal Adverse Reactions Zanaflex can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of Zanaflex (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the Zanaflex dosage should be decreased slowly [see Dosage and Administration (2.5)]. Reference ID: 5484759 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information: • Hypotension [see Warnings and Precautions (5.1)] • Liver Injury [see Warnings and Precautions (5.2)] • Sedation [see Warnings and Precautions (5.3)] • Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Withdrawal Adverse Reactions [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety of Zanaflex has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies (14)]. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day. The most common adverse reactions (>10% of patients treated with Zanaflex) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three- quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related. Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received Zanaflex where the frequency in the Zanaflex group was greater than the placebo group. Reference ID: 5484759 Table 1: Multiple Dose, Placebo-Controlled Studies—Adverse Reactions Reported in >2% of Patients Treated with Zanaflex Tablets and Incidence Greater than Placebo Adverse Reaction Placebo N = 261 % Zanaflex Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Liver test abnormality 2 6 Constipation 1 4 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 includes weakness, fatigue, and/or tiredness In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies (14)], the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness), and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less. Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported Adverse Reaction Placebo N = 48 % Zanaflex Tablet, 8mg, N = 45 % Zanaflex Tablet, 16 mg, N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10 * includes weakness, fatigue, and/or tiredness Reference ID: 5484759 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Zanaflex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Ventricular tachycardia, decreased blood pressure Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2)], hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations [see Warnings and Precautions (5.4)], depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions (5.5)], exfoliative dermatitis, rash 7 DRUG INTERACTIONS 7.1 Strong CYP1A2 Inhibitors Concomitant use of Zanaflex with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)]. 7.2 Moderate or Weak CYP1A2 Inhibitors Concomitant use of Zanaflex with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce Zanaflex dosage or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)]. 7.3 Oral Contraceptives Concomitant use of Zanaflex with oral contraceptives is not recommended. However, if concomitant use is clinically necessary and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)]. Reference ID: 5484759 7.4 Alcohol and Other CNS Depressants Alcohol increases the exposure of tizanidine after administration of Zanaflex. This was associated with an increase in adverse reactions of Zanaflex. Concomitant use of Zanaflex with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3)]. 7.5 α2-Adrenergic Agonists Concomitant use of Zanaflex with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative [see Warnings and Precautions (5.1)]. 7.6 Antihypertensive Medications Concomitant use of Zanaflex with antihypertensive medications may cause additive hypotensive effects [see Warnings and Precautions (5.1)]. Monitor patients who take Zanaflex with antihypertensive medications for hypotension. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of Zanaflex in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of tizanidine (0.3 to 100 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal and postnatal offspring mortality and reductions in body weight at doses of 30 mg/kg/day and above. Maternal toxicity was observed at the highest dose tested. The no-effect dose for embryofetal developmental toxicity in rats (3 mg/kg/day) is similar to the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Reference ID: 5484759 Oral administration of tizanidine (1 to 100 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal and postnatal offspring mortality at all doses. Maternal toxicity was observed at the highest dose tested. Oral administration of tizanidine (10 and 30 mg/kg/day) during the perinatal period of pregnancy (2-6 days prior to delivery) resulted in increased postnatal offspring mortality at both doses. A no-effect dose for embryofetal developmental toxicity in rabbit was not identified. The lowest dose tested (1 mg/kg/day) is less than the MRHD on a mg/m2 basis. In a pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. A no-effect dose for pre- and postnatal developmental toxicity was not identified. The lowest dose tested (3 mg/kg/day) is similar to the MRHD on a mg/m2 basis, respectively. 8.2 Lactation Risk Summary There are no data on the presence of tizanidine in human milk, the effects on the breastfed infant, or the effects on human milk production. Animal studies have reported the presence of tizanidine in the milk of lactating animals. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Zanaflex and any potential adverse effects on the breastfed infant from Zanaflex or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential There are no adequate and well-controlled studies in humans on the effect of Zanaflex on female or male reproductive potential. Oral administration of tizanidine to male and female rats resulted in adverse effects on fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of tizanidine (0, 1, 3, and 10 mg/kg/day) to juvenile rats from postnatal day (PND) 7 through PND 70 resulted in delayed sexual maturation in males at all doses, reduced body weight gain, delayed sexual maturation in females, and bilateral corneal crystals at the mid and high doses. Corneal crystals were still observed at the mid and high doses after a three-week recovery period. Neurobehavioral deficits were observed on a learning and memory task at the high dose. A no-effect dose for adverse effects on postnatal development not identified. 8.5 Geriatric Use Zanaflex is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are Reference ID: 5484759 more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of Zanaflex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Pharmacokinetic data showed that younger subjects cleared tizanidine faster than the elderly subjects [see Clinical Pharmacology (12.3)]. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with Zanaflex. 8.6 Renal Impairment In patients with renal insufficiency (creatinine clearance < 25 mL/min), clearance of tizanidine was reduced [see Clinical Pharmacology (12.3)]. In these patients, dosage reduction is recommended [see Dosage and Administration (2.3)]. Because the risk of adverse reactions to Zanaflex may be greater in patients with impaired renal function, monitor these patients closely for the onset or increase in severity of common adverse reactions [see Adverse Reactions (6.1)]. 8.7 Hepatic Impairment Zanaflex should be used with caution in patients with hepatic impairment. The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. In patients with hepatic impairment, dosage reduction is recommended [see Dosage and Administration (2.4)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Zanaflex contains tizanidine, which is not a controlled substance. 9.2 Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine. 9.3 Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Tizanidine is closely related to clonidine, which is often Reference ID: 5484759 abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used, especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be discontinued, the dose should be decreased slowly to minimize the risk of withdrawal symptoms [see Dosage and Administration (2.5)]. Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m2 basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration. 10 OVERDOSAGE A review of the safety surveillance database revealed cases of intentional and accidental Zanaflex overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs, including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases, a decrease in sensorium was observed including lethargy, somnolence, confusion, and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. Should overdose occur, ensure the adequacy of an airway and monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description (11)]. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center. 11 DESCRIPTION Zanaflex® contains tizanidine hydrochloride as the active ingredient, which is a central alpha2 adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3 benzothiadiazole monohydrochloride. It has a molecular formula of C9H8ClN5S-HCl and a molecular weight of 290.2. Its structural formula is: Reference ID: 5484759 N ~ \ s =-- I N Cl HCI Tizanidine hydrochloride is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine hydrochloride is slightly soluble in water and methanol; solubility in water decreases as the pH increases. Zanaflex capsules are for oral administration and contain 2, 4, or 6 mg tizanidine (equivalent to 2.29 mg, 4.58 mg, and 6.87 mg tizanidine hydrochloride, respectively), and the inactive ingredients colorants, gelatin, hypromellose, silicon dioxide, sugar spheres, and titanium dioxide. Zanaflex tablets are for oral administration and contain 4 mg tizanidine (equivalent to 4.58 mg tizanidine hydrochloride), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, microcrystalline cellulose, and stearic acid. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. 12.2 Pharmacodynamics The CNS depressant effects of tizanidine and alcohol are additive [see Warnings and Precautions (5.3) and Drug Interactions (7.4)]. 12.3 Pharmacokinetics Tizanidine has linear pharmacokinetics over the doses studied in clinical development [1 mg (half the recommended dosage) to 20 mg]. Zanaflex capsules and tablets are bioequivalent to each other under fasting conditions, but not under fed conditions (see Absorption, Effect of Food). Absorption Following oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass hepatic metabolism. Reference ID: 5484759 Effect of Food There are pharmacokinetic differences between Zanaflex capsules and Zanaflex tablets with respect to administration with food. A single dose of either two 4 mg tablets or two 4 mg capsules was administered under fed and fasting conditions in an open-label, four-period, randomized crossover study in 96 volunteers, of whom 81 were eligible for the statistical analysis. Pharmacokinetics under fed conditions were different than under fasting conditions and vary by dosage form. Tablets or Capsules - Fasting • Tmax was 1.0 hours after dosing • T ½ was approximately 2 hours. Tablets - Fed • Mean Cmax was increased by approximately 30% • Median Tmax was increased by 25 minutes, to 1 hour and 25 minutes. • Extent of absorption was increased approximately 30% Capsules - Fed • Mean Cmax was decreased by 20% (consequently, approximately 66% the Cmax for the tablet when administered with food) • Median Tmax was increased 2 to 3 hours • Extent of absorption was increased approximately 10% (consequently, approximately 80% of the amount absorbed from the tablet administered with food) Capsule Content Sprinkled on Applesauce Compared to administration of an intact capsule while fasting: • Cmax and AUC was increased 15%–20% • Tmax was decreased 15 minutes Reference ID: 5484759 6 "' .P "' .E. C 0 4 -~ i I g 3 8 I $ ! C i 2 / C " i:! I " I ~ 1 f n I Ii: • 0 2 l:I-CI A.:2: x•ma._...nn.WIIFlxd 0---0 812:a.illmg~lW:Nts'MIDJ!fbm .. C::2'14ln;l~ClpAi@IW.,foo(I /J,,--,6. 0;2111 •mgllnndtl4CapildN.WlliMIR:ald 12 14 16 18 20 tbn lltlmilhmQ 22 26 Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Zanaflex Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions Distribution Tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 L/kg (CV = 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins. Elimination Metabolism Tizanidine has a half-life of approximately 2.5 hours (CV=33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half- lives range from 20 to 40 hours. Excretion Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. Specific Populations Geriatric Patients No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg Zanaflex showed that younger subjects cleared the drug four times faster than the elderly subjects [see Use in Specific Populations (8.5)]. Patients with Hepatic Impairment The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would Reference ID: 5484759 be expected to have significant effects on pharmacokinetics of tizanidine [see Use in Specific Populations (8.7)]. Patients with Renal Impairment Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect [see Use in Specific Populations (8.6)]. Gender Effects No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data following single and multiple dose administration of 4 mg Zanaflex, however, showed that gender had no effect on the pharmacokinetics of tizanidine. Drug Interactions CYP1A2 Inhibitors The effects of coadministration of fluvoxamine or ciprofloxacin, both strong CYP1A2 inhibitors, on the pharmacokinetics of a single 4 mg dose of Zanaflex was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively, with coadministration of fluvoxamine. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively, with coadministration of ciprofloxacin [see Contraindications (4)]. There have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine [see Drug Interactions (7.2)]. In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. Oral Contraceptives No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and Zanaflex. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg Zanaflex, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Drug Interactions (7.3))]. Acetaminophen Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine. Reference ID: 5484759 Alcohol Alcohol increased the AUC and Cmax of tizanidine by approximately 20% and 15%, respectively [see Drug Interactions (7.4)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was no increase in tumors in either species. Mutagenesis Tizanidine was negative in in vitro (bacterial reverse mutation [Ames], mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay. Impairment of Fertility Oral administration of tizanidine to rats prior to and during mating and continuing during early pregnancy in females resulted in reduced fertility in male and female rats at doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 3 times and similar to the MRHD, respectively, on a mg/m2 basis. 14 CLINICAL STUDIES The efficacy of Zanaflex for the treatment of spasticity was demonstrated in two adequate and well-controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2). Single-Dose Study in Patients with Multiple Sclerosis with Spasticity In Study 1, 140 patients with spasticity caused by multiple sclerosis were randomized to receive single oral doses of 8 mg or 16 mg of Zanaflex, or placebo. Patients and assessors were blinded to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). Response was assessed by physical examination; muscle tone was rated on a 5-point scale (Ashworth score) as follows: • 0 = normal muscle tone Reference ID: 5484759 -5 C, 5 u -4 (/) = 0 -3 ;: .t:: "' <( -2 .!: i: _, C, E C, > 0 a. 0 E ____ -----r-------------------~ ----------------◄ ' ' ' --- ::::~~~~~:~~~-- --------' --------------------------------- T 1 place ------··1 ·----------1----------------------------------------- ! ' Hours Post-Dose • 1 = slight spastic catch • 2 = more marked muscle resistance • 3 = considerable increase in tone, making passive movement difficult • 4 = a muscle immobilized by spasticity Spasm counts were also collected. Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for Zanaflex compared to placebo was detected at 1, 2, and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg and 16 mg Zanaflex groups was indistinguishable from muscle tone in patients who received placebo. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse reactions including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group. Figure 2: Single Dose Study—Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Seven-Week Study in Patients with Spinal Cord Injury with Spasticity In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or Zanaflex. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. Reference ID: 5484759 -6~------------------------------~ j :: ::::::::::::::--r:::::: _______ -+■ __ '-;;:(mccca::':c~:-:·i~'::~cc::-:~:-:~:-:~e:-:'8::'m~g)'::', :5 ■ 1 -3 --------------1-----------~~------------------------------------1 ~ -2 E §? -~ e -------------------------------------------------------------------------1 -----------------------------------+--------------------------------+-----------< E • placebo • - o--l-------e----------l--------=======------+--------l • --------------1 ---------------------------------------------, 2~----~----------~---------~----~ End of Titration (Study Weol< 3) End of Maintenance (Study Week 7) Endpoint (Last Observation Carried Forward) At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the Zanaflex treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome), but also did not lead to any consistent advantage of Zanaflex treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. Figure 3: Seven Week Study—Mean Change in Muscle Tone 0.5–2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Zanaflex Capsules Zanaflex (tizanidine) capsules are two-piece hard gelatin shells containing 2 mg, 4 mg, or 6 mg tizanidine in bottles of 150 capsules available as follows: • The 2 mg capsules have a light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap: NDC 83107-001-15 • The 4 mg capsules have a white opaque body with a blue opaque cap with “4 MG” printed on the cap: NDC 83107-002-15 • The 6 mg capsules have a blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the capsules: NDC 83107-003-15 Zanaflex Tablets Zanaflex (tizanidine) tablets are uncoated containing 4 mg tizanidine in bottles of 150 tablets. The tablets have a quadrisecting score on one side and are debossed with “A594” on the other side: NDC 83107-004-15. Reference ID: 5484759 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure. 17 PATIENT COUNSELING INFORMATION Serious Drug Interactions Advise patients they should not take Zanaflex if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their healthcare providers when they start or stop taking any medication because of the risks associated with interaction between Zanaflex and other medicines [see Contraindications (4) and Drug Interactions (7)]. Zanaflex Dosing and Administration Tell patients to take Zanaflex exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules [see Dosage and Administration (2)]. Inform patients that they should not take more Zanaflex than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue Zanaflex, because rebound hypertension and tachycardia may occur [see Warnings and Precautions (5.6)]. Hypotension Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position [see Warnings and Precautions (5.1)]. Sedation Tell patients that Zanaflex may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions (5.3)]. Tell patients that the sedation may be additive when Zanaflex is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that Zanaflex decreases spasticity and caution should be used. Hypersensitivity Reactions Inform patients of the signs and symptoms of severe allergic reactions and instruct them to discontinue Zanaflex and seek immediate medical care should these signs and symptoms occur [see Warnings and Precautions (5.5)]. Reference ID: 5484759 Zanaflex® capsules is a registered trademark of Legacy Pharma Inc. Zanaflex® tablets is a registered trademark of Legacy Pharma Inc. Manufactured for: Legacy Pharma Inc. Georgetown, Grand Cayman KY1-9012 LEGACY LOGO – TO BE ADDED Reference ID: 5484759	custom-source	2025-02-12T15:47:02.083352	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020397s029,021447s017lbl.pdf', 'application_number': 21447, 'submission_type': 'SUPPL ', 'submission_number': 17}
80,333	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LUNSUMIO safely and effectively. See full prescribing information for LUNSUMIO. LUNSUMIO™ (mosunetuzumab-axgb) injection, for intravenous use Initial U.S. Approval: 2022 WARNING: CYTOKINE RELEASE SYNDROME See full prescribing information for complete boxed warning. Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving LUNSUMIO. Initiate treatment with the LUNSUMIO step-up dosing schedule to reduce the risk of CRS. Withhold LUNSUMIO until CRS resolves or permanently discontinue based on severity. (2.1, 2.4, 5.1) ---------------------------RECENT MAJOR CHANGES-------------------------- Warnings and Precautions (5.2) 11/2024 Warnings and Precautions (5.4) 11/2024 ----------------------------INDICATIONS AND USAGE-------------------------- LUNSUMIO is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). (1.1) -----------------------DOSAGE AND ADMINISTRATION---------------------- • Premedicate to reduce risk of cytokine release syndrome and infusion- related reactions. (2.3, 5.1) • Administer only as an intravenous infusion. (2.1) • Recommended dosage: o Cycle 1 Day 1 – 1 mg o Cycle 1 Day 8 – 2 mg o Cycle 1 Day 15 – 60 mg o Cycle 2 Day 1 – 60 mg o Cycle 3+ Day 1 – 30 mg See Full Prescribing Information for instructions on preparation and administration. (2.5) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Injection: • 1 mg/mL solution in a single-dose vial. (3) • 30 mg/30 mL (1 mg/mL) solution in a single-dose vial. (3) ------------------------------CONTRAINDICATIONS------------------------------ None. (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome: Can cause serious and life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS). Monitor patients for signs and symptoms of neurologic toxicity during treatment; withhold or permanently discontinue based on severity. (5.2) • Infections: Can cause serious or fatal infections. Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. (5.3) • Hemophagocytic Lymphohistiocytosis: Can cause serious or fatal reactions. For suspected cases, interrupt LUNSUMIO and evaluate and treat promptly. (5.4) • Cytopenias: Monitor complete blood cell counts during treatment. (5.5) • Tumor Flare: Can cause serious tumor flare reactions. Monitor patients at risk for complications of tumor flare. (5.6) • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.7, 8.1, 8.3) -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions (≥ 20%) are cytokine release syndrome, fatigue, rash, pyrexia, and headache. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreased lymphocyte count, decreased phosphate, increased glucose, decreased neutrophil count, increased uric acid, decreased white blood cell count, decreased hemoglobin, and decreased platelets. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------USE IN SPECIFIC POPULATIONS--------------------- Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: CYTOKINE RELEASE SYNDROME 1 INDICATIONS AND USAGE 1.1 Follicular Lymphoma 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing Information 2.2 Recommended Dosage 2.3 Recommended Premedication and Prophylactic Medication 2.4 Dosage Modifications for Adverse Reactions 2.5 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome 5.2 Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity 5.3 Infections 5.4 Hemophagocytic Lymphohistiocytosis 5.5 Cytopenias 5.6 Tumor Flare 5.7 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5484590 FULL PRESCRIBING INFORMATION WARNING: CYTOKINE RELEASE SYNDROME Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving LUNSUMIO. Initiate treatment with the LUNSUMIO step-up dosing schedule to reduce the risk of CRS. Withhold LUNSUMIO until CRS resolves or permanently discontinue based on severity [see Dosage and Administration (2.1 and 2.4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE 1.1 Follicular Lymphoma LUNSUMIO is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing Information • Administer LUNSUMIO to well-hydrated patients. • Premedicate before each dose in Cycle 1 and Cycle 2 [see Dosage and Administration (2.3)]. • Administer only as an intravenous infusion through a dedicated infusion line. Do not use an in-line filter to administer LUNSUMIO. Drip chamber filters can be used to administer LUNSUMIO. • LUNSUMIO should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as cytokine release syndrome and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 and 5.2)]. 2.2 Recommended Dosage The recommended dosage for LUNSUMIO is presented in Table 1. Administer for 8 cycles, unless patients experience unacceptable toxicity or disease progression. For patients who achieve a complete response, no further treatment beyond 8 cycles is required. For patients who achieve a partial response or have stable disease in response to treatment with LUNSUMIO after 8 cycles, an additional 9 cycles of treatment (17 cycles total) should be administered, unless a patient experiences unacceptable toxicity or disease progression. Reference ID: 5484590 Table 1. Recommended LUNSUMIO Dose and Schedule (21-Day Treatment Cycles) Day of Treatment Dose of LUNSUMIO Rate of Infusion Cycle 1 Day 1 1 mg Administer over a minimum of 4 hours. Day 8 2 mg Day 15 60 mg Cycle 2 Day 1 60 mg Administer over 2 hours if infusions from Cycle 1 were well-tolerated. Cycles 3+ Day 1 30 mg Table 2. Recommendations for Restarting Therapy with LUNSUMIO After Dose Delay Last Dose Administered Time Since the Last Dose Administered Action for Next Dose(s) 1 mg Cycle 1 Day 1 1 to 2 weeks Administer 2 mg (Cycle 1 Day 8), then resume the planned treatment schedule. Greater than 2 weeks Repeat 1 mg (Cycle 1 Day 1), then administer 2 mg (Cycle 1 Day 8) and resume the planned treatment schedule. 2 mg Cycle 1 Day 8 1 to 2 weeks Administer 60 mg (Cycle 1 Day 15), then resume the planned treatment schedule. Greater than 2 weeks to less than 6 weeks Repeat 2 mg (Cycle 1 Day 8), then administer 60 mg (Cycle 1 Day 15) and resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg (Cycle 1 Day 1) and 2 mg (Cycle 1 Day 8), then administer 60 mg (Cycle 1 Day 15) and resume the planned treatment schedule. 60 mg Cycle 1 Day 15 1 week to less than 6 weeks Administer 60 mg (Cycle 2 Day 1), then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg (Cycle 2 Day 1) and 2 mg (Cycle 2 Day 8), then administer 60 mg (Cycle 2 Day 15), followed by 30 mg (Cycle 3 Day 1) and then resume the planned treatment schedule. 60 mg Cycle 2 Day 1 3 weeks to less than 6 weeks Administer 30 mg (Cycle 3 Day 1), then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg (Cycle 3 Day 1) and 2 mg (Cycle 3 Day 8), then administer 30 mg (Cycle 3 Day 15), followed by 30 mg (Cycle 4 Day 1) and then resume the planned treatment schedule. 30 mg Cycle 3 onwards 3 weeks to less than 6 weeks Administer 30 mg, then resume the planned treatment schedule. Greater than or equal to 6 weeks Repeat 1 mg on Day 1 and 2 mg on Day 8 during the next cycle, then administer 30 mg on Day 15, followed by 30 mg on Day 1 of subsequent cycles. * For the Day 1, Day 8, and Day 15 doses in the next cycle, administer premedication as per Table 3 for all patients 2.3 Recommended Premedication and Prophylactic Medication Premedication to reduce the risk of cytokine release syndrome and infusion-related reactions are outlined in Table 3 [see Warnings and Precautions (5.1)]. Reference ID: 5484590 Table 3. Premedication to be Administered to Patients Prior to LUNSUMIO Infusion Treatment Cycle Patients Requiring Premedication Premedication Dosage Administration Corticosteroid Dexamethasone 20 mg intravenous or methylprednisolone 80 mg intravenous Complete at least 1 hour prior to infusion Cycle 1 and Cycle 2 All patients Antihistamine Diphenhydramine hydrochloride 50 mg to 100 mg or equivalent oral or intravenous antihistamine At least 30 minutes prior to infusion Antipyretic Oral acetaminophen (500 mg to 1,000 mg) At least 30 minutes prior to infusion Patients who Corticosteroid Dexamethasone 20 mg intravenous or methylprednisolone 80 mg intravenous Complete at least 1 hour prior to infusion Cycles 3+ experienced any grade CRS with the previous dose Antihistamine Diphenhydramine hydrochloride 50 mg to 100 mg or equivalent oral or intravenous antihistamine At least 30 minutes prior to infusion Antipyretic Oral acetaminophen (500 mg to 1,000 mg) At least 30 minutes prior to infusion 2.4 Dosage Modifications for Adverse Reactions See Tables 4 and 5 for the recommended dosage modifications for adverse reactions of CRS and neurologic toxicity, including immune effector cell-associated neurotoxicity (ICANS). See Table 6 for the recommended dosage modifications for other adverse reactions following administration of LUNSUMIO. Dosage Modifications for Cytokine Release Syndrome Identify cytokine release syndrome (CRS) based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold LUNSUMIO until CRS resolves, manage according to the recommendations in Table 4 and per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Table 4. Recommendations for Management of Cytokine Release Syndrome Gradea Presenting Symptoms Actionsb Grade 1 Fever ≥ 100.4°F (38°C)c • Withhold current infusion of LUNSUMIO and manage per current practice guidelines. o If symptoms resolve, restart infusion at the same rate. • Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO.d • Administer premedicatione prior to next dose of LUNSUMIO and monitor patient more frequently. Reference ID: 5484590 Gradea Presenting Symptoms Actionsb Grade 2 Fever ≥ 100.4°F (38°C)c with: Hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygenf by nasal cannula or blow-by. • Withhold current infusion of LUNSUMIO and manage per current practice guidelines. o If symptoms resolve, restart infusion at 50% rate. • Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO.d • Administer premedicatione prior to next dose of LUNSUMIO and consider infusing the next dose at 50% rate. • For the next dose of LUNSUMIO, monitor more frequently and consider hospitalization. Recurrent Grade 2 CRS • Manage per Grade 3 CRS. Grade 3 Fever ≥ 100.4°F (38°C)c with: Hypotension requiring a vasopressor (with or without vasopressin) and/or hypoxia requiring high flow oxygenf by nasal cannula, face mask, non-rebreather mask, or Venturi mask. • Withhold LUNSUMIO, manage per current practice guidelines and provide supportive therapy, which may include intensive care. • Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO.d • Administer premedicatione prior to next dose of LUNSUMIO and infuse the next dose at 50% rate. • Hospitalize for the next dose of LUNSUMIO. Recurrent Grade 3 CRS • Permanently discontinue LUNSUMIO. • Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. Grade 4 Fever ≥ 100.4°F (38°C)c with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation). • Permanently discontinue LUNSUMIO. • Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. a Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS. b If CRS is refractory to management, consider other causes including hemophagocytic lymphohistiocytosis [see Warnings and Precautions (5.4)]. c Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines. d Refer to Table 2 for information on restarting LUNSUMIO after dose delays [see Dosage and Administration (2.2)]. e Refer to Table 3 for additional information on premedication. f Low-flow oxygen defined as oxygen delivered at < 6 L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute. Dosage Modifications for Neurologic Toxicity, including ICANS Management recommendations for neurologic toxicity, including ICANS, is summarized in Table 5. At the first sign of neurologic toxicity, including ICANS, consider neurology evaluation and withholding of LUNSUMIO based on the type and severity of neurotoxicity. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care. Reference ID: 5484590 Table 5. Recommendations for Management of Neurologic Toxicity (including ICANS) Adverse Reaction Severity1,2 Actions Neurologic Toxicity1 (including ICANS2) Grade 1 • Continue LUNSUMIO and monitor neurologic toxicity symptoms. • If ICANS, manage per current practice guidelines. Grade 2 • Withhold LUNSUMIO until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 72 hours.3 • Provide supportive therapy, and consider neurologic evaluation. • If ICANS, manage per current practice guidelines. Grade 3 • Withhold LUNSUMIO until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 72 hours.3 • Provide supportive therapy, which may include intensive care, and consider neurology evaluation. • If ICANS, manage per current practice guidelines. • If recurrence of ICANS, permanently discontinue LUNSUMIO. Grade 4 • Permanently discontinue LUNSUMIO. • Provide supportive therapy, which may include intensive care, and consider neurology evaluation. • If ICANS, manage per current practice guidelines. 1 Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. 2 Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS. 3 See Table 2 for recommendations on restarting LUNSUMIO after dose delays [see Dosage and Administration (2.2)]. Table 6. Recommended Dosage Modification for Other Adverse Reactions Adverse Reactions1 Severity1 Actions Infections [see Warnings and Precautions (5.3)] Grades 1 – 4 • Withhold LUNSUMIO in patients with active infection until the infection resolves.2 • For Grade 4, consider permanent discontinuation of LUNSUMIO. Neutropenia [see Warnings and Precautions (5.4)] Absolute neutrophil count less than 0.5 × 109/L • Withhold LUNSUMIO until absolute neutrophil count is 0.5 × 109/L or higher.2 Other Adverse Reactions [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] Grade 3 or higher • Withhold LUNSUMIO until the toxicity resolves to Grade 1 or baseline.2 1 Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. 2 See Table 2 for recommendations on restarting LUNSUMIO after dose delays [see Dosage and Administration (2.2)]. 2.5 Preparation and Administration Preparation Reference ID: 5484590 Use aseptic technique to prepare LUNSUMIO. • Inspect the vial visually for any particulate matter, prior to administration. Do not use if the solution is discolored, or cloudy, or if foreign particles are present. • Determine the dose, the total volume of LUNSUMIO solution required, and the number of LUNSUMIO vials needed. Dilution 1. Withdraw the volume from an infusion bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP equal to the volume of the LUNSUMIO required for the patient’s dose and discard. Only use infusion bags made of polyvinyl chloride (PVC) or polyolefin (PO) such as polyethylene (PE) and polypropylene. 2. Withdraw the required volume of LUNSUMIO from the vial using a sterile needle and syringe and dilute into the infusion bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP according to Table 7. Discard any unused portion left in the vial. Table 7. Dilution of LUNSUMIO Dose of LUNSUMIO Volume of LUNSUMIO in 0.9% or 0.45% Sodium Chloride Solution Size of Infusion Bag 1 mg 1 mL 50 mL or 100 mL 2 mg 2 mL 50 mL or 100 mL 60 mg 60 mL 100 mL or 250 mL 30 mg 30 mL 50 mL, 100 mL, or 250 mL 3. Gently mix the intravenous bag by slowly inverting the bag. Do not shake. 4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if visibly opaque particles, discoloration, or foreign particles are observed. 5. Apply the peel-off label from the package insert to the infusion bag. 6. Immediately use diluted LUNSUMIO infusion solution. If not used immediately, the diluted solution can be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours and at ambient temperature 9°C to 30°C (48°F to 86°F) for up to 16 hours. Prior to administration, ensure the infusion solution comes to reach room temperature. Administration • Administer as an intravenous infusion only. • Do not use an in-line filter to administer LUNSUMIO. • Do not mix LUNSUMIO with, or administer through the same infusion line, as other medicinal products. • No incompatibilities have been observed between LUNSUMIO and intravenous infusion bags with product contacting materials of polyvinyl chloride (PVC), or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). In addition, no incompatibilities have been observed with infusion sets or infusion aids with product contacting materials of PVC, PE, polyurethane (PUR), polybutadiene (PBD), silicone, acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), Reference ID: 5484590 fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE), or with drip chamber filter membrane composed of polyamide (PA). 3 DOSAGE FORMS AND STRENGTHS LUNSUMIO is a sterile, colorless solution available as: • Injection: 1 mg/mL mosunetuzumab-axgb of solution in a single-dose vial • Injection: 30 mg/30 mL (1 mg/mL) mosunetuzumab-axgb of solution in a single-dose vial 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome LUNSUMIO can cause cytokine release syndrome (CRS), including serious or life-threatening reactions [see Adverse Reactions (6.1)]. Cytokine release syndrome occurred in 39% of patients who received LUNSUMIO at the recommended dose in the clinical trial, with Grade 1 CRS occurring in 28%, Grade 2 in 15%, Grade 3 in 2%, and Grade 4 in 0.5% of patients. Recurrent CRS occurred in 11% of patients. Most patients experienced CRS following doses of 1 mg on Cycle 1 Day 1 (15%), 2 mg on Cycle 1 Day 8 (5%), and 60 mg on Cycle 1 Day 15 (33%). Five percent of patients experienced CRS after receiving 60 mg on Cycle 2 Day 1 with 1% of patients experiencing CRS following subsequent dosages of LUNSUMIO. The median time to onset of CRS from the start of administration in Cycle 1 Day 1 was 5 hours (range: 1 hour to 3 days), Cycle 1 Day 8 was 28 hours (range: 5 hours to 3 days), Cycle 1 Day 15 was 25 hours (range: 0.1 hours to 16 days), and Cycle 2 Day 1 was 46 hours (range: 12 hours to 3 days). The median duration of CRS was 3 days (range: 1 to 29 days). Clinical signs and symptoms of CRS included, but were not limited to, fever, chills, hypotension, tachycardia, hypoxia, and headache. Concurrent neurologic adverse reactions occurred in 6% of patients and included but were not limited to headache, confusional state, and anxiety. Initiate therapy according to LUNSUMIO step-up dosing schedule to reduce the risk of CRS [see Dosage and Administration (2.3)]. Administer pretreatment medications to reduce the risk of CRS, ensure adequate hydration, and monitor patients following administration of LUNSUMIO accordingly. At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines and administer supportive care; withhold or permanently discontinue LUNSUMIO based on severity [see Dosage and Administration (2.4)]. Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution. 5.2 Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome LUNSUMIO can cause serious and life-threatening neurologic toxicity, including immune effector cell- associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1)]. Neurologic toxicity occurred in 39% of patients who received LUNSUMIO at the recommended dose in the clinical trial, with Grade 3 neurologic toxicity occurring in 3% of patients. The most frequent neurologic toxicities were headache (21%), peripheral neuropathy (13%), dizziness (11%), and mental status changes (6%, including confusional state, disturbance in attention, cognitive disorder, delirium, encephalopathy, and somnolence). ICANS was reported in 1% of patients (Grade 1: 0.5%, Grade 2: 0.5%) who received LUNSUMIO at the recommended dose in the clinical trial. Reference ID: 5484590 Across a broader clinical trial population, ICANS or suspected ICANS occurred in 2.1% (20/949) of patients who received LUNSUMIO. The most frequent manifestations included confusional state and lethargy. Nineteen patients had Grade 1-2 events and 1 patient had a Grade 3 event. The majority of cases (75%) occurred during the first cycle of treatment. The median time to onset was 17 days (range: 1 to 48 days). In total, 87% of cases resolved after a median duration of 3 days (range: 1-20 days). Coadministration of LUNSUMIO with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient, consider neurology evaluation as appropriate, and provide supportive therapy based on severity; withhold or permanently discontinue LUNSUMIO based on severity and follow management recommendations [see Dosage and Administration (2.4)]. Patients who experience neurologic toxicity such as tremors, dizziness, insomnia, severe neurotoxicity, or any other adverse reactions that impair consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution. 5.3 Infections LUNSUMIO can cause serious or fatal infections [see Adverse Reactions (6.1)]. Among patients who received LUNSUMIO at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 17%, with Grade 3 or 4 infections in 14%, and fatal infections in 0.9% of patients. The most common Grade 3 or greater infections were pneumonia, sepsis, and upper respiratory tract infection. Monitor patients for signs and symptoms of infection prior to and during treatment with LUNSUMIO and treat appropriately. LUNSUMIO should not be administered in the presence of active infection. Caution should be exercised when considering the use of LUNSUMIO in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Administer prophylactic antimicrobials according to guidelines. Withhold LUNSUMIO or consider permanent discontinuation of LUNSUMIO based on severity [see Dosage and Administration (2.4)]. 5.4 Hemophagocytic Lymphohistiocytosis LUNSUMIO can cause fatal or serious hemophagocytic lymphohistiocytosis (HLH). HLH is a potentially life- threatening, hyperinflammatory syndrome that is independent of CRS. Common manifestations include fever, elevated ferritin, hemophagocytosis, cytopenias, coagulopathy, hepatitis, and splenomegaly. Across a broader clinical trial population, HLH occurred in 0.5% (7/1536) of patients. Most cases (5/7) were identified within the first 28 days following initiation of LUNSUMIO, with 3 cases preceded by diagnosed or suspected CRS. Of the 7 cases of HLH, 6 had fatal outcomes, with 2 deaths from HLH alone and 4 deaths with concurrent unresolved HLH. Of the 7 cases of HLH, 4 occurred in the context of concurrent EBV and/or CMV infection. Monitor for clinical signs and symptoms of HLH. Consider HLH when the presentation of CRS is atypical or prolonged, or when there are features of macrophage activation. For suspected HLH, interrupt LUNSUMIO and evaluate and treat promptly for HLH per current practice guidelines. 5.5 Cytopenias LUNSUMIO can cause serious or severe cytopenias, including neutropenia, anemia, and thrombocytopenia [see Adverse Reactions (6.1)]. Reference ID: 5484590 Among patients who received the recommended dosage in the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 38%, decreased hemoglobin in 19%, and decreased platelets in 12% of patients. Grade 4 decreased neutrophils occurred in 19% and decreased platelets in 5% of patients. Febrile neutropenia occurred in 2%. Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue LUNSUMIO. Consider prophylactic granulocyte colony-stimulating factor administration as applicable [see Dosage and Administration (2.4)]. 5.6 Tumor Flare LUNSUMIO can cause serious or severe tumor flare [see Adverse Reactions (6.1)]. Among patients who received LUNSUMIO at the recommended dosage in the clinical trial, tumor flare occurred in 4% of patients. Manifestations included new or worsening pleural effusions, localized pain and swelling at the sites of lymphoma lesions, and tumor inflammation. Patients with bulky tumors or disease located in close proximity to airways or a vital organ should be monitored closely during initial therapy. Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare. If compression or obstruction develops, institute standard treatment of these complications. 5.7 Embryo-Fetal Toxicity Based on its mechanism of action, LUNSUMIO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LUNSUMIO and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Cytokine Release Syndrome [see Warnings and Precautions (5.1)] • Neurologic Toxicity, including Immune Effector Cell-associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2)] • Infections [see Warnings and Precautions (5.3)] • Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.4)] • Cytopenias [see Warnings and Precautions (5.5)] • Tumor Flare [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to LUNSUMIO as a single agent in GO29781 in 218 patients with hematologic malignancies in an open-label, multicenter, multi-cohort study. Patients received step-up doses of 1 mg on Cycle 1 Day 1 and 2 mg on Cycle 1 Day 8, followed by 60 mg on Cycle 1 Day 15, and 60 mg on Cycle 2 Day 1, then 30 mg every 3 weeks in subsequent cycles. A treatment cycle was 21 days. Among 218 patients who received LUNSUMIO, 52% were exposed for at least 8 cycles and 8% were exposed for 17 cycles. In this pooled safety population, the most common (≥ 20%) adverse reactions were cytokine release syndrome (39%), fatigue (36%), rash (34%), pyrexia (24%), and headache (21%). The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count (92%), decreased phosphate (41%), Reference ID: 5484590 increased glucose (40%), decreased neutrophil count (38%), increased uric acid (15%), decreased white blood cell count (22%), decreased hemoglobin (19%), and decreased platelets (12%). Relapsed or Refractory Follicular Lymphoma GO29781 The safety of LUNSUMIO was evaluated in GO29781, an open-label, multicenter, multi-cohort study which included a cohort of 90 patients with relapsed or refractory follicular lymphoma (FL) [see Clinical Studies (14)]. In this cohort, patients with relapsed or refractory FL were required to have received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. Patients received step-up doses of 1 mg on Cycle 1 Day 1 and 2 mg on Cycle 1 Day 8, followed by 60 mg on Cycle 1 Day 15 and 60 mg on Cycle 2 Day 1, then 30 mg every 3 weeks in subsequent cycles. A treatment cycle was 21 days. The median number of cycles was 8 (range: 1 – 17). In the relapsed or refractory FL cohort, 77% were exposed for at least 8 cycles and 12% were exposed for 17 cycles. The median age of the patients who received LUNSUMIO in the relapsed or refractory FL cohort was 60 years (range: 29 to 90 years), 61% were male, 82% were White, 4% were Black or African American, 9% were Asian, and 8% were Hispanic or Latino. Serious adverse reactions occurred in 47% of patients who received LUNSUMIO. Serious adverse reactions in ≥ 2% of patients included cytokine release syndrome, infection (including urinary tract infection, sepsis, pneumonia, EBV viremia, and COVID-19), renal insufficiency, pyrexia, and tumor flare. Permanent discontinuation of LUNSUMIO due to an adverse reaction occurred in 3% of patients. Adverse reactions resulting in permanent discontinuation of LUNSUMIO included cytokine release syndrome and EBV viremia. Dosage interruptions of LUNSUMIO due to an adverse reaction occurred in 37% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia, infection, and cytokine release syndrome. Table 8 summarizes the adverse reactions in patients with relapsed or refractory FL in GO29781. Table 8. Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory FL Who Received LUNSUMIO in GO29781 Adverse Reaction1 LUNSUMIO (N = 90) All Grades (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome 44 2.2 General disorders and administration site conditions Fatigue2 42 0 Pyrexia 29 1.1# Edema3 17 1.1 Chills 13 1.1# Skin and subcutaneous tissue disorders Rash4 39 4.4# Pruritus 21 0 Dry skin 16 0 Skin exfoliation 10 0 Nervous system Headache5 32 1.1# Reference ID: 5484590 Adverse Reaction1 LUNSUMIO (N = 90) All Grades (%) Grade 3 or 4 (%) Peripheral neuropathy6 20 0 Dizziness7 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain8 28 1.1# Arthralgia 11 0 Respiratory, thoracic, and mediastinal disorders Cough9 22 0 Dyspnea10 11 1.1# Gastrointestinal disorders Diarrhea 17 0 Nausea 17 0 Abdominal pain11 12 1.1# Infections Upper respiratory tract infection12 14 2.2# Urinary tract infection13 10 1.1# Psychiatric disorder Insomnia 12 0 1 Adverse reactions were graded based on CTCAE Version 4.0, with the exception of CRS, which was graded per ASTCT 2019 criteria 2 Fatigue includes fatigue, asthenia, and lethargy 3 Edema includes edema, edema peripheral, peripheral swelling, face edema, swelling face, pulmonary edema, fluid overload, and fluid retention 4 Rash includes rash, rash erythematous, exfoliative rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, erythema, palmar erythema, dermatitis, and dermatitis acneiform 5 Headache includes headache and migraine 6 Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, paresthesia, dysaesthesia, hypoaesthesia, burning sensation, and neuralgia 7 Dizziness includes dizziness and vertigo 8 Musculoskeletal pain includes musculoskeletal pain, back pain, myalgia, musculoskeletal chest pain, and neck pain 9 Cough includes cough, productive cough, and upper airway cough syndrome 10 Dyspnea includes dyspnea and dyspnea exertional 11 Abdominal pain includes abdominal pain, lower abdominal pain, and abdominal discomfort 12 Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, and rhinovirus infection 13 Urinary tract infection includes urinary tract infection and acute pyelonephritis # Only Grade 3 adverse reactions occurred Clinically relevant adverse reactions in < 10% of patients who received LUNSUMIO included pneumonia, sepsis, COVID-19, EBV viremia, mental status changes, tumor lysis syndrome, renal insufficiency, anxiety, motor dysfunction (including ataxia, gait disturbance and tremor), tumor flare, and ICANS. Table 9 summarizes the laboratory abnormalities in patients with relapsed or refractory FL in GO29781. Reference ID: 5484590 Table 9. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received LUNSUMIO in GO29781 Laboratory Abnormality LUNSUMIO1 All Grades (%) Grade 3 or 4 (%) Hematology Lymphocyte count decreased 100 98 Hemoglobin decreased 68 12 White blood cells decreased 60 13 Neutrophils decreased 58 40 Platelets decreased 46 10 Chemistry Phosphate decreased 78 46 Glucose increased 42 42 Aspartate aminotransferase increased 39 4.4 Gamma-glutamyl transferase increased 34 9 Magnesium decreased 34 0 Potassium decreased 33 6 Alanine aminotransferase increased 32 7 Uric acid increased 22 22 1 The denominator used to calculate the rate varied from 72 to 90 based on the number of patients with a baseline value and at least one post-treatment value. 7 DRUG INTERACTIONS Effect of LUNSUMIO on CYP450 Substrates LUNSUMIO causes release of cytokines [see Clinical Pharmacology (12.2)] that may suppress activity of CYP450 enzymes, resulting in increased exposure of CYP450 substrates. Increased exposure of CYP450 substrates is more likely to occur after the first dose of LUNSUMIO on Cycle 1 Day 1 and up to 14 days after the second 60 mg dose on Cycle 2 Day 1 and during and after CRS [see Warnings and Precautions (5.1)]. Monitor for toxicity or concentrations of drugs that are CYP450 substrates where minimal concentration changes may lead to serious adverse reactions. Consult the concomitant CYP450 substrate drug prescribing information for recommended dosage modification. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on the mechanism of action, LUNSUMIO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of LUNSUMIO in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with mosunetuzumab-axgb. Mosunetuzumab-axgb causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, mosunetuzumab-axgb can cause B-cell lymphocytopenia in infants exposed to mosunetuzumab-axgb in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, LUNSUMIO has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% – 20%, respectively. Reference ID: 5484590 8.2 Lactation Risk Summary There is no information regarding the presence of mosunetuzumab-axgb in human milk, the effect on the breastfed child, or milk production. Because human IgG is present in human milk, and there is potential for mosunetuzumab-axgb absorption leading to B-cell depletion, advise women not to breastfeed during treatment with LUNSUMIO and for 3 months after the last dose. 8.3 Females and Males of Reproductive Potential LUNSUMIO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating LUNSUMIO. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with LUNSUMIO and for 3 months after the last dose. 8.4 Pediatric Use The safety and efficacy of LUNSUMIO have not been established in pediatric patients. 8.5 Geriatric Use Among the 90 patients with relapsed or refractory follicular lymphoma treated with LUNSUMIO, 33% were 65 years of age or older, and 8% were 75 years of age or older. There is an insufficient number of patients 65 years of age or older and 75 years of age or older to assess whether there are differences in safety or effectiveness in patients 65 years of age and older compared to younger adult patients. 11 DESCRIPTION Mosunetuzumab-axgb is a bispecific CD20-directed CD3 T-cell engager. It is a humanized monoclonal anti CD20xCD3 T-cell-dependent bispecific antibody of the immunoglobulin G1 (IgG1) isotype. Mosunetuzumab axgb is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. The approximate molecular weight is 146 kDa. LUNSUMIO (mosunetuzumab-axgb) injection is a sterile, preservative-free, colorless solution for intravenous use. Each single-dose vial contains a 1 mL solution of mosunetuzumab-axgb (1 mg), acetic acid (0.4 mg), histidine (1.6 mg), methionine (1.5 mg), polysorbate 20 (0.6 mg), sucrose (82.1 mg), and Water for Injection, USP. The pH is 5.8. Each single-dose vial contains a 30 mL solution of mosunetuzumab-axgb (30 mg), acetic acid (12.8 mg), histidine (46.6 mg), methionine (44.8 mg), polysorbate 20 (18 mg), sucrose (2,462.4 mg), and Water for Injection, USP. The pH is 5.8. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mosunetuzumab-axgb is a T-cell engaging bispecific antibody that binds to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells and some healthy B-lineage cells. In vitro, mosunetuzumab-axgb activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells. Reference ID: 5484590 12.2 Pharmacodynamics After administration of the recommended dosage of LUNSUMIO, peripheral B-cell counts decreased to undetectable levels (< 5 cells/microliter) in most patients (92%) by Cycle 2 Day 1 and the depletion was sustained at later cycles including at Cycle 4 and Cycle 8. LUNSUMIO caused hypogammaglobulinemia (defined as IgG levels < 500 mg/dL). Among 67 patients with baseline IgG levels ≥ 500 mg/dL, 40% had their IgG level decreased to < 500 mg/dL after administration of the recommended dosage of LUNSUMIO. Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured, and transient elevation of cytokines were observed at doses of 0.4 mg and above. After administration of the recommended dosage of LUNSUMIO, the highest elevation of cytokines was observed within 24 hours after first dose on Cycle 1 Day 1 and after the first 60 mg dose on Cycle 1 Day 15. The elevated cytokine levels generally returned to baseline prior to the next infusion on Cycle 1 Day 8 and on Cycle 2 Day 1. Limited data is available in subsequent treatment cycles. 12.3 Pharmacokinetics Mosunetuzumab-axgb PK exposure increased proportionally over a dose range from 0.2 mg to 60 mg (0.007 to 2 times the recommended treatment dosage). PK exposures are summarized for the recommended dosage of LUNSUMIO in Table 10 and Figure 1. Table 10. Exposure Parameters of Mosunetuzumab-axgb AUC (day•μg/mL)1 Cmax (μg/mL)1 Ctrough (μg/mL)1 Cycle 1 (0 ‒ 21 days) 35.2 (36.6) 11.1 (36.7) 2.57 (54.0) Cycle 2 (21 ‒ 42 days) 90.3 (48.5) 13.6 (37.7) 1.97 (83.1) Steady state2 52.9 (40.7) 7.02 (37.9) 1.29 (59.9) 1 Values are geometric mean with geometric CV% 2 Steady state values are approximated at Cycle 4 (63 ‒ 84 days) Figure 1. Model-Predicted Mosunetuzumab Concentration Time Profile Geometric mean 90th percentile prediction interval 0 21 42 63 84 105 126 147 168 Time (Day) Distribution The mean (CV%) volume of distribution of mosunetuzumab-axgb was 5.49 L (31%). Reference ID: 5484590 Elimination The steady-state geometric mean (CV%) terminal elimination half-life of mosunetuzumab-axgb was 16.1 (17.3%) days. The geometric mean (CV%) clearance at baseline and at steady state are 1.08 L/day (63%) and 0.584 L/day (18%), respectively. Specific Populations There were no clinically significant differences in the pharmacokinetics of mosunetuzumab-axgb based on age (19 to 96 years), sex, race (Asian and Non-Asian), ethnicity (Hispanic/Latino and not Hispanic/Latino), mild or moderate renal impairment (estimated Creatinine clearance [CrCL] by Cockcroft-Gault formula: 30 to 89 mL/min), or mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST). The effects of severe renal impairment (CrCL 15 to 29 mL/min) or moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN with any AST) on the pharmacokinetics of mosunetuzumab-axgb are unknown. Drug Interaction Studies No clinical studies evaluating the drug interaction potential of mosunetuzumab-axgb have been conducted. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of mosunetuzumab-axgb. During treatment in Study GO29781 (up to 12 months) [see Clinical Studies (14)], using an enzyme-linked immunosorbent assay (ELISA), no patients (N = 418) treated with LUNSUMIO developed anti mosunetuzumab-axgb antibodies. Based on these data, the clinical relevance of anti-mosunetuzumab-axgb antibodies could not be assessed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with mosunetuzumab-axgb. No dedicated studies have been conducted to evaluate the effects of mosunetuzumab-axgb on fertility. No adverse effects on either male or female reproductive organs were identified in a 26-week repeat dose chronic toxicity study in sexually mature cynomolgus monkeys. 14 CLINICAL STUDIES The efficacy of LUNSUMIO was evaluated in an open-label, multicenter, multi-cohort study (GO29781, NCT02500407) in patients with relapsed or refractory follicular lymphoma (FL) who had received at least two prior therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The study excluded patients with active infections, history of autoimmune disease, prior allogeneic transplant, or any history of CNS lymphoma or CNS disorders. Patients received step-up doses of 1 mg on Cycle 1 Day 1 and 2 mg on Cycle 1 Day 8, followed by 60 mg on Cycle 1 Day 15, and 60 mg on Cycle 2 Day 1, then 30 mg every 3 weeks in subsequent cycles. A treatment cycle was 21 days. LUNSUMIO was administered for 8 cycles unless patients experienced progressive disease or unacceptable toxicity. After 8 cycles, patients with a complete response discontinued therapy; patients with a partial response or stable disease continued treatment up to 17 cycles, unless patients experienced progressive disease or unacceptable toxicity. Among the 90 patients with relapsed or refractory FL, the median age was 60 years (range: 29 to 90 years), 33% were 65 years of age or older, 61% were male, 82% were White, 9% were Asian, 4% were Black or African Reference ID: 5484590 American, and 8% were Hispanic or Latino. A total of 77% of patients had Stage III-IV disease, 34% had bulky disease, and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 3 (range: 2 to 10), with 38% receiving 2 prior therapies, 31% receiving 3 prior therapies, and 31% receiving more than 3 prior therapies. Seventy-nine percent of patients were refractory to prior anti-CD20 monoclonal antibody therapy, 53% were refractory to both anti-CD20 monoclonal antibody and alkylator therapy, 9% received prior rituximab plus lenalidomide therapy, 21% received prior autologous stem cell transplant, and 3% received prior CAR T therapy. Fifty-two percent of patients had progression of disease within 24 months of first systemic therapy. Efficacy was established on the basis of objective response rate (ORR) and duration of response (DOR) as assessed by an independent review facility according to standard criteria for NHL (Cheson 2007). The median follow-up for DOR was 14.9 months. The efficacy results are summarized in Table 11. Table 11. Efficacy Results in Patients with Relapsed or Refractory FL Response LUNSUMIO N = 90 Objective response rate (ORR), n (%) 72 (80) (95% CI) (70, 88) Complete response rate (CR), n (%) 54 (60) (95% CI) (49, 70) Partial response rate (PR), n (%) 18 (20) (95% CI) (12, 30) Duration of Response (DOR) N = 72 Median DOR1,2, months (95% CI) 22.8 (10, NR) Rate of Continued Response2 At 12 months, % 62 (95% CI) (50, 74) At 18 months, % 57 (95% CI) (44, 70) CI = confidence interval; NR = not reached 1 DOR is defined as the time from the initial occurrence of a documented PR or CR until the patient experienced an event (documented disease progression or death due to any cause, whichever occurs first), among patients who achieved a PR or CR. 2 Kaplan-Meier estimate. The median time to first response was 1.4 months (range: 1.1 to 8.9). 16 HOW SUPPLIED/STORAGE AND HANDLING LUNSUMIO (mosunetuzumab-axgb) injection is a sterile, colorless, preservative-free solution supplied as follows: • One 1 mg/mL single-dose vial in a carton (NDC 50242-159-01) • One 30 mg/30 mL (1 mg/mL) single-dose vial in a carton (NDC 50242-142-01). Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Cytokine Release Syndrome (CRS) – Discuss the signs and symptoms associated with CRS, including fever, chills, hypotension, tachycardia, hypoxia, and headache. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. Advise patients who experience symptoms that impair Reference ID: 5484590 consciousness not to drive and refrain from operating heavy or potentially dangerous machinery until events resolve [see Warnings and Precautions (5.1)]. Neurologic Toxicity, including ICANS – Discuss the signs and symptoms associated with neurologic toxicity, including ICANS, headache, peripheral neuropathy, dizziness, or mental status changes. Advise patients to immediately contact their healthcare provider if they experience any signs or symptoms of neurologic toxicity. Advise patients who experience neurologic toxicity that impairs consciousness to refrain from driving or operating heavy or potentially dangerous machinery until neurologic toxicity resolves [see Warnings and Precautions (5.2)]. Infections – Discuss the signs or symptoms associated with infection [see Warnings and Precautions (5.3)]. Hemophagocytic Lymphohistiocytosis (HLH) – Discuss the signs and symptoms associated with HLH, including fever, coagulopathy, cytopenias, and splenomegaly [see Warnings and Precautions (5.4)]. Cytopenias – Discuss the signs and symptoms associated with cytopenias, including neutropenia and febrile neutropenia, anemia, and thrombocytopenia [see Warnings and Precautions (5.5)]. Tumor Flare – Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.6)]. Embryo-Fetal Toxicity – Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with LUNSUMIO and for 3 months after the last dose [see Use in Specific Populations (8.3)]. Lactation – Advise women not to breastfeed during treatment with LUNSUMIO and for 3 months after the last dose [see Use in Specific Populations (8.2)]. Manufactured by: LUNSUMIO is a trademark of Genentech, Inc. Genentech, Inc. ©2025 Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 Reference ID: 5484590 MEDICATION GUIDE LUNSUMIO™ (lun-SUM-mee-oh) (mosunetuzumab-axgb) injection, for intravenous infusion What is the most important information I should know about LUNSUMIO? LUNSUMIO may cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with LUNSUMIO, and can also be severe or life-threatening. Get medical help right away if you develop any signs or symptoms of CRS at any time, including: ● fever of 100.4°F (38°C) or higher ● headache ● chills ● confusion ● low blood pressure ● feeling anxious ● fast or irregular heartbeat ● dizziness or light-headedness ● tiredness or weakness ● nausea ● difficulty breathing ● vomiting Due to the risk of CRS, you will receive LUNSUMIO on a “step-up dosing schedule”. ● The step-up dosing schedule is when you receive smaller “step-up” doses of LUNSUMIO on Day 1 and Day 8 of your first cycle of treatment. ● You will receive a higher dose of LUNSUMIO on Day 15 of your first cycle of treatment. ● If your dose of LUNSUMIO is delayed for any reason, you may need to repeat the “step-up dosing schedule.” ● Before each dose in Cycle 1 and Cycle 2, you will receive medicines to help reduce your risk of CRS. ● See “How will I receive LUNSUMIO?” for more information about how you will receive LUNSUMIO. Your healthcare provider will check you for CRS during treatment with LUNSUMIO and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with LUNSUMIO if you have severe side effects. See “What are the possible side effects of LUNSUMIO?” for more information about side effects. What is LUNSUMIO? LUNSUMIO is a prescription medicine used to treat adults with follicular lymphoma whose cancer has come back or did not respond to previous treatment, and who have already received two or more treatments for their cancer. It is not known if LUNSUMIO is safe and effective in children. Before receiving LUNSUMIO, tell your healthcare provider about all of your medical conditions, including if you: ● have ever had an infusion reaction after receiving LUNSUMIO. ● have an infection or have had an infection in the past which lasted a long time or keeps coming back. ● have or had Epstein-Barr Virus. ● are pregnant or plan to become pregnant. LUNSUMIO may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LUNSUMIO. Females who are able to become pregnant: o your healthcare provider should do a pregnancy test before you start treatment with LUNSUMIO. o you should use an effective method of birth control (contraception) during your treatment and for 3 months after the last dose of LUNSUMIO. ● are breastfeeding or plan to breastfeed. It is not known if LUNSUMIO passes into your breast milk. Do not breastfeed during treatment and for 3 months after the last dose of LUNSUMIO. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Reference ID: 5484590 How will I receive LUNSUMIO? ● LUNSUMIO will be given to you by your healthcare provider by infusion through a needle placed in a vein (intravenous infusion). ● After you complete the weekly “step-up dosing schedule” in Cycle 1, LUNSUMIO is given every 21 days. ● After Cycle 1 and Cycle 2, your healthcare provider will decide if you need to continue to take other medicines to help reduce side effects from LUNSUMIO during future cycles. ● Your healthcare provider will decide how many treatment cycles you will receive of LUNSUMIO. See “What is the most important information I should know about LUNSUMIO?” for more information about how you will receive LUNSUMIO. What should I avoid while receiving LUNSUMIO? Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, tremors, sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of CRS or neurologic problems. See “What is the most important information I should know about LUNSUMIO?” and “What are the possible side effects of LUNSUMIO?” for more information about signs and symptoms of CRS and neurologic problems. What are the possible side effects of LUNSUMIO? LUNSUMIO may cause serious side effects, including: See “What is the most important information I should know about LUNSUMIO?” ● neurologic problems. LUNSUMIO can cause serious and life-threatening neurologic problems. Your healthcare provider will check you for neurologic problems during treatment with LUNSUMIO. Your healthcare provider may also refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems during or after treatment with LUNSUMIO, including: o headache o sleepiness or trouble sleeping o numbness and tingling of the arms, legs, hands, or feet o tremors o dizziness o loss of consciousness o confusion and disorientation o seizures o difficulty paying attention or understanding things o muscle problems or muscle weakness o forgetting things or forgetting who or where you are o loss of balance or trouble walking o trouble speaking, reading, or writing o tiredness ● serious infections. LUNSUMIO can cause serious infections that may lead to death. Your healthcare provider will check you for signs and symptoms of infection before and during treatment. Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment with LUNSUMIO, including: o fever of 100.4°F (38°C) or higher o painful rash o cough o sore throat o chest pain o pain during urination o tiredness o feeling weak or generally unwell o shortness of breath ● hemophagocytic lymphohistiocytosis (HLH). LUNSUMIO can cause overactivity of the immune system, a condition called hemophagocytic lymphohistiocytosis (HLH). HLH can be life-threatening and has led to death in people treated with LUNSUMIO. Your healthcare provider will check you for HLH especially if your CRS lasts longer than expected. Signs and symptoms of HLH include: o fever o low blood cell counts o enlarged spleen o liver problems o easy bruising ● low blood cell counts. Low blood cell counts are common during treatment with LUNSUMIO and can also be serious or severe. Your healthcare provider will check your blood cell counts during treatment with LUNSUMIO. LUNSUMIO can cause the following low blood cell counts: o low white blood cell counts (neutropenia). Low white blood cells can increase your risk for infection. o low red blood cell counts (anemia). Low red blood cells can cause tiredness and shortness of breath. o low platelet counts (thrombocytopenia). Low platelet counts can cause bruising or bleeding problems. Reference ID: 5484590 ● growth in your tumor or worsening of tumor related problems (tumor flare). LUNSUMIO can cause serious or severe worsening of your tumor. Tell your healthcare provider if you develop any of these signs or symptoms of tumor flare during your treatment with LUNSUMIO: o chest pain o tender or swollen lymph nodes o cough o pain or swelling at the site of the tumor o trouble breathing Your healthcare provider may temporarily stop or permanently stop treatment with LUNSUMIO if you develop severe side effects. The most common side effects of LUNSUMIO include: tiredness, rash, fever, and headache. The most common severe abnormal blood test results with LUNSUMIO include: decreased phosphate, increased glucose, and increased uric acid levels. These are not all the possible side effects of LUNSUMIO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 General information about the safe and effective use of LUNSUMIO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about LUNSUMIO that is written for health professionals. What are the ingredients in LUNSUMIO? Active ingredient: mosunetuzumab-axgb Inactive ingredients: acetic acid, histidine, methionine, polysorbate 20, sucrose, and Water for Injection Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 U.S. License No.: 1048 LUNSUMIO is a trademark of Genentech, Inc. For more information, call 1-844-832-3687 or go to www.LUNSUMIO.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5484590	custom-source	2025-02-12T15:47:02.333259	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761263s005lbl.pdf', 'application_number': 761263, 'submission_type': 'SUPPL ', 'submission_number': 5}
80,354	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PRETOMANID TABLETS safely and effectively. See full prescribing information for PRETOMANID TABLETS. PRETOMANID tablets, for oral use Initial U.S. Approval: 2019 LIMITED POPULATION --------------------------- RECENT MAJOR CHANGES ------------------------- Dosage and Administration (2.1, 2.2) 11/2024 Warnings and Precautions (5.3, 5.4) 11/2024 --------------------------- INDICATIONS AND USAGE--------------------------- Limited Population: Pretomanid Tablet is an antimycobacterial indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis (TB) that is resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients. (1) Limitations of Use: (1) Pretomanid Tablets are not indicated in patients with: • Drug-sensitive (DS) TB • Latent infection due to Mycobacterium tuberculosis • Extra-pulmonary infection due to Mycobacterium tuberculosis • TB resistant to isoniazid and rifampin, who are responsive to standard therapy and not treatment-intolerant • TB with known resistance to any component of the combination Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen. ----------------------- DOSAGE AND ADMINISTRATION --------------------- Important Administration Instructions: (2.1) • Pretomanid Tablets must be administered only in combination with bedaquiline and linezolid as part of the recommended dosage regimen. • Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directly observed therapy (DOT). • Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food. • Doses of the combination regimen missed for safety reasons can be made up at the end of treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up. • Administer Pretomanid Tablets in combination with bedaquiline and linezolid as follows: (2.2) • Pretomanid Tablets: • Pretomanid Tablet 200 mg orally once daily for 26 weeks. Administer Pretomanid Tablets whole with water. • For patients with swallowing difficulties see the full prescribing information for crushing or soaking followed by crushing instructions of the Pretomanid Tablets. • Bedaquiline: • Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks for a total of 26 weeks. • Bedaquiline 200 mg orally once daily for 8 weeks followed by 100 mg once daily for 18 weeks, for a total of 26 weeks. • Linezolid: • Linezolid Preferred: 600 mg orally once daily for 26 weeks. Alternative: 1,200 mg orally once daily for 26 weeks. • If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce or interrupt linezolid dosing as necessary. --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Tablets: 200 mg (3) ------------------------------ CONTRAINDICATIONS ----------------------------- Pretomanid Tablets used in combination with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid is contraindicated. (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Hepatic adverse reactions were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor symptoms and signs and liver-related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs. (5.2) • Myelosuppression was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor complete blood counts. Decrease or interrupt linezolid dosing if significant myelosuppression develops or worsens. (5.3) • Peripheral and optic neuropathy were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor visual function. Obtain an ophthalmologic evaluation if there are symptoms of visual impairment. Decrease or interrupt linezolid dosing if neuropathy develops or worsens. (5.4) • QT prolongation was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops. (5.5) • Reproductive effects: Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated. (5.7, 13.1) • Lactic acidosis was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Consider interrupting linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid dosing if significant lactic acidosis develops. (5.8) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (≥ 10%) are peripheral neuropathy, anemia, nausea, acne, vomiting, increased transaminases, headache, musculoskeletal pain, dyspepsia, rash, pruritus, decreased appetite, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, hemoptysis and hyperamylasemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1 877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- • Strong or moderate CYP3A4 inducers such as rifampin or efavirenz: Avoid co-administration. (5.6, 7.1) • Organic anion transporter-3 (OAT3) substrates: Monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. (7.2) ----------------------- USE IN SPECIFIC POPULATIONS --------------------- • Lactation: Breastfeeding is not recommended. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5483888 1 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Recommended Dosage 2.3 Assessments Prior to Initiating the Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid 2.4 Discontinuation of Dosing 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with the Combination Treatment Regimen 5.2 Hepatotoxicity 5.3 Myelosuppression 5.4 Peripheral and Optic Neuropathy 5.5 QT Prolongation 5.6 Drug Interactions 5.7 Reproductive Effects 5.8 Lactic Acidosis 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Pretomanid 7.2 Effect of Pretomanid on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5483888 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Limited Population: Pretomanid Tablet is indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis (TB) resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients. Limitations of Use: • Pretomanid Tablets are not indicated in patients with: o Drug-sensitive (DS) TB o Latent infection due to Mycobacterium tuberculosis o Extra-pulmonary infection due to Mycobacterium tuberculosis o TB resistant to isoniazid and rifampin who are responsive to standard therapy and not treatment-intolerant o TB with known resistance to any component of the combination • Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen [see Dosage and Administration (2.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Pretomanid Tablets must be administered only in combination with bedaquiline and linezolid as part of the recommended dosage regimen [see Dosage and Administration (2.2)]. • Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directly observed therapy (DOT). • Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food [see Clinical Pharmacology (12.3)]. • Emphasize the need for compliance with the full course of therapy to patients [see Patient Counseling Information (17)]. • If the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid is interrupted by a healthcare provider for safety reasons, missed doses can be made up at the end of the treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up [see Dosage and Administration (2.4)]. • Dosing of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be extended beyond 26 weeks, if necessary [see Clinical Studies (14)]. 2.2 Recommended Dosage Reference ID: 5483888 3 I I Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food [see Clinical Pharmacology (12.3)]. The recommended dosage and duration for Pretomanid Tablets, bedaquiline and linezolid when administered in the combination regimen are as follows: Pretomanid Tablets: • Administer Pretomanid Tablet 200 mg orally (1 tablet of 200 mg), once daily, for 26 weeks with food. • Administer Pretomanid Tablets whole with water. • For adult patients with swallowing difficulties, use one of the following two methods: A) Crush and Suspend Pretomanid Tablets • Crush and suspend Pretomanid Tablet in one teaspoon (approximately 5 mL) of room temperature water in a drinking cup and mix well by vigorous stirring. • Orally administer the contents of the cup immediately. • To ensure no tablet residual is left in the cup, rinse with an additional one teaspoon (approximately 5 mL) of water and orally administer the contents of the cup immediately. • Do not store the mixture for later use. B) Soak and then Crush Pretomanid Tablets • Soak Pretomanid Tablet for 4 to 5 minutes in one teaspoon (approximately 5 mL) of room temperature water in a drinking cup and then any remaining solid should be crushed. Mix the contents of the cup well by vigorous stirring. • Orally administer the contents of the cup immediately. • To ensure no tablet residual is left in the cup, rinse with an additional one teaspoon (approximately 5 mL) of water and orally administer the contents of the cup immediately. • Do not store the mixture for later use. Bedaquiline: Use one of the following two dosage regimens of bedaquiline: • Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks, for a total of 26 weeks. • Bedaquiline 200 mg orally once daily for 8 weeks followed by 100 mg once daily for 18 weeks, for a total of 26 weeks. Linezolid: • Preferred linezolid dosage regimen: 600 mg orally once daily for 26 weeks. If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce linezolid dosage to 300 mg once daily or interrupt linezolid dosing [see Dosage and Administration (2.4), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)]. • Alternative linezolid dosage regimen: 1,200 mg orally once daily for 26 weeks. If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce linezolid dosage to 600 mg once daily, further reduce linezolid dosage to 300 mg once daily, or interrupt linezolid dosing [see Dosage and Administration (2.4), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)]. 2.3 Assessments Prior to Initiating the Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid Reference ID: 5483888 4 • Assess for symptoms and signs of liver disease (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly). Obtain laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) [see Warnings and Precautions (5.2)]. • Obtain complete blood count [see Warnings and Precautions (5.3)]. Obtain serum potassium, calcium, and magnesium and correct if abnormal [see Warnings and Precautions (5.5)]. Obtain an ECG before initiation of treatment [see Warnings and Precautions (5.5)]. 2.4 Discontinuation of Dosing If either bedaquiline or Pretomanid Tablets are discontinued, the entire combination regimen should also be discontinued. If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, bedaquiline and Pretomanid Tablets should also be discontinued. If linezolid is discontinued after the initial four weeks of consecutive treatment, continue administering bedaquiline and Pretomanid Tablets [see Dosage and Administration (2.2)]. 3 DOSAGE FORMS AND STRENGTHS Pretomanid Tablets, 200 mg, are white to off-white, oval tablets debossed with M on one side and P200 on the other side. 4 CONTRAINDICATIONS Pretomanid Tablets used in the combination regimen with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated. Refer to the bedaquiline and linezolid prescribing information. 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with the Combination Treatment Regimen Pretomanid Tablet is indicated for use as part of a regimen in combination with bedaquiline and linezolid. Refer to the prescribing information for bedaquiline and linezolid for additional risk information. Warnings and Precautions related to bedaquiline and linezolid also apply to their use in the combination regimen with Pretomanid Tablets. 5.2 Hepatotoxicity Hepatic adverse reactions were reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid [see Indications and Usage (1)] while on Pretomanid Tablets, especially in patients with impaired hepatic function. Reference ID: 5483888 5 Monitor symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at a minimum at baseline, at two weeks, and then monthly while on treatment and as needed. If evidence of new or worsening liver dysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. Interrupt treatment with the entire regimen if: • Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal. • Aminotransferase elevations are greater than 8 times the upper limit of normal. • Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond 2 weeks. 5.3 Myelosuppression Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia can be life threatening [see Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. When linezolid dosing, as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, was reduced, interrupted, or discontinued, the observed hematologic abnormalities were reversible. Complete blood counts should be monitored at a minimum at baseline, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Decreasing linezolid to half the initial dose or interrupting linezolid dosing should be considered in patients who develop or have worsening myelosuppression [see Dosage and Administration (2.2)]. 5.4 Peripheral and Optic Neuropathy Peripheral neuropathy and optic neuropathy were reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Neuropathy is a known adverse reaction of long-term linezolid use. Neuropathy associated with linezolid is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid dosing. When improvement in the peripheral neuropathy is observed, consider resuming linezolid at half the initial dose [see Dosage and Administration (2.2)]. Monitor visual function in all patients receiving the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid; if a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic evaluation. 5.5 QT Prolongation QT prolongation was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)]. QT prolongation is a known adverse reaction of bedaquiline. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with Reference ID: 5483888 6 the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor these electrolytes if QT prolongation is detected [see Adverse Reactions (6.1)]. The following may increase the risk for QT prolongation when patients are receiving bedaquiline as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid: a history of Torsade de Pointes, congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, uncompensated heart failure, or serum calcium, magnesium, or potassium levels below the lower limits of normal. If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit-risk assessment and with frequent ECG monitoring. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, obtain an ECG to detect QT prolongation. 5.6 Drug Interactions CYP3A4 Inducers Pretomanid may be in part metabolized by CYP3A4 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Avoid co-administration of strong or moderate CYP3A4 inducers, such as rifampin or efavirenz, during treatment with pretomanid. 5.7 Reproductive Effects Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. 5.8 Lactic Acidosis Lactic acidosis was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid should be considered. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed here and elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.2)] • Myelosuppression [see Warnings and Precautions (5.3)] Reference ID: 5483888 7 • Peripheral and Optic Neuropathy [see Warnings and Precautions (5.4)] • QT Prolongation [see Warnings and Precautions (5.5)] • Reproductive Effects [see Warnings and Precautions (5.7)] • Lactic Acidosis [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, refer to the prescribing information for the respective drugs for a description of the adverse reactions associated with their use. Approximately 3100 subjects have been exposed to Pretomanid Tablets, either alone or as part of a combination therapy in clinical trials. The registrational trial, Trial 1 (NCT02333799), was a single-arm, open-label trial conducted in three sites in South Africa in which adult patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extendable to 9 months) with 24 months of follow-up. One hundred and nine patients were treated; 76% were black, and 23% were of mixed race. Their ages ranged from 17 years to 60 years (mean 36 years), and all patients were from South Africa. Fifty-six (51%) patients were HIV-positive. There were 8 deaths. Six patients died while receiving treatment; all surviving patients, excluding one patient who withdrew consent, completed treatment. Two patients died during follow-up at Day 369 and Day 486, respectively. Trial 2 (NCT03086486) was a phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid in combination with Pretomanid Tablets plus bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non- responsive to standard therapy. A total of 181 patients were randomized to one of the 4 treatment arms, Pretomanid Tablets plus bedaquiline plus either 1,200 mg or 600 mg of linezolid for 26 weeks or for 9 weeks (not an approved dosing regimen), followed by a linezolid placebo for 17 weeks. Males represented 67% of the patients in the trial and the median age of all patients was 36 years. 64% of patients were White and the remaining patients were Black (36%). The treatment groups were comparable with respect to demographic characteristics. Most patients (93%) completed treatment. One patient died in the linezolid 1,200 mg for 9 weeks (not an approved dosing regimen) arm. Reference ID: 5483888 8 Common Adverse Reactions Reported in Trials 1 and 2 Table 1 summarizes the incidence of select adverse reactions occurring in ≥ 5% of patients treated for 26 weeks in Trials 1 and 2. Table 1: Select Adverse Reactions (All Grades) Reported in ≥ 5% of Patients Receiving the Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid in Trials 1 and 2 Pretomanid Tablets, Bedaquiline and Linezolid (1,200 mg) Combination Regimen (N = 154) Pretomanid Tablets, Bedaquiline and Linezolid (600 mg) Combination Regimen (N = 45) Adverse Reactions All Grades n (%) All Grades n (%) Peripheral neuropathy* 105 (68) 10 (22) Anemia* 48 (31) Nausea 46 (30) Acne* 44 (29) 6 (13) Vomiting 40 (26) Transaminases increased* 39 (25) 11 (24) Headache 34 (22) Musculoskeletal pain* 34 (22) Dyspepsia 30 (19) Rash* 29 (19) Pruritus* 25 (16) 3 (7) Decreased appetite 24 (16) Abdominal pain* 22 (14) Pleuritic pain 22 (14) 4 (9) Gamma-glutamyltransferase increased 20 (13) Hemoptysis 17 (11) Hyperamylasemia* 15 (10) Diarrhea 14 (9) Hypertension* 14 (9) Cough* 13 (8) Visual impairment* 13 (8) Hypoglycemia 12 (8) Neutropenia* 12 (8) 3 (7) Abnormal loss of weight 11 (7) Constipation 9 (6) Gastritis 9 (6) Hyperlipasemia* 9 (6) Insomnia 9 (6) Dry skin 8 (5) Select terms are collapsed, as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, sensory disturbance); anemia (anemia); acne (acne, dermatitis acneiform); transaminases increased (alanine aminotransferase [ALT]) increased, aspartate aminotransferase [AST] increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); hyperamylasemia (amylase increased, hyperamylasemia); hypertension (blood pressure increased, hypertension); cough (cough, productive cough); visual impairment (vision blurred, visual acuity reduced, visual impairment); neutropenia (neutropenia); hyperlipasemia (hyperlipasemia, lipase increased). Reference ID: 5483888 9 The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid (1,200 mg) at a rate of less than 5% in Trials 1 and 2: Gastrointestinal Disorders: pancreatitis, dysgeusia Investigations: blood creatine phosphokinase increase, blood creatinine increase, blood alkaline phosphatase increase Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia Metabolism and Nutrition Disorders: hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia, hyponatremia Nervous System Disorders: dizziness, seizure The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid (600 mg) at a rate of less than 5% in Trial 2: Blood and Lymphatic System Disorders: anemia, thrombocytopenia Metabolism and Nutrition Disorders: decreased appetite, hyperlipasemia, hypoglycemia, hypophosphatemia, hypomagnesemia, hyperkalemia Psychiatric Disorders: insomnia Nervous System Disorders: headache Vascular Disorders: hypertension Respiratory, Thoracic and Mediastinal Disorders: cough, hemoptysis Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting Skin and Subcutaneous Tissue Disorders: dry skin, rash Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain Laboratory Abnormalities Reported in Trials 1 and 2 Table 2 summarizes select laboratory abnormalities in patients treated for 26 weeks in Trials 1 and 2. Table 2: Select Laboratory Abnormalities in Clinical Trials Reference ID: 5483888 10 Parameter Multiples of Upper Limit of Normal (x ULN) Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid (1,200 mg) (N = 154) n (%) Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid (600 mg) (N = 45) n (%) Transaminases and Bilirubin Alanine Aminotransferase (ALT) > 3 and ≤ 5 X ULN 13 (8) 3 (7) > 5 and ≤ 8 X ULN 6 (4) 0 (0) > 8 X ULN 1 (1) 1 (2) Aspartate Aminotransferase (AST) > 3 and ≤ 5 X ULN 7 (5) 0 (0) > 5 and ≤ 8 X ULN 3 (2) 0 (0) > 8 X ULN 1 (1) 1 (2) Total Bilirubin > 1 X ULN and ≤ 2 X ULN 8 (5) 1 (2) > 2 X ULN 2 (1) 1 (2) Hematology Hemoglobin ≤ 7.9 g/dL 6 (4) 0 (0) Neutrophils Absolute Count ≤ 749/mm3 6 (4) 1 (2) Platelets ≤ 49,999/mm3 2 (1) 0 (0) Serum Chemistry Lipase > 2 X ULN 7 (5) 2 (4) ULN = upper limit of normal In Trial 1, 28% of patients experienced increased transaminases. Except for one patient who died due to pneumonia and sepsis, all patients who experienced increased transaminases were able to continue therapy and complete the full course of treatment. In Trial 2, 47 of 181 patients (26%) had one or more liver-related adverse reactions, with similar numbers in each group. Myelosuppression is a known adverse reaction of linezolid. In Trial 1, the most common hematopoietic cytopenia was anemia (37%). The majority of cytopenias began after 2 weeks of treatment. Three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anemia in 2 patients. All 3 serious adverse reactions resulted in interruption of linezolid or all components of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, and all resolved. In Trial 2, there was a greater incidence of myelosuppression, 29% versus 13%, for the 1,200 mg compared to the 600 mg linezolid 26-week group. Most of the myelosuppression-related adverse reactions were either grade 1 or grade 2 in severity. In the combined study data for Trial 1 and Trial 2, 2 patients reported serious adverse reactions of anemia with linezolid 1,200 mg, and none were reported in the 600 mg group. Peripheral and Optic Neuropathy Reference ID: 5483888 11 Peripheral neuropathy is a known adverse reaction of linezolid. In Trial 1, peripheral neuropathy was reported in 81% of patients. Most of these adverse reactions (64%) occurred after 8 weeks of treatment and resulted in dosing interruption, dose reduction, or discontinuation of linezolid. Severe, moderate, and mild peripheral neuropathy occurred in 22%, 32%, and 26% of patients, respectively. No adverse reaction related to peripheral neuropathy led to a discontinuation of the entire study regimen. In Trial 2, 17 (38%) patients reported an adverse reaction of peripheral neuropathy in the 1,200 mg 26-week treatment group; one of these reactions led to treatment discontinuation. In the 600 mg 26-week treatment group, 10 (22%) patients reported peripheral neuropathy, and none required linezolid treatment interruption or treatment discontinuation. Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%) in Trial 1 developed optic neuropathy after 16 weeks of treatment. Both were serious, confirmed on retinal examination as optic neuropathy/neuritis, and resulted in discontinuation of linezolid; both adverse reactions resolved. Overall, patients administered a linezolid dose of 600 mg twice daily had a similar safety profile to those administered a dose of 1,200 mg once daily. In Trial 2 overall, 4 (2%) patients reported an adverse reaction of optic neuropathy. All 4 patients were in the 1,200 mg linezolid 26-week treatment group (9%). The maximum severity was grade 1 (mild) for 1 patient, grade 2 (moderate) for 2 patients, and grade 3 (severe) for 1 patient. All patients had linezolid permanently discontinued except 1 patient who had already completed treatment when the adverse reaction occurred. Onset of optic neuropathy occurred after 3 months of treatment, and resolved. 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Pretomanid CYP3A4 Inducers Co-administration of pretomanid with rifampin and efavirenz resulted in a decrease in pretomanid plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid co-administration of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with rifampin, efavirenz, or other strong or moderate CYP3A4 inducers. Refer to the prescribing information for bedaquiline for additional information about drug interactions with CYP3A4. Lopinavir/Ritonavir Co-administration of pretomanid with lopinavir/ritonavir did not affect the plasma concentrations of pretomanid [see Clinical Pharmacology (12.3)]. Lopinavir/ritonavir can be co-administered with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. 7.2 Effect of Pretomanid on Other Drugs Reference ID: 5483888 12 Midazolam Co-administration of pretomanid with the CYP3A4 substrate, midazolam, resulted in no clinically significant effect on the pharmacokinetics of midazolam or its major metabolite, 1 hydroxy-midazolam [see Clinical Pharmacology (12.3)]. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be administered with CYP3A4 substrate drugs. Organic Anion Transporter-3 (OAT3), BCRP, OATP1B3 and P-gp Substrates The effect of co-administration of pretomanid on the pharmacokinetics of OAT3 substrates in humans is unknown. However, in vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter [see Clinical Pharmacology (12.3)], which could result in increased concentrations of OAT3 substrate drugs clinically and may increase the risk of adverse reactions associated with these drugs. If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate, indomethacin, ciprofloxacin), increase monitoring for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. Refer to the prescribing information of the co-administered drug for dosage reduction information. In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3 and P-gp [see Clinical Pharmacology (12.3)]. No clinical studies have been performed to investigate these interactions. Therefore, it cannot be excluded that co- administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRP substrates (e.g., rosuvastatin, prazosin, glyburide, sulfasalazine) and P-gp substrates (e.g., digoxin, dabigatran etexilate, verapamil) may increase their exposure. If pretomanid is co- administered with substrates of OATP1B3, BCRP, or P-gp, increased monitoring for drug- related adverse reactions to the co-administered medicinal product should be performed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no studies or available data on pretomanid use in pregnant women to inform any drug- associated risks. There are risks associated with active tuberculosis during pregnancy (see Clinical Considerations). When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, the pregnancy information for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid prescribing information for more information on bedaquiline and linezolid associated risks of use during pregnancy. In animal reproduction studies, there was increased post-implantation loss in the presence of maternal toxicity (reduced bodyweight and feed consumption) with oral administration of pretomanid during organogenesis in rats at doses about 4 times the exposure at the recommended Reference ID: 5483888 13 dose in humans. There were no adverse embryo fetal effects in rats or rabbits dosed with oral pretomanid during organogenesis at doses up to approximately 2 times the exposure in humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death. Data Animal Data In animal reproduction studies, pregnant rats were dosed orally with pretomanid at 10, 30, and 100 mg/kg/day during organogenesis (gestational Days 7 through 17). Rats showed increased post-implantation loss in the presence of maternal toxicity (including reduced body weight and feed consumption) at 100 mg/kg/day, approximately 4 times the exposure in humans for a 200 mg dose on an AUC basis. There were no adverse embryofetal effects in rats dosed with oral pretomanid during organogenesis at doses up to approximately 2 times the exposure in humans. Pregnant rabbits were dosed orally with pretomanid during organogenesis (gestational Days 7 through 19) at 10, 30, and 60 mg/kg/day. No evidence of adverse developmental outcomes was observed when oral doses of pretomanid were administered to dams during organogenesis (gestational Days 7 to 19) at doses up to 60 mg/kg/day (approximately 2 times the exposure in humans for a 200 mg dose on an AUC basis). In a pre- and postnatal development study, there were no adverse developmental effects in pups of pregnant rats orally dosed with up to 20 mg/kg/day from gestational Day 6 through lactation Day 20. Pups of pregnant females dosed at 60 mg/kg/day (about 2 times the exposure for the 200 mg dose) had lower body weights and a slight delay in the age at which the air-drop righting reflex developed. These effects occurred at a maternally toxic dose (based on maternal weight loss and reduced food consumption). 8.2 Lactation Risk Summary There is no information regarding the presence of pretomanid in human milk, or its effects on milk production or the breastfed infant. Pretomanid was detected in rat milk (see Data). When a Reference ID: 5483888 14 drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for adverse reactions in nursing infants, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Pretomanid Tablets and any potential adverse effects on the breastfed infant from Pretomanid Tablets or from the underlying maternal condition. When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, information on lactation for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid prescribing information for more information on their use during lactation. Data Animal Data In a pre- and postnatal development study in rats treated with pretomanid at doses 0.5 and 2 times the human exposure for a 200 mg dose (AUC) from gestational day 7 through lactation day 20, concentrations in milk on lactation day 14 were 1.4 and 1.6 times higher than the maximum concentration observed in maternal plasma, respectively. The concentration of pretomanid in rat milk does not necessarily predict the concentration of pretomanid in human milk. 8.3 Females and Males of Reproductive Potential Infertility Males Reduced fertility and/or testicular toxicity were observed in male rats and mice treated with oral pretomanid. These effects were associated with hormonal changes including decreased serum inhibin B and increased serum follicle stimulating hormone and luteinizing hormone in rodents [see Nonclinical Toxicology (13.1)]. Reduced fertility and testicular toxicity cannot be definitively ruled out in male human subjects at this time. 8.4 Pediatric Use Safety and effectiveness of Pretomanid Tablets in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment Reference ID: 5483888 15 The effect of hepatic impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known. 8.7 Renal Impairment The effect of renal impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known. 10 OVERDOSAGE There is no experience with the treatment of acute overdose with pretomanid. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. 11 DESCRIPTION Pretomanid is an oral nitroimidazooxazine antimycobacterial drug. Pretomanid is a white to off-white to yellow-colored powder. The chemical name for pretomanid is (6S)-2-Nitro-6-{[4-(trifluoromethoxy)phenyl]methoxy}-6,7-dihydro-5H-imidazo[2,1 b][1,3]oxazine. The molecular formula for pretomanid is C14H12F3N3O5, and the molecular weight is 359.26. The structural formula of pretomanid is as follows: O N O2N N O OCF3 Each Pretomanid Tablet contains 200 mg of pretomanid. The inactive ingredients are colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and sodium starch glycolate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pretomanid is a nitroimidazooxazine antimycobacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics Cardiac Electrophysiology A randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg), crossover, thorough QT study of pretomanid was performed in 74 healthy adult subjects. At 400 mg (2 Reference ID: 5483888 16 times the approved recommended dosage) and 1,000 mg (5 times the approved recommended dosage) single doses of pretomanid, no significant QT prolongation effect was detected. In Trial 1, patients received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 26 weeks. No patient had QTcF intervals greater than 480 msec, and 1 subject had a post-baseline increase of QTcF of greater than 60 msec following the combination regimen of 200 mg pretomanid once daily, 400 mg bedaquiline once daily for 2 weeks followed by 200 mg bedaquiline 3 times per week thereafter, and 1,200 mg linezolid daily. In Trial 2, in patients who received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 26 weeks, no patient had QTcF intervals greater than 480 msec or post-baseline increase of QTcF of greater than 60 msec following the combination regimen of 200 mg pretomanid once daily, 200 mg bedaquiline once daily for 8 weeks followed by 100 mg bedaquiline once daily thereafter, and 600 mg or 1,200 mg linezolid daily. 12.3 Pharmacokinetics Pretomanid AUC and Cmax were approximately dose proportional over a range of single oral doses from 50 mg (0.25 times the approved recommended dosage) to 200 mg (approved recommended dosage); at single doses greater than 200 mg and up to 1,000 mg (5 times the approved recommended dosage), AUC and Cmax increased in a less than dose proportional manner. Steady-state pretomanid plasma concentrations were achieved approximately 4 to 6 days following multiple dose administration of 200 mg, and the accumulation ratio was approximately 2. Pharmacokinetic parameters following single and multiple 200 mg doses of pretomanid in healthy adult subjects are summarized in Table 3. Table 3: Mean (SD) Pretomanid Pharmacokinetic Parameters in Healthy Adult Subjects Under Fasted and Fed Conditions PK Parameter Single Dose 200 mg; Fasted Single Dose 200 mg; Fed Steady State 200 mg QD; Fasted Cmax (µg/mL) 1.1 (0.2) 2.0 (0.3) 1.7 (0.3) AUCt (µg•hr/mL) †28.1 (8.0) †51.6 (10.1) §30.2 (3.7) AUCinf (µg•hr/mL) 28.8 (8.3) 53.0 (10.6) ND Tmax (hr) 4.0 (2.0, 6.0) 5.0 (3.0, 8.1) 4.5 (2.0, 8.0) Vd/F (L) 180 (51.3) 97.0 (17.2) ND CL/F (L/hr) 7.6 (2.5) 3.9 (0.8) ND t½ (hr) 16.9 (3.1) 17.4 (2.8) 16.0 (1.6) * - Median (minimum, maximum); †- AUC96hr; § - AUC24hr; ND - Not Determined. Absorption Effect of Food Administration of an oral tablet dose of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, Reference ID: 5483888 17 respectively) increased mean Cmax by 76% and mean AUCinf by 88% as compared with the fasted state (see also Table 3 above). Distribution The plasma protein binding of pretomanid is approximately 86.4%. Elimination See Table 3 above for estimates of apparent oral clearance and half-life of pretomanid. Metabolism Pretomanid is metabolized by multiple reductive and oxidative pathways, with no single pathway considered as major. In vitro studies using recombinant CYP3A4 demonstrated that this enzyme is responsible for up to approximately 20% of the metabolism of pretomanid. Excretion In healthy adult males receiving 1,100 mg oral 14C-radiolabeled pretomanid, a mean (SD) of 53% (3.4%) of a radioactive dose was excreted in urine and 38% (2.7%) in feces, primarily as metabolites; approximately 1% of the radioactive dose was excreted in the urine as unchanged pretomanid. Specific Populations No clinically significant differences in the pharmacokinetics of pretomanid were observed based on sex, body weight, race (Black, White, or other), pulmonary TB status (resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR resistant to isoniazid and rifampin and treatment intolerant or non-responsive to standard therapy), or HIV status. The effect of renal or hepatic impairment on the pharmacokinetics of pretomanid is unknown. Drug Interaction Studies Clinical Studies Efavirenz: Co-administration of 200 mg QD of pretomanid with efavirenz 600 mg QD for 7 days resulted in a decrease of pretomanid mean AUC by 35% and Cmax by 28%. Mean AUC and Cmax of efavirenz were not affected when given with pretomanid. Lopinavir/Ritonavir: Co-administration of 200 mg QD pretomanid with lopinavir/ritonavir 400/100 mg BID for 7 days resulted in a decrease of pretomanid mean AUC by 17% and Cmax by 13%. Mean AUC and Cmax of lopinavir were decreased by 14% and 17%, respectively, when given with pretomanid. Reference ID: 5483888 18 Rifampin: Co-administration of 200 mg QD pretomanid with rifampin 600 mg QD for 7 days resulted in a decrease of pretomanid mean AUC by 66% and Cmax by 53%. Midazolam: Co-administration of 400 mg (twice the approved recommended dosage) QD pretomanid for 14 days and a single 2 mg oral dose of midazolam on Day 14 resulted in a decrease in midazolam mean AUC by 15% and Cmax by 16%, and an increase in 1-hydroxy midazolam mean AUC by 14% and Cmax by 5%. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically Cytochrome P450 (CYP) Enzymes: CYP3A4 plays a role in the metabolism of pretomanid, i.e., up to 20%. Pretomanid is not a substrate of CYP2C9, CYP2C19, and CYP2D6. Pretomanid is not an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations based on in vitro studies. Pretomanid is not an inducer of CYP3A4. Transporter Systems: Pretomanid is an inhibitor of the OAT3 transporter in vitro, which could result in increased concentrations of OAT3 substrate medicinal products clinically and may increase the risk of adverse reactions associated with these medicines. No clinical drug-drug interaction studies have been conducted with OAT3 substrates [see Drug Interactions (7.2)]. In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3, and P-gp transporters. The effect of co-administration of pretomanid on the pharmacokinetics of BCRP, OATP1B3 and P-gp substrates in humans is unknown [see Drug Interactions (7.2)]. In vitro studies indicated that pretomanid does not inhibit human OAT1, OCT1, OCT2, OAT1B1, BSEP, MATE1, and/or MATE2-K mediated transport at clinically relevant concentrations of pretomanid. Pretomanid is not a substrate of OAT1, OAT3, OCT2, OAT1B1, OATP1B3, MATE1, MATE2-K, BCRP, and/or P-gp transporters. 12.4 Microbiology Mechanism of Action Pretomanid Tablet is a nitroimidazooxazine antimycobacterial drug. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobic conditions, against non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxide release. All of these activities require nitro-reduction of pretomanid within the mycobacterial cell by the deazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F420. Reduction of F420 is accomplished by the F420-dependent glucose-6-phosphate dehydrogenase, Fgd1. Resistance Mutations in five M. tuberculosis genes (ddn, fgd1, fbiA, fbiB, and fbiC) have been associated with pretomanid resistance. The products of these genes are involved in bioreductive activation Reference ID: 5483888 19 of pretomanid within the bacterial cell. Not all isolates with increased minimum inhibitory concentrations (MICs) have mutations in these genes, suggesting the existence of at least one other mechanism of resistance. The in vitro frequency of resistance development to pretomanid ranged from 10-7 to 10-5 at 2 to 6 times the pretomanid MICs. Cross-resistance of pretomanid with other compounds in the same class has been observed. Antimicrobial Activity Pretomanid has demonstrated in vitro activity against the M. tuberculosis complex. Pretomanid has also demonstrated anti-M. tuberculosis activity in animal models of tuberculosis [see Indications and Usage (1)]. In murine tuberculosis models, the 3-drug combination of pretomanid, bedaquiline, and linezolid reduced bacterial counts in the lungs to a greater extent and resulted in fewer relapses at 2 and 3 months post-therapy compared to 2-drug combinations of pretomanid, bedaquiline, and linezolid. In Trial 1, the pretomanid MIC was determined using the Mycobacterial Growth Indicator Tube (MGIT). The baseline pretomanid MIC for M. tuberculosis isolates in the trial ranged from 0.06 to 1 mcg/mL. In Trial 2, the pretomanid MIC increased from 1 mcg/mL to 16 mcg/mL in seven patients with paired baseline and post 16 weeks isolates. Five patients (two in the linezolid 1,200 mg for 9 weeks arm, three in the linezolid 600 mg for 9 weeks arm) relapsed or failed treatment and one had a favorable outcome. The 9-week dosing regimen is not an approved dosing regimen. Six of the seven patients had elevations in bedaquiline MICs at baseline. Susceptibility Testing For specific information regarding susceptibility test criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. A circulating metabolite of pretomanid, M50, was mutagenic in a bacterial reverse mutation assay. No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite was produced. In a 2-year study in rats, there was no evidence of carcinogenic risk. Mutagenesis Reference ID: 5483888 20 No mutagenic or clastogenic effects were detected in both an in vitro bacterial reverse mutation assay and an in vitro mammalian chromosome aberrations assay using a Chinese hamster ovary cell line. Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay. A metabolite of pretomanid was mutagenic in a bacterial reverse mutation assay. This metabolite represents approximately 6% of the human exposure (AUC) to pretomanid at the MRHD. Fertility In a fertility and general reproduction study in rats, male rats treated orally with pretomanid for 13 to 14 weeks had reduced fertility at 30 mg/kg/day and complete infertility at 100 mg/kg/day (approximately 1 and 2-times the human exposure for a 200 mg dose, respectively). At 100 mg/kg/day, males had testicular atrophy including hypospermia in the epididymal tubules and focal epithelial hyperplasia of the epididymal tubular epithelium. Following a 10-week treatment-free period, these effects were partially reversed in male rats given pretomanid at 30 mg/kg/day but not at 100 mg/kg/day. These effects were associated with increased serum follicle-stimulating hormone and decreased serum inhibin B concentrations. There were no effects of pretomanid in male rats treated for 13 weeks at 10 mg/kg/day (approximately half of the human exposure for a 200 mg dose). Pretomanid did not affect mating behavior in female rats given oral pretomanid at 100 mg/kg/day for two weeks (approximately twice the human exposure). Testicular toxicity was present in male mice treated orally for 13 weeks at 20 mg/kg/day [approximately equal to the human exposure (AUC) for a 200 mg dose]. There were no adverse testicular effects observed in mice given pretomanid at 6 mg/kg/day (0.2-times the human exposure for a 200 mg dose). Testicular toxicity was observed in male rats following 7 or 14 days of dosing with oral pretomanid at 100 mg/kg/day (approximately 2-times the human exposure for a 200 mg dose). The effects were partially reversible during a 6-month post treatment recovery period in rats treated with pretomanid for 7 days, but not 14 days. In a 3-month study, decreased sperm motility and total sperm count, and increased abnormal sperm ratio were noted in sexually mature monkeys given ≥ 150 mg/kg/day (approximately 3 times the human exposure for a 200 mg dose). 13.2 Animal Toxicology and/or Pharmacology Cataracts were observed in rats treated with pretomanid at doses of 300 mg/kg/day for 13 weeks or 100 mg/kg/day for 26 weeks. There were no cataracts observed in rats given oral pretomanid at 30 mg/kg/day (approximately 2 times the human exposure for a 200 mg dose) for 26 weeks. In monkeys given oral pretomanid at 450 mg/kg/day for 4 weeks and 300 mg/kg/day for 12 more weeks, cataracts were not present at the end of dosing but developed during the 13-week post treatment recovery period. In a subsequent study, cataracts were not observed following 13 Reference ID: 5483888 21 weeks treatment with up to 300 mg/kg/day oral pretomanid or during the 20-week post treatment recovery period. Further, no cataracts were observed in monkeys given oral pretomanid at 100 mg/kg/day for 39 weeks with a 12-week post treatment recovery. This is approximately 1- to 2 times the human exposure (AUC) for a 200 mg dose. 14 CLINICAL STUDIES Trial 1 Trial 1 (NCT02333799) was an open-label trial conducted in three centers in South Africa in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug (Population 1), or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy (Population 2). Fifty-six (51%) patients were HIV-positive. The patients received a combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 26 weeks (extended to 9 months in 2 patients) with 24 months of follow-up. The dosage of Pretomanid Tablets was 200 mg orally once daily. The dosage of bedaquiline was 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week for 24 weeks. The starting dose of linezolid was either 600 mg orally twice daily or 1,200 mg orally once daily. One hundred seven of the 109 patients enrolled were assessable for the primary efficacy analyses with two patients remaining in follow-up for the primary outcome assessment. Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion to positive status with a different M. tuberculosis strain), bacteriological relapse (culture conversion to positive status with the same M. tuberculosis strain), or clinical failure (an unfavorable status at, or before, end of treatment (EOT) or failing to attain culture negativity, or if the patient was withdrawn at or before EOT for clinical reasons including retreatment or changing treatment) through follow-up until 6 months after the EOT. Results are presented in Table 4. Of the 107 patients assessed, outcomes were classified as success for 95 (89%) patients and failure for 12 (11%) patients. The success rate significantly exceeded the historical success rates for TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug based on a literature review. The outcomes were similar in both HIV negative and HIV positive patients. Table 4: Outcomes Six Months After the End of Treatment in Population 1 and Population 2 in Trial 1 Outcome Total Population 1a Population 2b Total assessable 107 71 36 Success Success (culture negative status at 6 months post treatment) 95 (89%) 63 (89%) 32 (89%) Failure Death 7 6 1 Relapse post treatment 2 1* 1 Withdrawal, loss to follow-up, or contaminated cultures 3 1 2 Total Failure 12 (11%) 8 (11%) 4 (11%) Reference ID: 5483888 22 I aPopulation 1 = TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug; bPopulation 2 = TB resistant to isoniazid and rifampin, who were treatment-intolerant or nonresponsive to standard therapy * The patient died at Day 486. Trial 2 Trial 2 (NCT03086486) was a phase 3 partially blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid plus Pretomanid Tablets and bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy. A total of 181 patients were randomized to receive one of 4 treatment regimens, of which 45 each received 1,200 mg or 600 mg linezolid orally plus Pretomanid Tablets and bedaquiline for 26 weeks, and 46 and 45 patients received 1,200 mg or 600 mg linezolid orally for 9 weeks (not an approved dosing regimen), followed by linezolid placebo for 17 weeks, respectively, plus Pretomanid Tablets and bedaquiline for 26 weeks. The dosage of Pretomanid Tablets was 200 mg orally once daily for 26 weeks. The dosage of bedaquiline was 200 mg daily for 8 weeks, followed by 100 mg daily for 18 weeks. Treatment failure was defined as the incidence of bacteriologic failure, bacteriologic relapse or clinical failure through follow-up until 6 months after the end of treatment, which was identical to the definition of treatment failure in Trial 1. The success rate in each treatment arm significantly exceeded the historical success rates for TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug based on a literature review used in Trial 1. When used in combination with Pretomanid Tablets and bedaquiline, linezolid 600 mg once daily for 26 weeks is preferred over linezolid 1,200 mg once daily for 26 weeks [see Dosage and Administration (2.2)]. Among the 90 patients receiving linezolid for 26 weeks, the mean age of the patients was 38 years old with 68% being males. Most patients were White (64%), and the remaining patients were Black (36%). Most patients had a current diagnosis (a stratification factor) of pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug (46%) or pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug (44%), and the remainder were patients having pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy (6% and 4%, respectively). The results are presented in Table 5 below. Table 5: Outcomes Six Months After the End of Treatment* for All Randomized Patients§† in 26-Week Regimens in Trial 2: Outcome Linezolid 1,200 mg‡ 26 weeks Linezolid 600 mg‡ 26 weeks Reference ID: 5483888 23 (N = 44§) n (%) (N = 45) n (%) Success 41 (93%) 41 (91%) Relapse post treatment 0 1 (2%) Failure Re-treated post treatment 2 (5%) 1 (2%) Loss to follow-up or withdrawal 1 (2%) 2 (4%) Total Failure 3 (7%) 4 (9%) N = total number of patients in the relevant analysis population; n = number of patients in each category. *Linezolid was administered with Pretomanid Tablets and bedaquiline. ‡When used in combination with Pretomanid Tablets and bedaquiline, linezolid 600 mg once daily for 26 weeks is preferred over linezolid 1,200 mg once daily for 26 weeks based on safety profiles [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. §The primary efficacy analysis excluded one randomized subject who was lost to follow-up after repeated negative cultures during the follow-up period. †Refers to patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or patients with pulmonary TB resistant to isoniazid and rifampin, and who are treatment-intolerant or nonresponsive to standard therapy. 16 HOW SUPPLIED/STORAGE AND HANDLING Pretomanid Tablet 200 mg is packaged in either white, round, high-density polyethylene bottles with polypropylene child-resistant closure or child-resistant blister packages comprised of a polyvinylchloride film with foil and paper backing. Pretomanid Tablet 200 mg is a white to off-white, oval tablet debossed with M on one side and P200 on the other side. NDC Number Size 49502-476-26 Bottle of 26 49502-476-14 Unit dose blister pack of 14 (1 strip of 14 tablets) 49502-476-72 Bottle of 182 Store below 30°C (86°F). Dispense only in original container and keep container tightly closed. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Important Information on Co-administration of Pretomanid Tablets in Combination with Bedaquiline and Linezolid [see Dosage and Administration (2.1)] • Inform the patient or caregiver that Pretomanid Tablets administered as a combination regimen with bedaquiline and linezolid would be useful only in adult patients with TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive Reference ID: 5483888 24 to standard therapy. This regimen is not indicated for treatment in patients with latent infection or extra-pulmonary infection due to M. tuberculosis, drug-sensitive TB, TB resistant to isoniazid and rifampin who are responsive to standard therapy and not treatment- intolerant, or who have TB with known resistance to any component of the regimen (Pretomanid Tablets, bedaquiline, or linezolid). • Instruct the patient or caregiver that the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid must be administered by directly observed therapy (DOT). • Inform patients of safety concerns associated with linezolid and bedaquiline and advise the patient or their caregiver to read the Medication Guide for bedaquiline. Serious Adverse Reactions Advise patients that the following serious adverse reactions can occur with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid: liver enzyme abnormalities, myelosuppression including anemia, peripheral and optic neuropathy, and cardiac rhythm abnormalities [see Warnings and Precautions (5.2, 5.4)]. Additional serious adverse reactions can occur with the use of linezolid, including serotonin syndrome, lactic acidosis, and convulsions. Refer to the prescribing information for linezolid for additional counseling information for these serious adverse reactions. Peripheral and Optic Neuropathy Advise patients to promptly inform their physician if they experience changes in vision during linezolid therapy. Monitor visual function in all patients receiving linezolid. Counsel patients to obtain prompt ophthalmological evaluation if the patient experiences symptoms of visual impairment [see Warnings and Precautions (5.3)]. Interruption of Linezolid Dosing to Manage Linezolid Adverse Reactions Counsel patients that linezolid dosing may be modified or interrupted during the therapy to manage the known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy [see Dosage and Administration section (2.2) and Adverse Reactions (6)]. Compliance with Treatment Inform patients that Pretomanid Tablets must be taken as part of a combination regimen with bedaquiline and linezolid. Compliance with the full course of therapy must be emphasized. Advise patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed for the full prescribed duration of dosing. Skipping doses other than as directed by a physician or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that their Mycobacterium may develop resistance and the disease will not be treatable by the regimen or other antibacterial drugs in the future. Important Administration Instructions Reference ID: 5483888 25 [Ili]Mylan® • Inform patients to take the regimen with food. Doses of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid missed for safety reasons can be made up at the end of treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up. If bedaquiline and/or Pretomanid Tablets are permanently discontinued, the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid should be discontinued. • Advise patients who have difficulty swallowing tablets that Pretomanid Tablets can be crushed and suspended in water at room temperature. Alternately, the tablet can be soaked for 4 to 5 minutes in room temperature water and then the remaining solid crushed [see Dosage and Administration (2.2)]. Use in Patients with Hepatic or Renal Impairment Advise patients to inform their physician if they have a history of liver or kidney problems. The safety and effectiveness of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid in populations with hepatic or renal impairment have not been established. Use with Alcohol and Other Medications Advise patients to discuss with their physician the other medications they are taking and other medical conditions before starting treatment with Pretomanid Tablets. Advise patients to abstain from alcohol, hepatotoxic medications, and herbal products [see Drug Interactions (7)]. Manufactured by: Mylan Laboratories Limited Hyderabad, 500 096, India Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Under license from TB Alliance. MS:MXA:PRET:RX7 Reference ID: 5483888 26 1 MEDICATION GUIDE Pretomanid Tablets (Pre-TOH-mah-nid) Limited Population What is the most important information I should know about the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid? Pretomanid Tablets are for use only as part of a combination antibiotic regimen that includes Pretomanid Tablets, bedaquiline, and linezolid. Treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can cause serious side effects. See “What are the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?” Read the Medication Guide that comes with bedaquiline. Ask your healthcare provider for information about linezolid. The serious side effects that can happen when taking bedaquiline and linezolid can also happen when taken in the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. What is the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid? Pretomanid Tablets are a prescription medicine used as part of a combination regimen with bedaquiline and linezolid. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid includes three prescription antibiotics that are used together in adults to treat tuberculosis (TB) of the lungs that is resistant to other classes of antibiotics (isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibiotic) or in adults who cannot tolerate or do not respond to treatment for TB that is resistant to two specific antibiotics (isoniazid and rifampin). Pretomanid Tablets are not for use in people who have: • TB that is not resistant to antibiotics. • an inactive (latent) TB infection. • a type of TB other than TB of the lungs. • TB resistant to isoniazid and rifampin who can tolerate or who respond to medicines usually used to treat this type of TB. • TB that is known to be resistant to Pretomanid Tablets, bedaquiline, or linezolid. It is not known if Pretomanid Tablets are safe and effective for use except in combination with bedaquiline and linezolid as part of the recommended dosing regimen. It is not known if Pretomanid Tablets are safe and effective in children. Pretomanid Tablets were approved by FDA using the Limited Population pathway. This means FDA has approved this drug for a limited and specific patient population, and studies on the drug may have only answered focused questions about its safety and effectiveness. Do not take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if: • you have been told by your healthcare provider not to take bedaquiline or linezolid. Before you take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems. See “What are the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?” • have kidney problems. • have or have had an abnormal heart rhythm (ECG) or other heart problems, including heart failure. • have a family history of a heart problem called “congenital long QT syndrome.” • have decreased thyroid gland function (hypothyroidism). • have HIV infection. • have been told that you have low levels of calcium, magnesium or potassium in your blood. • have ever had a seizure. • are pregnant or plan to become pregnant. It is not known if pretomanid will harm your unborn baby. Talk to your healthcare provider about the possible risks to your baby if you take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid while you are pregnant. • are breastfeeding or plan to breastfeed. It is not known if pretomanid passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Reference ID: 5483888 2 Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. You should not take herbal products or medicines that can harm your liver during treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid regimen may affect how other medicines work, and other medicines may affect how the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid works. Especially tell your healthcare provider if you take: • a type of medicine called a CYP3A4 inducer, such as efavirenz or rifampin. Ask your healthcare provider if you are not sure. How should I take the combination regimen of Pretomanid Tablets, bedaquiline and linezolid? • Pretomanid Tablets must only be taken with bedaquiline and linezolid as part of the dosing regimen prescribed by your healthcare provider. • Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid exactly as your healthcare provider tells you to take it. • It is important that you complete the full course of treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, and not miss any doses, even if you feel better before you have completed the full course of treatment. Missing doses may decrease the effectiveness of the treatment and increase the chance that your TB will not be treatable by the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid or other medicines. • Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for a total of 26 weeks. o Your healthcare provider will tell you if you should take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for longer than 26 weeks. o Your healthcare provider will tell you if you should stop taking linezolid before you have taken it for 26 weeks or if you should reduce your dose of linezolid due to side effects. • Your healthcare provider or caregiver will watch you take your doses of Pretomanid Tablets, bedaquiline, and linezolid. • Take Pretomanid Tablets, bedaquiline, and linezolid with food. o If you can swallow whole tablets:  Swallow tablets whole with water. o If you cannot swallow whole tablets:  Crush 200 mg of Pretomanid Tablets (1 tablet) and mix with 1 teaspoon (5 mL) of room temperature drinking water. Mix well in a drinking cup.  Swallow mixture immediately.  Make sure no remaining medicine is left in the drinking cup. Rinse well with another 1 teaspoon (5 mL) of room temperature drinking water and swallow the mixture immediately.  Do not store mixture for later use. Or  Soak 200 mg of Pretomanid Tablets (1 tablet) in 1 teaspoon (5 mL) of room temperature drinking water for 4 to 5 minutes in a drinking cup. Then crush the tablet in the drinking cup. Mix the medicine in the drinking cup well by stirring.  Swallow the mixture immediately.  Make sure no remaining medicine is left in the drinking cup. Rinse well with another 1 teaspoon (5 mL) of room temperature drinking water and swallow the mixture immediately.  Do not store the mixture for later use. • Week 1 and Week 2: o Take 200 mg of Pretomanid Tablets (1 tablet), 400 mg of bedaquiline, and 600 mg of linezolid 1 time each day. Or o Take 200 mg of Pretomanid Tablets (1 tablet), 400 mg of bedaquiline, and 1,200 mg of linezolid 1 time each day. • Week 3 to Week 26: o Take 200 mg of Pretomanid Tablets (1 tablet) and 600 mg of linezolid 1 time each day. Or o Take 200 mg of Pretomanid Tablets (1 tablet) and 1,200 mg of linezolid 1 time each day. o Take 200 mg of bedaquiline 3 times a week.  Take your doses of bedaquiline at least 48 hours apart. For example, you may take bedaquiline on Monday, Wednesday, and Friday every week from Week 3 to Week 26. Or • Week 1 to Week 8: Reference ID: 5483888 3 o Take 200 mg of bedaquiline 1 time each day for 8 weeks. Then take 100 mg of bedaquiline 1 time each day for 18 weeks, for a total of 26 weeks. • You may need to take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for longer than 26 weeks. Talk with your healthcare provider. • Do not miss a dose of Pretomanid Tablets, bedaquiline, or linezolid unless instructed to do so by your healthcare provider. If you miss doses or do not complete the total 26 weeks of treatment, your treatment may not work as well, and your TB may be harder to treat. • If your healthcare provider tells you to stop taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for a period of time, follow the instructions given to you by your healthcare provider for taking the missed doses at the end of your treatment. You should not make up any missed doses of linezolid alone that your healthcare provider told you not to take due to side effects. • If you miss a dose of Pretomanid Tablets, bedaquiline, or linezolid and you are not sure what to do, talk to your healthcare provider as soon as possible. • If you take too much Pretomanid Tablets, go to the nearest hospital emergency room right away. Do not stop taking Pretomanid Tablets, bedaquiline, or linezolid without first talking to your healthcare provider. What should I avoid when taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid? • You should not drink alcohol while taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. What are the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid? The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid may cause serious side effects including: • See “What is the most important information I should know about the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?” • Liver problems. Your healthcare provider should do blood tests to check your liver at least before you start taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, 2 weeks after starting treatment, and then monthly during treatment. Tell your healthcare provider right away if you have symptoms of liver problems, such as: o unusual tiredness o loss of appetite o nausea o yellowing of your skin or the whites of your eyes o dark (tea-colored) urine o tenderness in the upper right side of your stomach-area (abdomen) See “What should I avoid when taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?” • Low blood cell counts. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can cause low red blood cell counts (anemia), low white blood cell counts (leukopenia), low blood platelet counts (thrombocytopenia) or a combination of low red and white blood cell counts and low blood platelet counts (pancytopenia). Low blood cell counts are a side effect of linezolid. Anemia is a common side effect of linezolid, but can be serious and life-threatening. Low blood cell counts were reversible when linezolid treatment was reduced, stopped for a period of time, or stopped permanently. Your healthcare provider should check your blood cell counts at least before you start taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, 2 weeks after starting treatment, and then monthly during treatment. Your healthcare provider may lower the dose or stop treatment with linezolid if you develop or have worsening blood cell counts. • Nerve problems in your arms, hands, legs, and feet (peripheral neuropathy). The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can cause nerve problems in your arms, hands, legs, and feet. Tell your healthcare provider if you have symptoms of nerve problems in your arms, hands, legs, or feet, including: o numbness o burning o a feeling of “pins and needles” o tremors o problems with balance o weakness • Vision problems. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can cause nerve problems in your eyes (optic neuropathy). Nerve problems in your eyes can cause problems with your vision. Tell your healthcare provider right away if you have symptoms of nerve problems in your eyes, such as changes in vision. Reference ID: 5483888 4 Nerve problems in your arms, hands, legs, feet, and eyes are common side effects of long-term use of linezolid, but can be serious. Nerve problems caused by linezolid were generally reversible or improved when symptoms of nerve problems were monitored by the healthcare provider and linezolid treatment was reduced, stopped for a period of time, or stopped permanently. • Heart rhythm problem called QT prolongation. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can cause a heart rhythm problem. Heart rhythm problem is a side effect of bedaquiline. Your healthcare provider should do a test called an electrocardiogram (ECG) to check your heart before you start taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid and at least 2, 12, and 24 weeks after starting treatment. Tell your healthcare provider right away if you: o have a change in heartbeat (a fast or irregular heartbeat) o feel dizzy or faint • Effects on male fertility. It is not known if pretomanid can cause fertility problems in males. This could affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. • Build-up of an acid in your blood (lactic acidosis). The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can cause a build-up of acid in your blood. A build-up of acid in your blood is a side effect of linezolid. • Call your healthcare provider right away if you have nausea and vomiting that keep coming back. The most common side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid include: • nausea • acne • vomiting • abnormal blood tests that may be due to injury to your liver • headache • muscle and bone pain • heartburn • rash • itching • decreased appetite • stomach area (abdominal) pain • chest pain that worsens when you breathe or cough • coughing up blood • abnormal blood tests that may be due to injury to your pancreas These are not all the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Pretomanid Tablets? • Store Pretomanid Tablets, bedaquiline, and linezolid below 86°F (30°C). Ask your pharmacist if you have questions about how to store bedaquiline and linezolid. • Keep Pretomanid Tablets in the original container with the container tightly closed. Keep Pretomanid Tablets and all medicines out of the reach of children. General information about the safe and effective use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Pretomanid Tablets, bedaquiline, or linezolid for a condition for which it was not prescribed. Do not give Pretomanid Tablets, bedaquiline, or linezolid to other people, even if they have the same symptoms that you have. This may harm them. You can ask your pharmacist or healthcare provider for information about Pretomanid Tablets, bedaquiline, and linezolid that is written for health professionals. What are the ingredients in the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid? Pretomanid Tablets active ingredient: pretomanid Pretomanid Tablets inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and sodium starch glycolate The ingredients for bedaquiline can be found in the Medication Guide for bedaquiline. The ingredients for linezolid can be found in the information about linezolid that is written for health professionals. [iii]Mylan® Reference ID: 5483888 5 Manufactured by: Mylan Laboratories Limited Hyderabad, 500 096, India Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Under license from TB Alliance. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). MS:MXA:MG:PRET:RX6 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5483888	custom-source	2025-02-12T15:47:03.156297	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212862s008lbl.pdf', 'application_number': 212862, 'submission_type': 'SUPPL ', 'submission_number': 8}
80,356	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRODELVY safely and effectively. See full prescribing information for TRODELVY TRODELVY® (sacituzumab govitecan-hziy) for injection, for intravenous use Initial U.S. Approval: 2020 WARNING: NEUTROPENIA AND DIARRHEA See full prescribing information for complete boxed warning. Severe or life threatening neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti- infective treatment in patients with febrile neutropenia without delay. (2.3, 5.1) Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses. (2.3, 5.2) -----------------------------RECENT MAJOR CHANGES------------------------ Indications and Usage, Locally Advanced or Metastatic Urothelial Cancer – Accelerated Approval (text removed) (1.2) 11/2024 ----------------------------INDICATIONSANDUSAGE---------------------------- TRODELVY is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with: Locally Advanced or Metastatic Breast Cancer • Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. (1.1, 14.1) • Unresectable locally advanced or metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine- based therapy and at least two additional systemic therapies in the metastatic setting. (1.1, 14.2) ------------------------DOSAGEANDADMINISTRATION----------------------- • Do NOT substitute TRODELVY for or use with other drugs containing irinotecan or its active metabolite SN-38. (2.1) • For intravenous infusion only. Do not administer as an intravenous push or bolus. • The recommended dose is 10 mg/kg once weekly on Days 1 and 8 of continuous 21-day treatment cycles until disease progression or unacceptable toxicity. (2.2) • Premedication for prevention of infusion reactions and prevention of chemotherapy-induced nausea and vomiting is recommended. (2.2) • Monitor patients during the infusion and for at least 30 minutes after completion of infusion. Treatment interruption and/or dose reduction may be needed to manage adverse reactions. (2.2) • See Full Prescribing Information for preparation and administration instructions. (2.4) ---------------------DOSAGE FORMS AND STRENGTHS------------------------ For injection: 180 mg lyophilized powder in single-dose vials for reconstitution. (3) -------------------------------CONTRAINDICATIONS------------------------------ Severe hypersensitivity reaction to TRODELVY. (4, 5.3) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Hypersensitivity and Infusion-Related Reactions: Hypersensitivity reactions including severe anaphylactic reactions have been observed. Monitor patients for infusion-related reactions. Permanently discontinue TRODELVY if severe or life-threatening reactions occur. (5.3) • Nausea/Vomiting: Use antiemetic preventive treatment and withhold TRODELVY for patients with Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment. (5.4) • Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia following initiation of TRODELVY treatment. (5.5) • Embryo-Fetal Toxicity: TRODELVY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.6, 8.1, 8.3) -------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence > 25%) are (including laboratory abnormalities) were decreased leukocyte count, decreased neutrophil count, decreased hemoglobin, diarrhea, nausea, decreased lymphocyte count, fatigue, alopecia, constipation, increased glucose, decreased albumin, vomiting, decreased appetite, decreased creatinine clearance, increased alkaline phosphatase, decreased magnesium, decreased potassium, and decreased sodium. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-888-983-4668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS-------------------------------- • UGT1A1 inhibitors or inducers: Avoid concomitant use. (7) --------------------------USE IN SPECIFIC POPULATIONS---------------------- • Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 11/2024 Reference ID: 5484095 FULL PRESCRIBING INFORMATION: CONTENTS WARNING: NEUTROPENIA AND DIARRHEA 1 INDICATIONS AND USAGE 1.1 Locally Advanced or Metastatic Breast Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Important Use Information 2.2 Recommended Dosage 2.3 Dose Modifications for Adverse Reactions 2.4 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia 5.2 Diarrhea 5.3 Hypersensitivity and Infusion Related Reactions 5.4 Nausea and Vomiting 5.5 Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Trodelvy 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICALPHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 12.6 Immunogenicity 13 NONCLINICALTOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Locally Advanced or Metastatic Triple-Negative Breast Cancer 14.2 Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5484095 FULL PRESCRIBING INFORMATION WARNING: NEUTROPENIA AND DIARRHEA • Severe or life threatening neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis [see Dosage and Administration (2.3)]. Initiate anti-infective treatment in patient with febrile neutropenia without delay [see Warnings and Precautions (5.1)]. • Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide [see Warnings and Precautions (5.2)]. If severe diarrhea occurs, withhold TRODELVY until resolved to < Grade 1 and reduce subsequent doses [see Dosage and Administration (2.3)]. 1 INDICATIONS AND USAGE 1.1 Locally Advanced or Metastatic Breast Cancer • TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. • TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. 2 DOSAGE AND ADMINISTRATION 2.1 Important Use Information Do NOT substitute TRODELVY for or use with other drugs containing irinotecan or its active metabolite SN-38. 2.2 Recommended Dosage The recommended dosage of TRODELVY is 10 mg/kg administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles. Continue treatment until disease progression or unacceptable toxicity. Do not administer TRODELVY at doses greater than 10 mg/kg. Administer TRODELVY as an intravenous infusion only. Do not administer as an intravenous push or bolus. First infusion: Administer infusion over 3 hours. Observe patients during the infusion and for at least 30 minutes following the initial dose, for signs or symptoms of infusion-related reactions [see Warning and Precautions (5.3)]. Subsequent infusions: Administer infusion over 1 to 2 hours if prior infusions were tolerated. Observe patients during the infusion and for at least 30 minutes after infusion. Reference ID: 5484095 Premedication Prior to each dose of TRODELVY, premedication for prevention of infusion reactions and prevention of chemotherapy- induced nausea and vomiting (CINV) is recommended. • Premedicate with antipyretics, H1 and H2 blockers prior to infusion, and corticosteroids may be used for patients who had prior infusion reactions. • Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist, as well as other drugs as indicated). 2.3 Dose Modifications for Adverse Reactions Infusion-related Reactions Slow or interrupt the infusion rate of TRODELVY if the patient develops an infusion-related reaction. Permanently discontinue TRODELVY for life-threatening infusion-related reactions [see Warnings and Precautions (5.3)] Dose Modifications for Adverse Reactions Withhold or discontinue TRODELVY to manage adverse reactions as described in Table 1. Do not re-escalate the TRODELVY dose after a dose reduction for adverse reactions has been made. Table 1: Dose Modifications for Adverse Reactions Adverse Reaction Occurrence Dose Modification Severe Neutropenia [see Warnings and Precautions (5.1)] Grade 4 neutropenia ≥ 7 days OR Grade 3-4 febrile neutropenia, OR At time of scheduled treatment, Grade 3-4 neutropenia which delays dosing by 2 or 3 weeks for recovery to ≤ Grade 1 First 25% dose reduction and administer granulocyte-colony stimulating factor (G-CSF). Second 50% dose reduction and administer G-CSF. Third Discontinue treatment and administer G-CSF. At time of scheduled treatment, Grade 3-4 neutropenia which delays dosing beyond 3 weeks for recovery to ≤ Grade 1 First Discontinue treatment and administer G-CSF. Reference ID: 5484095 Adverse Reaction Occurrence Dose Modification Severe Non-Neutropenic Toxicity Grade 4 non-hematologic toxicity of any duration, OR Any Grade 3-4 nausea, vomiting or diarrhea due to treatment that is not controlled with antiemetics and anti-diarrheal agents [see Warnings and Precautions (5.2, 5.4)], OR Other Grade 3-4 non-hematologic toxicity persisting > 48 hours despite optimal medical management, OR At time of scheduled treatment, Grade 3-4 non-neutropenic hematologic or non-hematologic toxicity, which delays dose by 2 or 3 weeks for recovery to ≤ Grade 1 First 25% dose reduction Second 50% dose reduction Third Discontinue treatment In the event of Grade 3-4 non-neutropenic hematologic or non- hematologic toxicity, which does not recover to ≤ Grade 1 within 3 weeks First Discontinue treatment 2.4 Preparation and Administration Reconstitution • TRODELVY is a hazardous drug. • Follow applicable special handling and disposal procedures1. • Calculate the required dose (mg) of TRODELVY based on the patient’s body weight at the beginning of each treatment cycle (or more frequently if the patient’s body weight changed by more than 10% since the previous administration) [see Dosage and Administration (2.2)]. • Allow the required number of vials to warm to room temperature. • Using a sterile syringe, slowly inject 20 mL of 0.9% Sodium Chloride Injection, USP, into each 180 mg TRODELVY vial. Each vial contains overfill to compensate for liquid loss during preparation and after reconstitution, the total resulting volume delivers a concentration of 10 mg/mL. • Gently swirl vials and allow to dissolve for up to 15 minutes. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be free of visible particulates, clear and yellow. Do not use the reconstituted solution if it is cloudy or discolored. • Use immediately to prepare a diluted TRODELVY infusion solution. Dilution • Calculate the required amount of the reconstituted TRODELVY solution needed to obtain the appropriate dose according to the patient’s body weight. • Determine the final volume of the infusion solution to deliver the appropriate dose at a TRODELVY concentration range of 1.1 mg/mL to 3.4 mg/mL. • Use 0.9% Sodium Chloride Injection, USP only since the stability of the reconstituted TRODELVY solution has not been determined with other infusion-based solutions. Use a polyvinyl chloride, polypropylene/polyethylene, polyolefin, or ethylene vinyl acetate infusion bag. • Withdraw and discard the volume of 0.9% Sodium Chloride Injection, USP from the final infusion bag that is necessary to achieve the indicated TRODELVY concentration following the addition of the calculated amount of reconstituted TRODELVY solution. Reference ID: 5484095 • Withdraw the calculated amount of the reconstituted TRODELVY solution from the vial(s) using a syringe. Discard any unused portion remaining in the vial(s). • To minimize foaming, slowly inject the calculated amount of reconstituted TRODELVY solution into the infusion bag. Do not shake the contents. • If not used immediately, the infusion bag containing TRODELVY solution can be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours protected from light. After refrigeration, administer diluted solution at room temperature up to 25°C (77°F) within 8 hours (including infusion time). Do Not Freeze or Shake. Administration • Administer TRODELVY as an intravenous infusion. Protect infusion bag from light. The infusion bag should be covered during administration to the patient until dosing is complete. It is not necessary to cover the infusion tubing or to use light-protective tubing during the infusion. • An infusion pump may be used. • Do not mix TRODELVY, or administer as an infusion, with other medicinal products. • Upon completion of the infusion, flush the intravenous line with 20 mL 0.9% Sodium Chloride Injection, USP. 3 DOSAGE FORMS AND STRENGTHS For injection: 180 mg off-white to yellowish lyophilized powder in a single-dose vial. 4 CONTRAINDICATIONS TRODELVY is contraindicated in patients who have experienced a severe hypersensitivity reaction to TRODELVY [see Warnings and Precautions (5.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe, life-threatening, or fatal neutropenia can occur in patients treated with TRODELVY. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6% of patients. The median time to first onset of neutropenia (including febrile neutropenia) was 16 days and has occurred earlier in some patient populations [see Warnings and Precautions (5.5)]. Neutropenic colitis occurred in 1.4% of patients. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Dose modifications may be required due to neutropenia. Administer G-CSF as clinically indicated or indicated in Table 1 [see Dosage and Administration (2.3)]. 5.2 Diarrhea TRODELVY can cause severe diarrhea. Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 diarrhea occurred in 11% of all patients treated with TRODELVY. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold TRODELVY for Grade 3-4 diarrhea at the time of scheduled treatment administration and resume when resolved to ≤Grade 1 [see Dosage and Administration (2.3)]. At the onset of diarrhea, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after Reference ID: 5484095 diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment with TRODELVY (e.g., abdominal cramping, diarrhea, salivation, etc.) can receive appropriate premedication (e.g., atropine) for subsequent treatments. 5.3 Hypersensitivity and Infusion-Related Reactions Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY treatment. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions [see Contraindications (4)]. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients treated with TRODELVY. Grade 3-4 hypersensitivity occurred in 2% of patients treated with TRODELVY. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%. Premedication for infusion reactions in patients receiving TRODELVY is recommended. Have medications and emergency equipment to treat infusion-related reactions, including anaphylaxis, available for immediate use when administering TRODELVY [see Dosage and Administration (2.2)]. Closely monitor patients for hypersensitivity and infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion [see Dosage and Administration (2.3)]. Permanently discontinue TRODELVY for Grade 4 infusion-related reactions [see Dosage and Administration (2.3)]. 5.4 Nausea and Vomiting TRODELVY is emetogenic. Nausea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 3% of patients. Vomiting occurred in 35% of all patients treated with TRODELVY. Grade 3-4 vomiting occurred in 2% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV) [see Dosage and Administration (2.2)]. Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment administration and resume with additional supportive measures when resolved to ≤Grade 1 [see Dosage and Administration (2.3)]. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting. 5.5 Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia; and may be at increased risk for other adverse reactions when treated with TRODELVY. The incidence of neutropenia and anemia was analyzed in 948 patients who received TRODELVY and had UGT1A1 genotype results. In patients homozygous for the UGT1A1 28 allele (n=112), the incidence of Grade 3-4 neutropenia was 58%. In patients heterozygous for the UGT1A128 allele (n=420), the incidence of Grade 3-4 neutropenia was 49%. In patients homozygous for the wild-type allele (n=416), the incidence of Grade 3-4 neutropenia was 43% [see Clinical Reference ID: 5484095 - Pharmacology (12.5)]. In patients homozygous for the UGT1A1 28 allele, the incidence of Grade 3-4 anemia was 21%. In patients heterozygous for the UGT1A128 allele, the incidence of Grade 3-4 anemia was 10%. In patients homozygous for the wild-type allele, the incidence of Grade 3-4 anemia was 9%. The median time to first neutropenia including febrile neutropenia was 9 days in patients homozygous for the UGT1A128 allele, 15 days in patients heterozygous for the UGT1A128 allele, and 20 days in patients homozygous for the wild-type allele. The median time to first anemia was 21 days in patients homozygous for the UGT1A128 allele, 25 days in patients heterozygous for the UGT1A128 allele, and 28 days in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 enzyme activity [see Dosage and Administration (2.3)]. 5.6 Embryo-Fetal Toxicity Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Neutropenia [see Warnings and Precautions (5.1)] • Diarrhea [see Warnings and Precautions (5.2)] • Hypersensitivity and Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Nausea and Vomiting [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The pooled safety population described in the Warnings and Precautions section reflect exposure to TRODELVY in 1063 patients, which included 366 patients with mTNBC and 322 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer from IMMU-132-01, ASCENT, and TROPiCS-02; and 375 patients with other tumor types. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses of 10 mg/kg until disease progression or unacceptable toxicity. Among the 1063 patients treated with TRODELVY, the median duration of treatment was 4.1 months (range: 0 to 63 months). In this pooled safety population, the most common (> 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%). Reference ID: 5484095 Locally Advanced or Metastatic Triple-Negative Breast Cancer ASCENT Study The safety of TRODELVY was evaluated in a randomized, active-controlled, open-label study (ASCENT) in patients with mTNBC who had previously received a taxane and at least two prior chemotherapies. Patients were randomized (1:1) to receive either TRODELVY (n=258) or single agent chemotherapy (n=224) and were treated until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. For patients treated with TRODELVY, the median duration of treatment was 4.4 months (range: 0 to 23 months). Serious adverse reactions occurred in 27% of patients receiving TRODELVY. Serious adverse reactions in > 1% of patients receiving TRODELVY included neutropenia (7%), diarrhea (4%), and pneumonia (3%). Fatal adverse reactions occurred in 1.2% of patients who received TRODELVY, including respiratory failure (0.8%) and pneumonia (0.4%). TRODELVY was permanently discontinued for adverse reactions in 5% of patients. Adverse reactions leading to permanent discontinuation in ≥ 1 % of patients who received TRODELVY were pneumonia (1%) and fatigue (1%). Adverse reactions leading to a treatment interruption of TRODELVY occurred in 63% of patients. The most frequent (≥5%) adverse reactions leading to a treatment interruption were neutropenia (47%), diarrhea (5%), respiratory infection (5%), and leukopenia (5%). Adverse reactions leading to a dose reduction of TRODELVY occurred in 22% of patients. The most frequent (>4%) adverse reactions leading to a dose reduction were neutropenia (11%) and diarrhea (5%). Granulocyte-colony stimulating factor (G-CSF) was used in 44% of patients who received TRODELVY. Tables 2 and 3 summarize adverse reactions and laboratory abnormalities, respectively, in the ASCENT study. Table 2: Adverse Reactions in ≥ 10% of Patients with mTNBC in ASCENT TRODELVY (n=258) Single Agent Chemotherapy (n=224) Adverse Reaction All Grades % Grade 3 - 4 % All Grades % Grade 3 - 4 % Gastrointestinal disorders Diarrhea 59 11 17 1 Nausea 57 3 26 0.4 Vomiting 33 2 16 1 Constipation 37 0.4 23 0 Abdominal Pain 30 3 12 1 Stomatitisi 17 2 13 1 General disorders and administration site conditions Fatigueii 65 6 50 9 Pyrexia 15 0.4 14 2 Reference ID: 5484095 Infections and infestation Urinary tract infection 13 0.4 8 0.4 Upper respiratory tract infection 12 0 3 0 Metabolism and nutrition disorders Decreased appetite 28 2 21 1 Musculoskeletal and connective tissue disorders Back pain 16 1 14 2 Arthralgia 12 0.4 7 0 Nervous system disorders Headache 18 0.8 13 0.4 Dizziness 10 0 7 0 Psychiatric disorders Insomnia 11 0 5 0 Respiratory, thoracic and mediastinal disorders Cough 24 0 18 0.4 Skin and subcutaneous tissue disorders Alopecia 47 0 16 0 Rash 12 0.4 5 0.4 Pruritus 10 0 3 0 Single agent chemotherapy included one of the following single-agents: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (except if patient had ≥ Grade 2 neuropathy, n=52). Graded per NCI CTCAE v.5.0. i. Including stomatitis, glossitis, mouth ulceration, and mucosal inflammation ii. Including fatigue and asthenia Table 3: Laboratory Abnormalities in > 10% of Patients with mTNBC in ASCENT Laboratory Abnormality TRODELVY (n=258) Single Agent Chemotherapy (n=224) All Grades (%) Grade 3 - 4 (%) All Grades (%) Grade 3 - 4 (%) Hematology Decreased hemoglobin 94 9 57 6 Decreased lymphocyte count 88 31 40 24 Decreased leukocyte count 86 41 53 25 Decreased neutrophil count 78 49 48 36 Decreased platelet count 23 1.2 25 2.7 Reference ID: 5484095 Laboratory Abnormality TRODELVY (n=258) Single Agent Chemotherapy (n=224) All Grades (%) Grade 3 - 4 (%) All Grades (%) Grade 3 - 4 (%) Chemistry Increased glucose 49 2.3 43 2.8 Decreased calcium 36 1.6 21 1.4 Decreased magnesium 33 0.4 20 0 Decreased potassium 33 4.3 28 0.9 Increased albumin 32 0.8 25 1.4 Increased aspartate aminotransferase 27 1.2 32 1.4 Increased alanine aminotransferase 26 1.2 26 1.8 Increased alkaline phosphatase 26 0 17 0.5 Decreased phosphate 26 7.8 20 3.3 Decreased sodium 22 0.4 17 0.5 Increased lactate dehydrogenase 18 0 22 0 Decreased glucose 10 0 3.2 0 Study IMMU-132-01 The safety of TRODELVY was evaluated in a single-arm, open-label study (IMMU-132-01) in patients with mTNBC and other malignancies, which included 108 patients with mTNBC who had received at least two prior anticancer therapies for metastatic disease [see Clinical Studies (14.1)]. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses up to 10 mg/kg until disease progression or unacceptable toxicity. The median treatment duration in these 108 patients was 5.1 months (range: 0 to 51 months). Serious adverse reactions occurred in 31% of the patients. Serious adverse reactions in > 1% of patients receiving TRODELVY included febrile neutropenia (6%) vomiting (5%), nausea (3%), dyspnea (3%), diarrhea (4%), anemia (2%), pleural effusion, neutropenia, pneumonia, dehydration (each 2%). TRODELVY was permanently discontinued for adverse reactions in 2% of patients. Adverse reactions leading to permanent discontinuation were anaphylaxis, anorexia/fatigue, headache (each 0.9%). Forty- five percent (45%) of patients experienced an adverse reaction leading to treatment interruption. The most common adverse reaction leading to treatment interruption was neutropenia (33%). Adverse reactions leading to dose reduction occurred in 33% of patients treated with TRODELVY, with 24% having one dose reduction, and 9% with two dose reductions. The most common adverse reaction leading to dose reductions was neutropenia/febrile neutropenia. Tables 4 and 5 summarize adverse reactions and laboratory abnormalities occurring in ≥10% of patients with mTNBC in the IMMU-132-01 study. Reference ID: 5484095 Table 4: Adverse Reactions in ≥ 10% of Patients with mTNBC in IMMU-132-01 Adverse Reaction TRODELVY (n=108) Grade 1-4 (%) Grade 3-4 (%) Any adverse reaction 100 71 Gastrointestinal disorders 95 21 Nausea 69 6 Diarrhea 63 9 Vomiting 49 6 Constipation 34 1 Abdominal paini 26 1 Mucositisii 14 1 General disorders and administration site conditions 77 9 Fatigueiii 57 8 Edemaiv 19 0 Pyrexia 14 0 Metabolism and nutrition disorders 68 22 Decreased appetite 30 1 Dehydration 13 5 Skin and subcutaneous tissue disorders 63 4 Alopecia 38 0 Rashv 31 3 Pruritus 17 0 Dry Skin 15 0 Nervous system disorders 56 4 Headache 23 1 Dizziness 22 0 Neuropathyvi 24 0 Dysgeusia 11 0 Infections and infestations 55 12 Urinary Tract Infection 21 3 Respiratory Infectionvii 26 3 Musculoskeletal and connective tissue disorders 54 1 Back pain 23 0 Arthralgia 17 0 Pain in extremity 11 0 Respiratory, thoracic and mediastinal disorders 54 5 Coughviii 22 0 Dyspneaix 21 3 Reference ID: 5484095 Table 4: Adverse Reactions in ≥ 10% of Patients with mTNBC in IMMU-132-01 Adverse Reaction TRODELVY (n=108) Grade 1-4 (%) Grade 3-4 (%) Psychiatric disorders 26 1 Insomnia 13 0 Graded per NCI CTCAE v. 4.0 i. Including abdominal pain, distention, pain (upper), discomfort, tenderness. ii Including stomatitis, esophagitis, and mucosal inflammation iii Including fatigue and asthenia. iv Including edema; and peripheral, localized, and periorbital edema v Including rash; maculopapular, erythematous, generalized rash; dermatitis acneiform; skin disorder, irritation, and exfoliation vi Including gait disturbance, hypoesthesia, muscular weakness, paresthesia, peripheral and sensory neuropathy vii Including lower and upper respiratory tract infection, pneumonia, influenza, viral upper respiratory infection, bronchitis and respiratory syncytial virus infection viii Includes cough and productive cough ix Includes dyspnea and exertional dyspnea Table 5: Laboratory Abnormalities observed in ³ 10% of Patients while receiving TRODELVY in IMMU-132-01 Laboratory Abnormality TRODELVY (n=108) All Grades (%) Grade 3-4 (%) Hematology Decreased hemoglobin 93 6 Decreased leukocyte count 91 26 Decreased neutrophil count 82 32 Increased activated partial thromboplastin time 60 12 Decreased platelet count 30 3 Chemistry Increased alkaline phosphatase 57 2 Decreased magnesium 51 3 Decreased calcium 49 3 Increased aspartate aminotransferase 45 3 Decreased albumin 39 1 Increased alanine aminotransferase 35 2 Increased glucose 31 2.8 Reference ID: 5484095 Laboratory Abnormality TRODELVY (n=108) All Grades (%) Grade 3-4 (%) Decreased phosphate 29 5 Decrease magnesium 27 1.9 Decreased phosphate 27 6.5 Decreased sodium 25 4.7 Decreased potassium 24 3.7 Decreased glucose 19 2 Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer TROPiCS-02 Study The safety of TRODELVY was evaluated in a randomized, active-controlled, open-label, study (TROPiCS-02) in patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer whose disease has progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and a taxane; patients received at least two prior chemotherapies in the metastatic setting (one of which could be in the neoadjuvant or adjuvant setting if progression occurred within 12 months). Patients were randomized (1:1) to receive either TRODELVY (n=268) or single agent chemotherapy (n=249) and were treated until disease progression or unacceptable toxicity [see Clinical Studies (14.2)].For patients treated with TRODELVY, the median duration of treatment was 4.1 months (range: 0 to 63 months). Serious adverse reactions occurred in 28% of patients receiving TRODELVY. Serious adverse reactions in >1% of patients receiving TRODELVY included diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). Fatal adverse reactions occurred in 2% of patients who received TRODELVY including arrhythmia, COVID-19, nervous system disorder, pulmonary embolism, and septic shock (each 0.4%). TRODELVY was permanently discontinued for adverse reactions in 6% of patients. The most frequent (≥0.5%) adverse reactions leading to permanent discontinuation in patients who received TRODELVY were asthenia, general physical health deterioration, and neutropenia (each 0.7%). Adverse reactions leading to a treatment interruptions of TRODELVY occurred in 66% of patients. The most frequent (≥5%) adverse reaction leading to treatment interruption was neutropenia (50%). Adverse reaction leading to a dose reduction of TRODELVY occurred in 33% of patients. The most frequent (>5%) adverse reaction leading to dose reduction were neutropenia (16%) and diarrhea (8%). G-CSF was used in 54% of patients who received TRODELVY. Tables 6 and 7 summarize adverse reactions and laboratory abnormalities in the TROPiCS-02 study. Reference ID: 5484095 Table 6: Adverse Reactions in ≥ 10% of Patients with HR+/HER2- mBC in TROPiCS-02 TRODELVY (n=268) Single Agent Chemotherapy (n=249) Adverse Reaction All Grades % Grade 3 - 4 % All Grades % Grade 3 - 4 % Gastrointestinal disorders Diarrhea 62 10 23 1 Nausea 59 1 35 3 Constipation 34 1 25 0 Vomiting 23 1 16 2 Abdominal Pain 20 0 14 0 Dyspepsiai 11 0 6 0 General disorders and administration site conditions Fatigueii 60 8 51 4 Metabolism and nutrition disorders Decreased appetite 21 2 21 0 Hypokalemia 10 2 4 0 Musculoskeletal and connective tissue disorders Arthralgia 15 0 12 0 Nervous system disorders Headache 16 1 15 1 Respiratory, thoracic and mediastinal disorders Dyspnea iii 20 0 17 0 Cough 12 0 7 0 Skin and subcutaneous tissue disorders Alopecia 48 0 19 0 Pruritus 12 0 2 0 Single agent chemotherapy included one of the following single-agents: eribulin (n=130), vinorelbine (n=63), gemcitabine (n=56), or capecitabine (n=22). Graded per NCI CTCAE v.5.0. i.. Including dyspepsia, gastroesophageal reflux disease. ii. Including fatigue, asthenia. iii. Including dyspnea; exertional dyspnea Other clinically significant adverse reactions in TROPiCS-02 (≤ 10%) include: hypotension (5%), pain (5%), rhinorrhea (5%), hypocalcemia (3%), nasal congestion (3%), skin hyperpigmentation, (3%), colitis or neutropenic colitis (2%), hyponatremia (2%), pneumonia (2%), proteinuria (1%), enteritis (0.4%). Reference ID: 5484095 Table 7: Laboratory Abnormalities in > 10% of Patients with HR+/HER2- mBC in TROPiCS-02 Laboratory Abnormality TRODELVY (n=268) Single Agent Chemotherapy (n=249) All Grades (%) Grade 3 - 4 (%) All Grades (%) Grade 3 4 (%) Hematology Decreased leukocyte count 88 38 73 26 Decreased neutrophil count 83 53 67 40 Decreased hemoglobin 73 8 59 5 Decreased lymphocyte count 65 21 47 14 Decreased platelet count 21 1 30 4 Eosinophilia 13 0 4 0 Chemistry Increased glucose 37 0 31 0 Decreased albumin 32 0 27 0.4 Decreased creatinine clearance 24 2 19 1 Increased alkaline phosphatase 23 0 23 1 Decreased potassium 22 3 12 0.4 Increased alanine aminotransferase 21 1 31 2 Decreased sodium 19 1 17 0.4 Decreased magnesium 18 0 15 0 Decreased phosphate 17 0 10 0 Increased phosphate 16 0 16 0 Increased lactate dehydrogenase 16 0 28 0 Increased aspartate aminotransferase 15 2 25 1 Increased potassium 14 2 9 0 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on TRODELVY UGT1A1 Inhibitors Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38 [see Warning and Precaution (5.5) and Clinical Pharmacology (12.3, 12.5)]. Avoid administering UGT1A1 inhibitors with TRODELVY. UGT1A1 Inducers Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers [see Warning and Precaution (5.5) and Clinical Pharmacology (12.3, 12.5)]. Avoid administering UGT1A1 inducers with TRODELVY. Reference ID: 5484095 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. TRODELVY contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. Data Animal data There were no reproductive and developmental toxicology studies conducted with sacituzumab govitecan-hziy. 8.2 Lactation Risk Summary There is no information regarding the presence of sacituzumab govitecan-hziy or SN-38 in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of TRODELVY. Contraception Females TRODELVY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Males Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose. Infertility Females Based on findings in animals, TRODELVY may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness of TRODELVY have not been established in pediatric patients. Reference ID: 5484095 8.5 Geriatric Use Of the 366 patients with TNBC who were treated with TRODELVY, 19% of patients were 65 years and 3% were 75 years and older. No overall differences in safety and effectiveness were observed between patients ≥ 65 years of age and younger patients. Of the 322 patients with HR+/HER2- breast cancer who were treated with TRODELVY, 26% of patients were 65 years and older and 6% were 75 years and older. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger patients. There was a higher discontinuation rate due to adverse reactions in patients aged 65 years or older (14%) compared with younger patients (3%). 8.6 Hepatic Impairment No adjustment to the starting dosage is required when administering TRODELVY to patients with mild hepatic impairment [see Clinical Pharmacology (12.3)]. The safety of TRODELVY in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × upper limit of normal [ULN]) hepatic impairment has not been established. TRODELVY has not been tested in patients with AST or ALT > 3 ULN without liver metastases, or AST or ALT > 5 ULN with liver metastases. No recommendations can be made for the starting dosage in these patients. 10 OVERDOSAGE In a clinical trial, planned doses of up to 18 mg/kg (approximately 1.8 times the maximum recommended dose of 10 mg/kg) of TRODELVY were administered. In these patients, a higher incidence of severe neutropenia was observed. 11 DESCRIPTION Sacituzumab govitecan-hziy is a Trop-2 directed antibody and topoisomerase inhibitor conjugate, composed of the following three components: • the humanized monoclonal antibody, hRS7 IgG1κ (also called sacituzumab), which binds to Trop-2 (the trophoblast cell-surface antigen-2); • the drug SN-38, a topoisomerase inhibitor; • a hydrolysable linker (called CL2A), which links the humanized monoclonal antibody to SN-38. The recombinant monoclonal antibody is produced by mammalian (murine myeloma) cells, while the small molecule components SN-38 and CL2A are produced by chemical synthesis. Sacituzumab govitecan-hziy contains on average 7 to 8 molecules of SN-38 per antibody molecule. Sacituzumab govitecan-hziy has a molecular weight of approximately 160 kilodaltons. Sacituzumab govitecan-hziy has the following chemical structure. Reference ID: 5484095 n Where n~7.6 SN-38/Mab hRS7 lgGk (antibody) 0 Link r TRODELVY (sacituzumab govitecan-hziy) for injection is a sterile, preservative-free, off-white to yellowish lyophilized powder for intravenous use in a 50 mL clear glass single-dose vial, with a rubber stopper and crimp-sealed with an aluminum flip-off cap. Each single-dose vial of TRODELVY delivers 180 mg sacituzumab govitecan-hziy, 71.7 mg 2-(N-morpholino) ethane sulfonic acid (MES), 1.8 mg polysorbate 80 and 153.99 mg trehalose. Reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP, results in a concentration of 10 mg/mL with a pH of 6.5. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sacituzumab govitecan-hziy is a Trop-2-directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker. Pharmacology data suggest that sacituzumab govitecan-hziy binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death. Sacituzumab govitecan-hziy decreased tumor growth in mouse xenograft models of triple-negative breast cancer. 12.2 Pharmacodynamics The TRODELVY exposure-response relationships and pharmacodynamic time course for efficacy have not been fully characterized. Cardiac electrophysiology The maximum mean change from baseline was 9.7 msec (the upper bound of the two-sided 90% confidence interval is 16.8 msec) at the recommended dose. A positive exposure-response relationship was observed between QTc increases and SN-38 concentrations. Reference ID: 5484095 12.3 Pharmacokinetics The serum pharmacokinetics of sacituzumab govitecan-hziy and SN-38 were evaluated in patients with mBC who received sacituzumab govitecan-hziy as a single agent at a dose of 10 mg/kg. The pharmacokinetic parameters of sacituzumab govitecan-hziy and free SN-38 are presented in Table 8. Table 8: Summary of Mean PK Parameters (CV%) of Sacituzumab Govitecan-hziy and Free SN-38 Sacituzumab govitecan-hziy (N=693) Free SN-38 (N=681) Cmax [ng/mL] 239000 (11%) 98.0 (45%) AUC0-168 [ngh/mL] 5640000 (22%) 3696 (56%) Parameters estimated based on population PK analyses Cmax: maximum serum concentration from 0-168 hours after the first dose AUC0-168: area under serum concentration curve through 168 hours after the first dose Distribution Based on population pharmacokinetic analysis, steady state volume of distribution of sacituzumab govetican-hziy is 3.6L. Elimination The median elimination half-life (t1/2) of sacituzumab govitecan-hziy and free SN-38 in patients with metastatic triple negative breast cancer was 23.4 and 17.6 hours, respectively. Based on population pharmacokinetic analysis, the estimated mean (%CV) clearance of the sacituzumab govitecan-hziy is 0.13 L/h (12%). Metabolism No metabolism studies with sacituzumab govitecan-hziy have been conducted. SN-38 (the small molecule moiety of sacituzumab govitecan-hziy) is metabolized via UGT1A1. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients. Specific Populations Pharmacokinetic analyses in patients treated with TRODELVY did not identify an effect of age (27 to 88 years), race (White, Black, or Asian), or mild renal impairment to moderate renal impairment (CLcr 30 to 89 mL/min) on the pharmacokinetics of sacituzumab govitecan-hziy. Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan-hziy. There are no data on the pharmacokinetics of sacituzumab govitecan-hziy in patients with severe renal impairment (CLcr 15 to 29 mL/min), or end-stage renal disease (CLcr < 15 mL/min). Patients with Hepatic Impairment The exposure of sacituzumab govitecan-hziy is similar in patients with mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or bilirubin >1.0 to ≤ 1.5 ULN with any AST; n=257) to patients with normal hepatic function (total bilirubin or AST < ULN; n=526). Sacituzumab govitecan-hziy and free SN-38 exposures are unknown in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × ULN) hepatic impairment. Drug Interaction Studies No drug-drug interaction studies were conducted with sacituzumab govitecan-hziy or its components. Inhibitors or inducers of UGT1A1 may increase or decrease SN-38 exposure, respectively [see Drug Interactions (7)]. Reference ID: 5484095 12.5 Pharmacogenomics SN-38 is metabolized via UGT1A1 [see Clinical Pharmacology (12.3)]. Genetic variants of the UGT1A1 gene such as the UGT1A128 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous or heterozygous for the UGT1A128 allele are at increased risk for neutropenia, febrile neutropenia, and anemia from TRODELVY compared to individuals who are wildtype (1/1) [see Warnings and Precautions (5.5)]. Approximately 20% of the Black or African American population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A128 allele (28/28). Approximately 40% of the Black or African American population, 50% of the White population, and 25% of the East Asian population are heterozygous for the UGT1A128 allele (1/28). Decreased function alleles other than UGT1A128 may be present in certain populations. 12.6 Immunogenicity The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of TRODELVY. During the median 4-month treatment period across clinical studies in patients treated with TRODELVY, 9 (1.1%) of 785 patients developed antibodies to sacituzumab govitecan; 6 of these patients (0.8% of all patients treated with TRODELVY) had neutralizing antibodies against sacituzumab govitecan. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of sacituzumab govitecan is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with sacituzumab govitecan-hziy. SN-38 was clastogenic in an in vitro mammalian cell micronucleus test in Chinese hamster ovary cells and was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Fertility studies with sacituzumab govitecan-hziy have not been conducted. In a repeat-dose toxicity study in cynomolgus monkeys, intravenous administration of sacituzumab govitecan-hziy on Day 1 and Day 4 resulted in endometrial atrophy, uterine hemorrhage, increased follicular atresia of the ovary, and atrophy of vaginal epithelial cells at doses ≥ 60 mg/kg (≥6 times the human recommended dose of 10 mg/kg based on body weight). 14 CLINICAL STUDIES 14.1 Locally Advanced or Metastatic Triple-Negative Breast Cancer ASCENT Efficacy was evaluated in a multicenter, open-label, randomized study (ASCENT; NCT02574455) conducted in 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior chemotherapies for breast cancer (one of which could be in the neoadjuvant or adjuvant setting provided progression occurred within a 12 month period). All patients received previous taxane treatment in either the adjuvant, neoadjuvant, or advanced stage unless there was a contraindication or intolerance to taxanes during or at the end of the first taxane cycle. Magnetic resonance imaging (MRI) to determine brain metastases was required prior to enrollment for patients with known or suspected brain metastases. Patients with brain metastases were allowed to enroll up to a pre defined maximum of 15% of patients in the ASCENT study. Patients with known Gilbert’s disease or bone-only disease were excluded. Reference ID: 5484095 Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21-day (n=267) or physician’s choice of single agent chemotherapy (n=262). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (n=52). Patients were treated until disease progression or unacceptable toxicity. The major efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline (i.e., BMNeg) as measured by a blinded, independent, centralized review assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS). The median age of patients in the full population (n = 529) was 54 years (range: 27 to 82 years); 99.6% were female; 79% were White, 12% were Black/African American; and 81% of patients were < 65 years of age. All patients had an ECOG performance status of 0 (43%) or 1 (57%). Forty-two percent of patients had hepatic metastases, 9% were BRCA1/BRCA2 mutational status positive, and 70% were TNBC at diagnosis. Twelve percent had baseline brain metastases previously treated and stable (n=61; 32 on TRODELVY arm and 29 on single agent chemotherapy arm). Overall, 29% of patients had received prior PD-1/PD-L1 therapy. Thirteen percent of patients in the TRODELVY group in the full population received only 1 prior line of systemic therapy in the metastatic setting. The efficacy results are summarized in Table 9 and are shown in Figure 1 and Figure 2. Efficacy results for the subgroup of patients who had received only 1 prior line of systemic therapy in the metastatic setting (in addition to having disease recurrence or progression within 12 months of neoadjuvant/adjuvant systemic therapy) were consistent with those who had received at least two prior lines in the metastatic setting. Table 9: Efficacy Results from ASCENT All Randomized Patients TRODELVY n=267 Single Agent Chemotherapy n=262 Progression-Free Survival1 per BICR Disease Progression or Death (%) 190 (71%) 171 (65%) Median PFS in months (95% CI) 4.8 (4.1, 5.8) 1.7 (1.5, 2.5) Hazard ratio2 (95% CI) 0.43 (0.35, 0.54) p-value <0.0001 Overall Survival Deaths (%) 179 (67%) 206 (79%) Median OS in months (95% CI) 11.8 (10.5, 13.8) 6.9 (5.9, 7.6) Hazard ratio2 (95% CI) 0.51 (0.41, 0.62) p-value <0.0001 1 PFS is defined as the time from the date of randomization to the date of the first radiological disease progression or death due to any cause, whichever comes first. 2 Stratified log-rank test adjusted for stratification factors: number of prior chemotherapies, presence of known brain metastases at study entry, and region. CI = Confidence Interval Reference ID: 5484095 100 80 - :,!! ~ Cl) LL 60 a. 0 ~ :c 40 ra .0 0 ... a. 20 0 0 -\ I t t \ ~-\ I ~ '--.. - Trodelvy .._ - - Chemotherapy•---~- •- - + Censored "'"----+--,._+-++----------------• •+ 3 6 9 12 15 Time (months) Number of patients at risk 18 Trodelvy 267 251 184 145 135 110 82 64 55 38 34 25 23 17 16 14 9 8 8 5 Chemotherapy 262 199 87 41 37 23 13 9 7 6 4 2 2 2 2 0 0 O 0 100 80 - :,!! ~ Cl) 0 60 0 ~ :c 40 ra .0 0 .. a. 20 - Trodelvy -- Chemotherapy + Censored 0 0 3 6 9 12 15 Time (months) Number of patients at risk 18 21 3 1 0 0 21 0 0 24 24 Trodelvy 267 260 250 242 232 219 208 189 174 164 145 127 116 109 98 76 56 46 39 31 21 13 8 1 0 0 Chemotherapy 262 239 222 192 174 150 132 113 97 84 64 58 52 46 42 34 24 17 14 9 6 5 3 2 0 27 Figure 1: Kaplan-Meier Plot of PFS by BICR (All Randomized Patients) in ASCENT Figure 2: Kaplan-Meier Plot of OS (All Randomized Patients) in ASCENT An exploratory analysis of PFS in patients with previously treated, stable brain metastases showed a stratified HR of 0.65 (95% CI: 0.35, 1.22). The median PFS in the TRODELVY arm was 2.8 months (95% CI: 1.5, 3.9) and the median PFS with single agent chemotherapy was 1.6 months (95% CI: 1.3, 2.9). Exploratory OS analysis in the same population Reference ID: 5484095 showed a stratified HR of 0.87 (95% CI: 0.47, 1.63). The median OS in the TRODELVY arm was 6.8 months (95% CI: 4.7, 14.1) and the median OS with single agent chemotherapy was 7.4 months (95% CI: 4.7, 11.1). IMMU-132-01 The efficacy of TRODELVY was evaluated in a multicenter, single-arm, study (NCT01631552) that enrolled 108 patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior anticancer therapies for metastatic disease. Patients with bulky disease, defined as a mass >7 cm, were not eligible. Patients with treated brain metastases not receiving high dose steroids (> 20 mg prednisone or equivalent) for at least four weeks were eligible. Patients with known Gilbert’s disease were excluded. Patients received TRODELVY 10 mg/kg intravenously on Days 1 and 8 of a 21-day treatment cycle. Patients were treated with TRODELVY until disease progression or intolerance to the therapy. Tumor imaging was obtained every 8 weeks, with confirmatory CT/MRI scans obtained 4-6 weeks after an initial partial or complete response, until progression requiring treatment discontinuation. Major efficacy outcome measures were investigator assessed overall response rate (ORR) using RECIST 1.1 and duration of response. The median age was 55 years (range: 31 to 80 years); 87% of patients were younger than 65 years. The majority of patients were female (99%) and White (76%). At study entry, all patients had an ECOG performance status of 0 (29%) or 1 (71%). Seventy-six percent had visceral disease, 42% had hepatic metastases, 56% had lung/pleura metastases, and 2% had brain metastases. Twelve patients (11%) had Stage IV disease at the time of initial diagnosis. The median number of prior systemic therapies received in the metastatic setting was 3 (range: 2 to 10). Prior chemotherapies in the metastatic setting included carboplatin or cisplatin (69%), gemcitabine (55%), paclitaxel or docetaxel (53%), capecitabine (51%), eribulin (45%), doxorubicin (24%), vinorelbine (16%), cyclophosphamide (19%), and ixabepilone (8%). Overall, 98% of patients had received prior taxanes and 86% had received prior anthracyclines either in the (neo)adjuvant or metastatic setting. Table 10 summarizes the efficacy results. Table 10: Efficacy results for patients with mTNBC in IMMU-132-01 TRODELVY (N=108) Overall Response Rate i ORR (95% CI) 33.3% (24.6, 43.1) Complete response 2.8% Partial response 30.6% Response duration i Number of responders 36 Median, Months (95% CI) 7.7 (4.9, 10.8) Range, Months 1.9+, 30.4+ % with duration ≥6 months 55.6% % with duration ≥12 months 16.7% i investigator assessment CI: confidence interval +: denotes ongoing Reference ID: 5484095 14.2 Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer TROPiCS-02 Study The efficacy of TRODELVY was evaluated in a multicenter, open label, randomized study (TROPiCS-02; NCT03901339) conducted in 543 patients with unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer whose disease has progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and a taxane; patients received at least two prior chemotherapies in the metastatic setting (one of which could be in the neoadjuvant or adjuvant setting if recurrence occurred within 12 months). Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21 day cycle (n=272) or single agent chemotherapy (n=271). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=130), vinorelbine (n=63), gemcitabine (n=56), or capecitabine (n=22). Randomization was stratified by the following factors: prior chemotherapy regimens for metastatic disease (2 vs. 3-4), visceral metastasis (Yes or No), and endocrine therapy in the metastatic setting for at least 6 months (Yes or No). Patients were treated until disease progression or unacceptable toxicity. Administration of TRODELVY was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. The primary efficacy outcome measure was PFS as determined by BICR per RECIST v1.1. Additional efficacy measures included OS, ORR by BICR, and DOR by BICR. The median age of patients in the study population was 56 years (range: 27–86 years), 26% of patients were 65 years or over. The majority of patients were female (99%); 67% were White, 4% were Black and 3% were Asian, and 26% were of unknown race. Patients received a median of 7 (range: 3 to 17) prior systemic regimens in any setting and 3 (range: 0 to 8) prior systemic chemotherapy regimens in the metastatic setting. Approximately 42% of patients had 2 prior chemotherapy regimens for treatment of metastatic disease compared to 58% of patients who had 3 to 4 prior chemotherapy regimens and all patients had an ECOG performance status of 0 (45%) or 1 (55%). Ninety-five percent of patients had visceral metastases. Most patients received endocrine therapy in the metastatic setting for ≥ 6 months (86%). TRODELVY demonstrated a statistically significant improvement in PFS and OS versus single agent chemotherapy. The efficacy results are summarized in Table 11 and Figure 3 and Figure 4. Table 11: Efficacy Results from TROPiCS-02 All Randomized Patients TRODELVY n=272 Single Agent Chemotherapy n=271 Progression-Free Survival by BICR1 Median PFS in months (95% CI) 5.5 (4.2, 7.0) 4.0 (3.1, 4.4) Hazard ratio (95% CI) 0.661 (0.529, 0.826) p-value2 0.0003 Overall Survival3 Median OS in months (95% CI) 14.4 (13.0, 15.7) 11.2 (10.1, 12.7) Hazard ratio (95% CI) 0.789 (0.646, 0.964) p-value2 0.0200 Objective Response Rate3 by BICR Reference ID: 5484095 100 90 l .~ 80 :c .2l 70 2 n. 60 <ii .2!: 2:: 50 ::, en ~ 40 u.. C: 30 0 .iii Kl 20 a, 0 a: 10 - TrodeJvy - - - Chemotherapy + Censored 0 0 3 Number of patients at risk T rode Ivy 'l12 , 4S Chemotherapy m HIS 6 82 41 9 44 17 12 Time (months) 22 4 15 12 1 I I 18 6 1 21 3 0 24 0 0 Response Rate, % (95% CI) 21.0 (16.3, 26.3) 14.0 (10.1, 18.7) Odds ratio (95% CI) 1.625 (1.034, 2.555) p-value 0.0348 Duration of Response3 (DOR) by BICR Median DOR in months (95% CI) 8.1 (6.7, 9.1) 5.6 (3.8, 7.9) 1 PFS is defined as the time from the date of randomization to the date of the first radiological disease progression or death due to any cause, whichever comes first. 2 Stratified log-rank test adjusted for stratification factors: prior chemotherapy regimens for metastatic disease (2 vs. 3-4), visceral metastasis (Y/N), and endocrine therapy in the metastatic setting for at least 6 months (Yes or No). BICR = Blinded Independent Central Review; CI = Confidence Interval 3 Second interim OS analysis (conducted when 390 OS events were observed) Figure 3: Kaplan-Meier Plot of PFS by BICR in TROPiCS-02 Reference ID: 5484095 100 90 --- 80 ~ ' g 70 15 --8 60 ..... ........... .... ., e a.. ~ 50 -~ 40 ::, V) ~ 30 '1J 6 20 Trodclvy 10 Chemotherapy + Censored 0 0 3 6 9 Number uf palienls al risk Trodelvy 272 252 221 1$7 Chemotherapy 271 246 196 164 '\. ... '..... .... ~ 12 160 122 15 120 92 18 21 Time (months) 80 53 "10 49 --; -+- 24 27 30 33 36 31 20 4 2 0 Z3 13 5 0 Figure 4: Kaplan-Meier Plot of OS in TROPiCS-02 15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. 16 HOW SUPPLIED/STORAGE AND HANDLING TRODELVY (sacituzumab govitecan-hziy) for injection is a sterile, off-white to yellowish lyophilized powder in a single- dose vial. Each TRODELVY vial is individually boxed in a carton: • NDC 55135-132-01 contains one 180 mg vial Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of reconstitution. Do not freeze. TRODELVY is a hazardous drug. Follow applicable special handling and disposal procedures1. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Neutropenia Advise patients of the risk of neutropenia. Instruct patients to immediately contact their healthcare provider if they experience fever, chills, or other signs of infection [see Warnings and Precautions (5.1)]. Reference ID: 5484095 Diarrhea Advise patients of the risk of diarrhea. Instruct patients to immediately contact their healthcare provider if they experience diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours [see Warnings and Precautions (5.2)]. Hypersensitivity and Infusion-Related Reactions Inform patients of the risk of serious infusion reactions and anaphylaxis. Instruct patients to immediately contact their healthcare provider if they experience facial, lip, tongue, or throat swelling, urticaria, difficulty breathing, lightheadedness, dizziness, chills, rigors, wheezing, pruritus, flushing, rash, hypotension, or fever that occur during or within 24 hours following the infusion [see Warnings and Precautions (5.3)]. Nausea/Vomiting Advise patients of the risk of nausea and vomiting. Premedication according to established guidelines with a two or three drug regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) is also recommended. Additional antiemetics, sedatives, and other supportive measures may also be employed as clinically indicated. All patients should receive take-home medications for preventing and treating delayed nausea and vomiting, with clear instructions. Instruct patients to immediately contact their healthcare provider if they experience uncontrolled nausea or vomiting [see Warnings and Precautions (5.4)]. Embryo-Fetal Toxicity Advise female patients to contact their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Contraception Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of TRODELVY [see Use in Specific Populations (8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of TRODELVY [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY [see Use in Specific Populations (8.2)]. Infertility Advise females of reproductive potential that TRODELVY may impair fertility [see Use in Specific Populations (8.3)]. Manufactured by: Gilead Sciences, Inc. 333 Lakeside Dr. Foster City, CA 94404, USA U.S. License No. 2258 Reference ID: 5484095 Patient Information TRODELVY® (troh-DELL-vee) (sacituzumab govitecan-hziy) for injection, for intravenous use What is the most important information I should know about TRODELVY? TRODELVY can cause serious side effects, including: • Low white blood cell count (neutropenia). Low white blood cell counts are common with TRODELVY and can sometimes be severe and lead to infections that can be life-threatening or cause death. Your healthcare provider should check your blood cell counts during treatment with TRODELVY. If your white blood cell count is too low, your healthcare provider may need to lower your dose of TRODELVY, give you a medicine to help prevent low blood cell count with future doses of TRODELVY, or in some cases may stop TRODELVY. Your healthcare provider may need to give you antibiotic medicines if you develop fever while your white blood cell count is low. Call your healthcare provider right away if you develop any of the following signs of infection during treatment with TRODELVY: o fever o shortness of breath o chills o burning or pain when you urinate o cough • Severe diarrhea. Diarrhea is common with TRODELVY and can also be severe. Severe diarrhea can lead to loss of too much body fluid (dehydration) and kidney problems. Your healthcare provider should monitor you for diarrhea and give you medicine as needed to help control your diarrhea. If you lose too much body fluid, your healthcare provider may need to give you fluids and electrolytes to replace body salts. If you develop diarrhea during treatment with TRODELVY, your healthcare provider should check to see if diarrhea may be caused by an infection. Your healthcare provider may decrease your dose or stop TRODELVY if your diarrhea is severe and cannot be controlled with anti-diarrheal medicines. Call your healthcare provider right away: o the first time that you get diarrhea during treatment with TRODELVY o if you have black or bloody stools o if you have symptoms of losing too much body fluid and body salts, such as lightheadedness, dizziness or faintness o if you are unable to take fluids by mouth due to nausea or vomiting o if you are not able to get your diarrhea under control within 24 hours What is TRODELVY? TRODELVY is a prescription medicine used to treat adults with: • a type of breast cancer called triple-negative breast cancer (TNBC), which is estrogen and progesterone hormone receptor (HR)-negative and human epidermal growth factor receptor 2 (HER2)-negative. TRODELVY may be used: o when your breast cancer has spread to other parts of the body (metastatic) or cannot be removed by surgery, and o if you previously received two or more prior treatments, including at least one treatment for metastatic disease. • a type of breast cancer that is HR-positive and HER2-negative. TRODELVY may be used: o when your breast cancer has spread to other parts of the body or cannot be removed by surgery, and if you previously received endocrine therapy and at least two additional treatments for metastatic disease. It is not known if TRODELVY is safe and effective in people with moderate or severe liver problems. It is not known if TRODELVY is safe and effective in children. Do not receive TRODELVY if you have had a severe allergic reaction to TRODELVY. Ask your healthcare provider if you are not sure. Reference ID: 5484095 Before receiving TRODELVY, tell your healthcare provider about all of your medical conditions, including if you: • have been told that you carry a gene for uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)28. People who carry this gene have an increased risk of getting side effects with TRODELVY, especially low white blood cell counts, a fever while your white blood cell count is low, and low red blood cell counts. See “What is the most important information I should know about TRODELVY?” • have liver problems. • are pregnant or plan to become pregnant. TRODELVY can harm your unborn baby. Your healthcare provider should check to see if you are pregnant before you start receiving TRODELVY. o Females who can become pregnant should use effective birth control during treatment and for 6 months after your last dose of TRODELVY. Talk to your healthcare provider about birth control choices that may be right for you during this time. Tell your healthcare provider right away if you become pregnant during treatment with TRODELVY. o Males with a female partner who can become pregnant should use effective birth control during treatment and for 3 months after your last dose of TRODELVY. • are breastfeeding or plan to breastfeed. It is not known if TRODELVY passes into your breastmilk and can harm your baby. Do not breastfeed during treatment and for 1 month after your last dose of TRODELVY. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain medicines may affect the way TRODELVY works. How will I receive TRODELVY? • Your healthcare provider will give you TRODELVY into your vein through an intravenous (IV) line. • TRODELVY is given 1 time each week, on Day 1 and on Day 8 of a 21-day treatment cycle. • You will receive the first dose of TRODELVY over 3 hours. If you tolerate the first dose well, future doses may be given over 1 to 2 hours. • Before each dose of TRODELVY, you will receive medicines to help prevent infusion-related reactions, and nausea and vomiting. • You will be monitored for side effects during and for at least 30 minutes after you receive each infusion of TRODELVY. • Your healthcare provider may slow down or temporarily stop your infusion of TRODELVY if you have an infusion- related reaction, or permanently stop TRODELVY if you have a life-threatening infusion-related reaction. • Your healthcare provider will decide how long you will continue to receive TRODELVY. What are the possible side effects of TRODELVY? TRODELVY can cause serious side effects, including: • See “What is the most important information I should know about TRODELVY?” • Allergic and infusion-related reactions. Serious allergic reactions can happen during treatment with TRODELVY, including life-threatening allergic reactions, and infusion-related reactions. Tell your healthcare provider or nurse right away if you get any of the following symptoms of an allergic or infusion-related reaction during your infusion of TRODELVY or within 24 hours after you receive a dose of TRODELVY: o swelling of your face, lips, tongue, or throat o difficulty breathing or wheezing o hives o lightheadedness, dizziness, feeling faint or pass out o skin rash, itching, or flushing of your skin o chills or shaking chills (rigors) o fever • Nausea and vomiting. Nausea and vomiting are common with TRODELVY and can sometimes be severe. Before each dose of TRODELVY, you will receive medicines to help prevent nausea and vomiting. You should be given medicines to take home with you, along with instructions about how to take them to help prevent and treat any nausea and vomiting after you receive TRODELVY. Call your healthcare provider right away if you have nausea or vomiting that is not controlled with the medicines prescribed for you. Your healthcare provider may decide to decrease your dose or stop TRODELVY if your nausea and vomiting is severe and cannot be controlled with anti- nausea medicines. Reference ID: 5484095 The most common side effects of TRODELVY include: • decreased white blood cell (leukocyte and • decreased appetite lymphocyte) and red blood cell counts • changes in kidney function test • feeling tired or weak • increased levels of enzyme called alkaline • hair loss phosphatase in the blood (test for liver or bone problems) • constipation • decreased levels of magnesium, potassium, and • increased sugar levels in the blood sodium in the blood • decreased protein levels (albumin) in the blood TRODELVY may cause fertility problems in females, which could affect your ability to have a baby. Talk to your healthcare provider if fertility is a concern for you. These are not all of the possible side effects of TRODELVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of TRODELVY. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about TRODELVY that is written for health professionals. What are the ingredients in TRODELVY? Active ingredient: sacituzumab govitecan-hziy Inactive ingredients: 2-(N-morpholino) ethane sulfonic acid (MES), polysorbate 80 and trehalose Manufactured by: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA U.S. License No. 2258 761115-GS-00X For more information about TRODELVY, go to www.TRODELVY.com or call 1-888-983-4668. The Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5484095	custom-source	2025-02-12T15:47:03.694569	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761115s058lbl.pdf', 'application_number': 761115, 'submission_type': 'SUPPL ', 'submission_number': 58}
80,342	I I ____________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VRAYLAR safely and effectively. See full prescribing information for VRAYLAR. VRAYLAR® (cariprazine) capsules, for oral use Initial U.S. Approval: 2015 WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. ○ Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis. (5.1) ○ Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Safety and effectiveness of VRAYLAR have not been established in pediatric patients (5.2, 8.4) ----------------------------RECENT MAJOR CHANGES--------------------------- Dosage and Administration (2.6) 11/2024 -------------------------------INDICATIONS AND USAGE-------------------------- VRAYLAR is an atypical antipsychotic indicated for: • Treatment of schizophrenia in adults (1) • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults (1) • Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults (1) • Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults (1) -------------------------DOSAGE AND ADMINISTRATION---------------------- • Administer VRAYLAR orally once daily with or without food (2) Starting Dose Recommended Dose Schizophrenia (2.2) 1.5 mg daily 1.5 mg to 6 mg daily Bipolar Mania (2.3) 1.5 mg daily 3 mg to 6 mg daily Bipolar Depression (2.4) 1.5 mg daily 1.5 mg or 3 mg daily Adjunctive therapy to antidepressants for MDD (2.5) 1.5 mg daily 1.5 mg or 3 mg daily • Schizophrenia and Bipolar Mania: Maximum recommended daily dosage is 6 mg. Dosages above 6 mg daily do not confer significant benefit, but increase the risk of dose-related adverse reactions (2.2, 2.3) • Bipolar Depression: Maximum recommended daily dosage is 3 mg (2.4) • Adjunctive therapy for treatment of MDD: Maximum recommended daily dosage is 3 mg (2.5) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg (3) -------------------------------CONTRAINDICATIONS-------------------------- • Known hypersensitivity to VRAYLAR (4) -----------------------WARNINGS AND PRECAUTIONS--------------------- • Cerebrovascular Adverse Reactions in Elderly Patients with Dementia- Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) (5.3) • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4) • Tardive Dyskinesia: Discontinue if appropriate (5.5) • Late-Occurring Adverse Reactions: Because of VRAYLAR’s long half- life, monitor for adverse reactions and patient response for several weeks after starting VRAYLAR and with each dosage change (5.6) • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain (5.7) • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell counts (WBC) or history of leukopenia or neutropenia. Consider discontinuing VRAYLAR if a clinically significant decline in WBC occurs in absence of other causative factors (5.8) • Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.9) • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.11) • Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.12) ----------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) were (6.1): • Schizophrenia: extrapyramidal symptoms and akathisia • Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness • Bipolar depression: nausea, akathisia, restlessness, and extrapyramidal symptoms • Adjunctive treatment of MDD: akathisia, restlessness, fatigue, constipation, nausea, insomnia, increased appetite, dizziness, and extrapyramidal symptoms To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------DRUG INTERACTIONS------------------------------ • Strong and Moderate CYP3A4 inhibitors: Reduce VRAYLAR dosage(2.6, 7) • CYP3A4 inducers: Concomitant use is not recommended (2.6, 7) ----------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnancy: Based on animal data, may cause fetal harm. (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 11/2024 Reference ID: 5484584 ____________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information 2.2 Recommended Dosage in Schizophrenia 2.3 Recommended Dosage in Manic or Mixed Episodes Associated with Bipolar I Disorder 2.4 Recommended Dosage in Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) 2.5 Recommended Dosage for Adjunctive Therapy to Antidepressants for the Treatment of Major Depressive Disorder 2.6 Dosage Modifications for CYP3A4 Inhibitors and Inducers 2.7 Treatment Discontinuation 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis 5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults 5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis 5.4 Neuroleptic Malignant Syndrome (NMS) 5.5 Tardive Dyskinesia 5.6 Late-Occurring Adverse Reactions 5.7 Metabolic Changes 5.8 Leukopenia, Neutropenia, and Agranulocytosis 5.9 Orthostatic Hypotension and Syncope 5.10 Falls 5.11 Seizures 5.12 Potential for Cognitive and Motor Impairment 5.13 Body Temperature Dysregulation 5.14 Dysphagia 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Smoking 8.9 Other Specific Populations 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Human Experience 10.2 Management of Overdosage 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Schizophrenia 14.2 Manic or Mixed Episodes Associated with Bipolar I Disorder 14.3 Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) 14.4 Adjunctive Treatment of Major Depressive Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5484584 FULL PRESCRIBING INFORMATION WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for the treatment of patients with dementia- related psychosis [see Warnings and Precautions (5.1)]. Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for the emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.2)]. The safety and effectiveness of VRAYLAR have not been established in pediatric patients [see Use in Specific Populations (8.4)]. 1. INDICATIONS AND USAGE VRAYLAR® is indicated for: • Treatment of schizophrenia in adults [see Clinical Studies (14.1)] • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults [see Clinical Studies (14.2)] • Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults [see Clinical Studies (14.3)] • Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14.4)] 2. DOSAGE AND ADMINISTRATION 2.1 General Dosing Information VRAYLAR is given orally once daily and can be taken with or without food. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Prescribers should monitor patients for adverse reactions and treatment response for several weeks after starting VRAYLAR and after each dosage change [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 2.2 Recommended Dosage in Schizophrenia The starting dosage of VRAYLAR is 1.5 mg orally once daily. The recommended dosage range is 1.5 mg to 6 mg orally once daily. The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg orally once daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [see Adverse Reactions (6.1), Clinical Studies (14.1)]. Reference ID: 5484584 2.3 Recommended Dosage in Manic or Mixed Episodes Associated with Bipolar I Disorder The starting dosage of VRAYLAR is 1.5 mg orally once daily. Increase the dosage to 3 mg orally once daily on Day 2. The recommended dosage range is 3 mg to 6 mg orally once daily. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg orally once daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [see Adverse Reactions (6.1), Clinical Studies (14.2)]. 2.4 Recommended Dosage in Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) The starting dosage of VRAYLAR is 1.5 mg orally once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg orally once daily on Day 15. Maximum recommended dosage is 3 mg orally once daily. 2.5 Recommended Dosage for Adjunctive Therapy to Antidepressants for the Treatment of Major Depressive Disorder The starting dosage of VRAYLAR is 1.5 mg orally once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg orally once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions [see Adverse Reactions (6.1)]. Maximum recommended dosage is 3 mg orally once daily. 2.6 Dosage Modifications for CYP3A4 Inhibitors and Inducers Initiating VRAYLAR While Taking a Strong or Moderate CYP3A4 Inhibitor Dosage modifications for the starting dosage of VRAYLAR in patients taking a strong or moderate CYP3A4 inhibitor are presented in Table 1: Table 1: Dosage Modifications for the Starting Dosage of VRAYLAR in Patients Taking a Strong or Moderate CYP3A4 Inhibitor VRAYLAR Starting Dosage When Taking a Strong CYP3A4 Inhibitor When Taking a Moderate CYP3A4 Inhibitor Schizophrenia Start at 1.5 mg orally every 3 days; increase to 1.5 mg orally every other day, if needed Start at 1.5 mg orally every other day; increase to 1.5 mg orally daily, if needed* Bipolar Mania Bipolar Depression 1.5 mg orally every 3 days 1.5 mg orally every other day Adjunctive therapy for treatment of MDD Depending upon clinical response and tolerability. Reference ID: 5484584 Initiating a Strong or Moderate CYP3A4 Inhibitor While Taking a Stable Dosage of VRAYLAR Dosage recommendations for patients initiating a strong or moderate CYP3A4 inhibitor while on a stable dose of VRAYLAR (see Table 2):e: Table 2: Dosage Modifications for VRAYLAR When Initiating a Strong or Moderate CYP3A4 Inhibitor and While Taking a Stable Dose of VRAYLAR Currently on VRAYLAR Dosage VRAYLAR Dosage When Initiating a Strong CYP3A4 Inhibitor VRAYLAR Dosage When Initiating a Moderate CYP3A4 Inhibitor 1.5 or 3 mg once daily 1.5 mg orally every 3 days 1.5 mg orally every other day 4.5 or 6 mg once daily 1.5 mg orally every other day 1.5 mg orally once daily When the strong or moderate CYP3A4 inhibitor is discontinued, the VRAYLAR dosage may need to be increased based on clinical response and tolerability [see Drug Interactions (7)]. Dosage Modifications for Patients Concomitantly Taking VRAYLAR with CYP3A4 Inducers Concomitant use of VRAYLAR and a CYP3A4 inducer has not been evaluated and is not recommended [see Dosage and Administration (2.1), Warnings and Precautions (5.6), Drug Interactions (7), Clinical Pharmacology (12.3)]. 2.7 Treatment Discontinuation Following discontinuation of VRAYLAR, the decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients’ clinical symptoms; the plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week [see Clinical Pharmacology (12.3)]. There are no systematically collected data to specifically address switching patients from VRAYLAR to other antipsychotics or concerning concomitant administration with other antipsychotics. 3. DOSAGE FORMS AND STRENGTHS VRAYLAR (cariprazine) capsules are available in four strengths. • 1.5 mg capsules: White cap and body imprinted with “FL 1.5” • 3 mg capsules: Green to blue-green cap and white body imprinted with “FL 3” • 4.5 mg capsules: Green to blue-green cap and body imprinted with “FL 4.5” • 6 mg capsules: Purple cap and white body imprinted with “FL 6” 4. CONTRAINDICATIONS VRAYLAR is contraindicated in patients with history of a hypersensitivity reaction to cariprazine. Reactions have ranged from rash, pruritus, urticaria, and reactions suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face). 5. WARNINGS AND PRECAUTIONS 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and Reference ID: 5484584 largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo- treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3)]. 5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 3. Table 3: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥65 years old 6 fewer patients * VRAYLAR is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo- controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing VRAYLAR, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal Reference ID: 5484584 stroke. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)]. 5.4 Neuroleptic Malignant Syndrome (NMS) Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue VRAYLAR and provide intensive symptomatic treatment and monitoring. 5.5 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including VRAYLAR. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, VRAYLAR should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on VRAYLAR, drug discontinuation should be considered. However, some patients may require treatment with VRAYLAR despite the presence of the syndrome. 5.6 Late-Occurring Adverse Reactions Adverse reactions may first appear several weeks after the initiation of VRAYLAR treatment, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures [see Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3)]. Monitor for adverse reactions, including extrapyramidal symptoms (EPS) or akathisia, and patient response for several weeks after a patient has begun VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug. Reference ID: 5484584 5.7 Metabolic Changes Atypical antipsychotic drugs, including VRAYLAR, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. There have been reports of hyperglycemia in patients treated with VRAYLAR. Although all drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment. Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with VRAYLAR and placebo. In the long-term, open- label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%). Bipolar Disorder In six placebo-controlled trials up to 8-weeks of adult patients with bipolar disorder (mania or depression), the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with VRAYLAR and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%). Adjunctive Treatment of Major Depressive Disorder In two 6-week placebo-controlled trials of adult patients with major depressive disorder, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) was greatest in the VRAYLAR 3 mg per day + antidepressant therapy arm (3.2%) compared with those taking VRAYLAR 1.5 mg per day + antidepressant therapy (2%) or those placebo-treated (1.3%). The proportion of patients with shifts from normal to borderline (≥100 and <126 mg/dL) or from borderline to high were similar in patients treated with VRAYLAR and placebo. In a long-term, open-label adjunctive treatment of MDD study, 7% patients with normal hemoglobin A1c baseline values developed elevated levels (> 6%). In one 8-week placebo-controlled trial of adult patients with major depressive disorder, the changes from baseline to end of the trial in fasting glucose were similar among the VRAYLAR and placebo + antidepressant therapy treatment groups. During the 8-week trial, serum insulin levels increased by 12 pmol/L in the VRAYLAR 1 mg to 2 mg per day group, 20 pmol/L in the VRAYLAR 2 mg to 4.5 mg per day group, and 8.5 pmol/L in the placebo group. Dyslipidemia Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL, and triglycerides were similar in patients treated with VRAYLAR and placebo. Reference ID: 5484584 Bipolar Disorder In six placebo-controlled trials up to 8-weeks of adult patients with bipolar disorder (mania or depression), the proportion of patients with shifts in fasting total cholesterol, LDL, HDL, and triglycerides were similar in patients treated with VRAYLAR and placebo. Adjunctive Treatment of Major Depressive Disorder In two 6-week placebo-controlled trials of adult patients with major depressive disorder, the proportion of patients with shifts in total cholesterol, fasting LDL, HDL, and fasting triglycerides were similar in patients treated with VRAYLAR and placebo. Weight Gain Weight gain has been observed with use of atypical antipsychotics, including VRAYLAR. Monitor weight at baseline and frequently thereafter. Tables 4, 5, 6, and 7 show the change in body weight occurring from baseline to endpoint in 6-week trials of schizophrenia, 3-week bipolar mania trials, 6-week and 8-week bipolar depression trials, and 6-week and 8-week trials of adjunctive treatment for major depressive disorder, respectively. Table 4. Change in Body Weight (kg) in 6-Week Schizophrenia Trials VRAYLAR* Placebo (N=573) 1.5 - 3 mg/day (N=512) 4.5 - 6 mg/day (N=570) 9 - 12⸰ mg/day (N=203) Mean Change at Endpoint +0.3 +0.8 +1 +1 Proportion of Patients with Weight Increase (≥7%) 5% 8% 8% 17% Data shown by modal daily dose, defined as most frequently administered dose per patient ⸰The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. In long-term, uncontrolled trials with VRAYLAR in schizophrenia, the mean changes from baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively. Table 5. Change in Body Weight (kg) in 3-Week Bipolar Mania Trials VRAYLAR Placebo (N=439) 3 - 6 mg/day (N=259) 9 - 12⸰ mg/day (N=360) Mean Change at Endpoint +0.2 +0.5 +0.6 Proportion of Patients with Weight Increase (≥7%) 2% 1% 3% Data shown by modal daily dose, defined as most frequently administered dose per patient ⸰The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Table 6. Change in Body Weight (kg) in two 6-Week and one 8-Week Bipolar Depression Trials VRAYLAR Placebo (N=463) 1.5 mg/day (N=467) 3 mg/day (N=465) Reference ID: 5484584 Mean Change at Endpoint -0.1 +0.7 +0.4 Proportion of Patients with Weight Increase (≥7%) 1% 3% 3% Table 7. Change in Body Weight (kg) in two 6-Week and one 8-Week Adjunctive Treatment for Major Depressive Disorder Trials VRAYLAR 6-week Trials Placebo +ADT (N=503) 1.5 mg/day +ADT (N=502) 3 mg/day +ADT (N=503) Mean Change at Endpoint +0.2 +0.7 +0.7 Proportion of Patients with Weight Increase (≥7%) 1% 2% 2% 8-week Trial Placebo + ADT (N=266) 1 to 2 mg/day + ADT (N=273) 2 to 4.5 mg/day + ADT (N=273) Mean Change at Endpoint 0 +0.9 +0.9 Proportion of Patients with Weight Increase (≥7%) 2% 2% 3% In the long-term, open-label adjunctive treatment of MDD trial, 2 patients (0.6%) discontinued due to weight increase. VRAYLAR was associated with mean change from baseline in weight of 1.7 kg at Week 26. In the long-term, open-label adjunctive treatment of MDD trial, 19% of patients demonstrated a ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight. 5.8 Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of VRAYLAR at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue VRAYLAR in patients with absolute neutrophil count < 1000/mm3 and follow their WBC until recovery. 5.9 Orthostatic Hypotension and Syncope Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of VRAYLAR and was not more frequent on VRAYLAR than placebo. Syncope was not observed. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart Reference ID: 5484584 disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. VRAYLAR has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. 5.10 Falls Antipsychotics, including VRAYLAR, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.11 Seizures Like other antipsychotic drugs, VRAYLAR may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. 5.12 Potential for Cognitive and Motor Impairment VRAYLAR, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, or motor skills. In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of VRAYLAR-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of VRAYLAR-treated patients compared to 4% of placebo-treated patients. In two 6-week and one 8-week trials of depressive episodes of bipolar I disorder, VRAYLAR- treated patients reported 7% somnolence and 4% in the placebo-treated patients. In 6-week adjunctive treatment of major depressive disorder trials, somnolence was reported in 6% of VRAYLAR-treated patients compared to 4% of placebo-treated patients. In one 8-week adjunctive treatment of major depressive disorder trial, somnolence was reported in 11% of VRAYLAR-treated patients compared to 6% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with VRAYLAR does not affect them adversely. 5.13 Body Temperature Dysregulation Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use VRAYLAR with caution in patient who may experience these conditions. 5.14 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with VRAYLAR. VRAYLAR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)] Reference ID: 5484584 • Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions (5.2)] • Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.3)] • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4)] • Tardive Dyskinesia [see Warnings and Precautions (5.5)] • Late Occurring Adverse Reactions [see Warnings and Precautions (5.6)] • Metabolic Changes [see Warnings and Precautions (5.7)] • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)] • Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)] • Falls [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)] • Body Temperature Dysregulation [see Warnings and Precautions (5.13)] • Dysphagia [see Warnings and Precautions (5.14)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The information below is derived from an integrated clinical study database for VRAYLAR consisting of 6,722 adult patients exposed to one or more doses of VRAYLAR for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder, bipolar depression, and adjunctive treatment of major depressive disorder in placebo-controlled studies. This experience corresponds with a total experience of 1,182.8 patient-years. A total of 4,329 VRAYLAR-treated patients had at least 6 weeks and 296 VRAYLAR-treated patients had at least 48 weeks of exposure. Patients with Schizophrenia The following findings are based on four placebo-controlled, 6-week schizophrenia trials with VRAYLAR doses ranging from 1.5 to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment: There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia. Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in Table 8. Table 8. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials System Organ Class / Preferred Term Placebo (N= 584) (%) VRAYLAR 1.5 to 3 mg/day (N=539) (%) 4.5 to 6 mg/day (N=575) (%) 9 to 12 mg/day⸰ (N=203) (%) Cardiac Disorders Reference ID: 5484584 Table 8. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials System Organ Class / Preferred Term Placebo (N= 584) (%) VRAYLAR* 1.5 to 3 mg/day (N=539) (%) 4.5 to 6 mg/day (N=575) (%) 9 to 12 mg/day⸰ (N=203) (%) Tachycardiaa 1 2 2 3 Gastrointestinal Disorders Abdominal painb 5 3 4 7 Constipation 5 6 7 10 Diarrheac 3 1 4 5 Dry Mouth 2 1 2 3 Dyspepsia 4 4 5 5 Nausea 5 5 7 8 Toothache 4 3 3 6 Vomiting 3 4 5 5 General Disorders/Administration Site Conditions Fatigued 1 1 3 2 Infections and Infestations Nasopharyngitis 1 1 1 2 Urinary tract infection 1 1 <1 2 Investigations Blood creatine phosphokinase increased 1 1 2 3 Hepatic enzyme increasede <1 1 1 2 Weight increased 1 3 2 3 Metabolism and Nutrition Disorders Decreased appetite 2 1 3 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 1 2 1 2 Back pain 2 3 3 1 Pain in extremity 3 2 2 4 Nervous System Disorders Akathisia 4 9 13 14 Extrapyramidal symptomsf 8 15 19 20 Headacheg 13 9 11 18 Somnolenceh 5 5 8 10 Dizziness 2 3 5 5 Psychiatric Disorders Agitation 4 3 5 3 Insomniai 11 12 13 11 Restlessness 3 4 6 5 Anxiety 4 6 5 3 Reference ID: 5484584 Table 8. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials System Organ Class / Preferred Term Placebo (N= 584) (%) VRAYLAR* 1.5 to 3 mg/day (N=539) (%) 4.5 to 6 mg/day (N=575) (%) 9 to 12 mg/day⸰ (N=203) (%) Respiratory, Thoracic and Mediastinal Disorders Cough 2 1 2 4 Skin and Subcutaneous Disorders Rash 1 <1 1 2 Vascular Disorders Hypertensionj 1 2 3 6 Note: Figures rounded to the nearest integer * Data shown by modal daily dose, defined as most frequently administered dose per patient aTachycardia terms: heart rate increased, sinus tachycardia, tachycardia bAbdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain cDiarrhea terms: diarrhea, frequent bowel movements dFatigue terms: asthenia, fatigue eHepatic enzyme increase terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased fExtrapyramidal Symptoms terms: bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, Musculoskeletal stiffness, oculogyric crisis, oromandibular dystonia, parkinsonism, salivary hypersecretion, tardive dyskinesia, torticollis, tremor, trismus gHeadache terms: headache, tension headache hSomnolence terms: hypersomnia, sedation, somnolence iInsomnia terms: initial insomnia, insomnia, middle insomnia, terminal insomnia jHypertension terms: blood pressure diastolic increased, blood pressure increased, blood pressure systolic increased, hypertension ⸰ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Patients with Bipolar Mania The following findings are based on three placebo-controlled, 3-week bipolar mania trials with VRAYLAR doses ranging from 3 to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment: The adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received VRAYLAR discontinued treatment due to an adverse reaction, compared with 7% of placebo-treated patients in these trials. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in Table 9. Reference ID: 5484584 Table 9. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials System Organ Class / Preferred Term Placebo (N= 442) (%) VRAYLAR* 3 to 6 mg/day (N=263) (%) 9 to 12 mg/day⸰ (N=360) (%) Cardiac Disorders Tachycardiaa 1 2 1 Eye Disorders Vision blurred 1 4 4 Gastrointestinal Disorders Nausea 7 13 11 Constipation 5 6 11 Vomiting 4 10 8 Dry mouth 2 3 2 Dyspepsia 4 7 9 Abdominal painb 5 6 8 Diarrheac 5 5 6 Toothache 2 4 3 General Disorders/Administration Site Conditions Fatigued 2 4 5 Pyrexiae 2 1 4 Investigations Blood creatine phosphokinase increased 2 2 3 Hepatic enzymes increasedf <1 1 3 Weight increased 2 2 3 Metabolism and Nutrition Disorders Decreased appetite 3 3 4 Musculoskeletal and Connective Tissue Disorders Pain in extremity 2 4 2 Back pain 1 1 3 Nervous System Disorders Akathisia 5 20 21 Extrapyramidal Symptomsg 12 26 29 Headacheh 13 14 13 Dizziness 4 7 6 Somnolencei 4 7 8 Psychiatric Disorders Insomniaj 7 9 8 Restlessness 2 7 7 Reference ID: 5484584 Table 9. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials System Organ Class / Preferred Term Placebo (N= 442) (%) VRAYLAR* 3 to 6 mg/day (N=263) (%) 9 to 12 mg/day⸰ (N=360) (%) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 2 1 3 Vascular Disorders Hypertensionk 1 5 4 Note: Figures rounded to the nearest integer Data shown by modal daily dose, defined as most frequently administered dose per patient aTachycardia terms: heart rate increased, sinus tachycardia, tachycardia bAbdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, cDiarrhea: diarrhea, frequent bowel movements dFatigue terms: asthenia, fatigue ePyrexia terms: body temperature increased, pyrexia fHepatic enzymes increased terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased gExtrapyramidal Symptoms terms: bradykinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, tremor hHeadache terms: headache, tension headache iSomnolence terms: hypersomnia, sedation, somnolence jInsomnia terms: initial insomnia, insomnia, middle insomnia kHypertension terms: blood pressure diastolic increased, blood pressure increased, hypertension ⸰ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Patients with Bipolar Depression The following findings are based on three placebo-controlled, two 6-week and one 8-week bipolar depression trials with VRAYLAR doses of 1.5 mg and 3 mg once daily. Adverse Reactions Associated with Discontinuation of Treatment: There were no adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo. Overall, 6% of the patients who received VRAYLAR discontinued treatment due to an adverse reaction, compared with 5% of placebo-treated patients in these trials. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): nausea, akathisia, restlessness, and extrapyramidal symptoms. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 10. Reference ID: 5484584 Table 10. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in Two 6-Week and One 8-Week Bipolar Depression Trials Placebo (N=468) (%) VRAYLAR 1.5 mg/day (N=470) (%) 3 mg/day (N=469) (%) Restlessness 3 2 7 Akathisia 2 6 10 Extrapyramidal symptomsa 2 4 6 Dizziness 2 4 3 Somnolenceb 4 7 6 Nausea 3 7 7 Increased appetite 1 3 3 Weight increase <1 2 2 Fatiguec 2 4 3 Insomniad 7 7 10 aExtrapyramidal symptoms terms: akinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle tightness, musculoskeletal stiffness, myoclonus, oculogyric crisis, salivary hypersecretion, tardive dyskinesia, tremor bSomnolence terms: hypersomnia, sedation, somnolence cFatigue terms: asthenia, fatigue, malaise dInsomnia terms: initial insomnia, insomnia, insomnia related to another mental condition, middle insomnia, sleep disorder, terminal insomnia Adjunctive Therapy in Major Depressive Disorder The following findings are based on two placebo-controlled, fixed-dose 6-week trials with VRAYLAR doses of 1.5 and 3 mg once daily plus an antidepressant and one placebo-controlled, flexible-dose 8-week trial with VRAYLAR doses of (1 to 2 mg) and (2 to 4.5 mg) once daily plus an antidepressant for adjunctive therapy in MDD. Adverse Reactions Associated with Discontinuation of Treatment: The adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 6% of the patients who received VRAYLAR discontinued treatment due to an adverse reaction, compared with 3% of placebo-treated patients in these trials. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): Akathisia, nausea, and insomnia occurred in two 6-week, fixed-dose trials. Akathisia, restlessness, fatigue, constipation, nausea, increased appetite, dizziness, insomnia, and extrapyramidal symptoms occurred in one 8-week flexible-dose trial. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 11. Table 11. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-Treated Patients and > Placebo-Treated Adult Patients in Two Fixed-Dose 6 Reference ID: 5484584 Week Placebo-Controlled Trials of Adjunctive Treatment of Major Depressive Disorder System Organ Class/ Preferred Term Placebo + ADT (N=503) (%) VRAYLAR 1.5 mg/day + ADT (N=502) (%) 3 mg/day + ADT (N=503) (%) Eye Disorders Vision Blurred <1 <1 2 Gastrointestinal Disorders Nausea 3 7 6 Dry Mouth 2 3 3 Constipation 1 2 2 Vomiting 1 1 2 General Disorders Fatigue 2 3 3 Investigations Weight increased 1 2 2 Nervous System Disorders Akathisiaa 2 7 10 Somnolenceb 4 5 7 Extrapyramidal Symptomsc 4 5 6 Psychiatric Disorders Insomniad 5 9 10 Restlessness 2 4 4 Anxiety 1 2 1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 1 1 2 Note: Figures rounded to the nearest integer aAkathisia terms: akathisia, psychomotor hyperactivity, feeling jittery, nervousness, tension bSomnolence terms: hypersomnia, sedation, lethargy, somnolence cExtrapyramidal symptoms terms: drooling, dyskinesia, extrapyramidal disorder, hypotonia, muscle contractions involuntary, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, musculoskeletal stiffness, myoclonus, oromandibular Reference ID: 5484584 dystonia, parkinsonism, resting tremor, restless legs syndrome, stiff leg syndrome, salivary hypersecretion, stiff tongue, tardive dyskinesia, tremor, trismus dInsomnia terms: initial insomnia, insomnia, middle insomnia, poor sleep quality, sleep disorder, terminal insomnia Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1 mg to 2 mg per day or 2 mg to 4.5 mg per day doses are shown in Table 12. Reference ID: 5484584 Table 12. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-Treated Patients and > Placebo-Treated Adult Patients in a Flexible-dose 8-Week Placebo-Controlled Trial of Adjunctive Treatment of Major Depressive Disorder System Organ Class/ Preferred Term Placebo + ADT (N=266) (%) VRAYLAR 1 to 2 mg/day + ADT (N=273) (%) VRAYLAR 2 to 4.5 mg/day + ADT (N=273) (%) Cardiac disorders Palpitations 1 2 <1 Eye disorders Vision blurred 1 1 4 Gastrointestinal disorders Nausea 5 7 13 Constipation 2 2 5 Dry mouth 3 5 4 Vomiting <1 1 3 General disorders Fatigue 4 7 10 Edema <1 2 1 Infections Nasopharyngitis 2 4 1 Investigations Increased appetite 2 2 5 Weight increased 1 2 3 Musculoskeletal and Connective Tissue disorders Back pain 1 2 3 Myalgia 0 1 2 Nervous System disorders Akathisiaa 3 8 23 Extrapyramidal symptomsb 5 12 18 Somnolencec 6 10 11 Dizziness 2 4 5 Psychiatric disorders Insomniad 8 14 16 Restlessness 3 8 8 Agitation <1 <1 3 Anxiety <1 1 3 aAkathisia terms: akathisia, feeling jittery, nervousness, tension bExtrapyramidal symptoms terms: cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, jaw stiffness, muscle contractions involuntary, muscle disorder, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, musculoskeletal stiffness, nuchal rigidity, parkinsonism, psychomotor retardation, reduced facial expression, resting tremor, restless legs syndrome, sensation of heaviness, salivary hypersecretion, tremor cSomnolence terms: hypersomnia, sedation, lethargy, somnolence dInsomnia terms: initial insomnia, insomnia, middle insomnia, terminal insomnia, sleep disorder, poor sleep quality Reference ID: 5484584 Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms (EPS) and Akathisia In schizophrenia, bipolar mania, bipolar depression and adjunctive treatment of major depressive disorder trials, data were objectively collected using the Simpson Angus Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Rating Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline). In 6-week schizophrenia trials, the incidence of reported adverse reactions related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for VRAYLAR-treated patients versus 8% for placebo-treated patients. These reactions led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 0.5% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. In 3-week bipolar mania trials, the incidence of reported adverse reactions related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for VRAYLAR-treated patients versus 12% for placebo-treated patients. These reactions led to a discontinuation in 1% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for VRAYLAR- treated patients versus 5% for placebo-treated patients. These reactions led to discontinuation in 2% of VRAYLAR-treated patients versus 0% of placebo-treated patients. In the two 6-week and one 8-week bipolar depression trials, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness was 4% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These reactions led to discontinuation in 0.4% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These reactions led to discontinuation in 1.5% of VRAYLAR- treated patients versus 0% of placebo-treated patients. Reference ID: 5484584 In the two 6-week adjunctive treatment of major depressive disorder trials, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness, was 6% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.6% of placebo-treated patients. The combined incidence of akathisia and restlessness was 12% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 2% of VRAYLAR-treated patients versus 0.4% of placebo-treated patients. In one 8-week adjunctive treatment of major depressive disorder trial, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness, was 12% for VRAYLAR-treated patients versus 5% for placebo-treated patients. These reactions led to discontinuation in 1% of VRAYLAR-treated patients versus 0.4% of placebo-treated patients. The incidence of akathisia and restlessness was 22% for VRAYLAR-treated patients versus 6% for placebo-treated patients. These reactions led to discontinuation in 3% of VRAYLAR-treated patients versus 0.0% of placebo-treated patients. Cataracts The development of cataracts was observed in nonclinical studies [see Nonclinical Toxicology (13.2)]. Cataracts were reported during the premarketing clinical trials of cariprazine; however, the duration of trials was too short to assess any association to cariprazine usage. Vital Signs Changes There were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 - 12 mg/day VRAYLAR-treated patients with schizophrenia. Pooled data from 6-week schizophrenia trials are shown in Table 13, and from 3-week bipolar mania trials are shown in Table 14. Table 13. Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials Placebo (N=574) VRAYLAR 1.5 - 3 mg/day (N=512) 4.5 - 6 mg/day (N=570) 9- 12 mg/day⸰ (N=203) Supine Systolic Blood Pressure (mmHg) +0.9 +0.6 +1.3 +2.1 Supine Diastolic Blood Pressure (mmHg) +0.4 +0.2 +1.6 +3.4 * Data shown by modal daily dose, defined as most frequently administered dose per patient ⸰ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Reference ID: 5484584 Table 14. Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials Placebo (N=439) VRAYLAR* 3 - 6 mg/day (N=259) 9 – 12 mg/day⸰ (N=360) Supine Systolic Blood Pressure (mmHg) -0.5 +0.8 +1.8 Supine Diastolic Blood Pressure (mmHg) +0.9 +1.5 +1.9 * Data shown by modal daily dose, defined as most frequently administered dose per patient ⸰ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. In the two 6-week and one 8-week bipolar depression trials, there were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. VRAYLAR-treated patients’ supine blood pressure increased by 0.1 to 0.3 mmHg; placebo-treated patients’ supine blood pressure increased by 0.2 mmHg. In two 6-week and one 8-week adjunctive treatment of major depressive disorder trials, there were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. At the end of the 6-week trials, VRAYLAR-treated patients’ supine systolic blood pressure decreased by 0.1 to 0.7 mmHg; placebo-treated patients’ supine systolic blood pressure decreased by 0.1 mmHg. VRAYLAR-treated patients’ supine diastolic blood pressure increased by 0.1 mmHg and placebo-treated patients’ supine diastolic blood pressure increased by 0.2 mmHg. Changes in Laboratory Tests The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for VRAYLAR-treated patients, increasing with dose, and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for VRAYLAR-treated patients depending on dose group administered and 2% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week and 8-week bipolar depression trials ranged between 0% and 0.5% for VRAYLAR-treated patients depending on dose group administered and 0.4% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in two 6-week adjunctive treatment of major depressive disorder trials ranged between 0% and 1% for VRAYLAR-treated patients depending on dose group administered and 0% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for VRAYLAR-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in VRAYLAR and placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 6-week and 8-week bipolar depression trials ranged between 0.2% and 1% for VRAYLAR-treated patients versus 0.2% for placebo- treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in two 6-week Reference ID: 5484584 adjunctive treatment of major depressive disorder trials ranged between 0.6% and 0.8% for VRAYLAR- treated patients versus 0% for placebo-treated patients. Other Adverse Reactions Observed During the Pre-marketing Evaluation of VRAYLAR Adverse reactions listed below were reported by patients treated with VRAYLAR at doses of ≥ 1.5 mg once daily within the premarketing database of 5,763 VRAYLAR-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the VRAYLAR label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) [only those not already listed in the tabulated results from placebo-controlled studies appear in this listing]; those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1,000 patients (rare). Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis Hepatobiliary Disorders: Rare: hepatitis Metabolism and Nutrition Disorders: Frequent: decreased appetite; Rare: hyponatremia Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Rare: ischemic stroke Psychiatric Disorders: Infrequent: suicide ideation; Rare: completed suicide, suicide attempts Renal and Urinary Disorders: Infrequent: pollakiuria Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of VRAYLAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders – Stevens-Johnson syndrome 7 DRUG INTERACTIONS Table 15 displays clinically significant drug interactions with VRAYLAR. Reference ID: 5484584 Table 15. Clinically Significant Drug Interactions with VRAYLAR Strong or Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of VRAYLAR with a strong or moderate CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone [see Clinical Pharmacology (12.3)]. Intervention: If VRAYLAR is used with a strong or moderate CYP3A4 inhibitor, reduce VRAYLAR dosage [see Dosage and Administration (2.6)]. CYP3A4 Inducers Clinical Impact: CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear [see Clinical Pharmacology (12.3)]. Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended [see Dosage and Administration (2.1, 2.6)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). There are no available data on VRAYLAR use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. The major active metabolite of cariprazine, DDCAR, has been detected in adult patients up to 12 weeks after discontinuation of VRAYLAR [see Clinical Pharmacology (12.3)]. Based on animal data, VRAYLAR may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Reference ID: 5484584 Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Administration of cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day, which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i.e. sum of cariprazine, DCAR, and DDCAR), caused fetal developmental toxicity at all doses, which included reduced body weight, decreased male anogenital distance, and skeletal malformations of bent limb bones, scapula, and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/day based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day, which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine, caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to those of the first generation pups. Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine, was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs. 8.2 Lactation Risk Summary Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for VRAYLAR and any potential adverse effects on the breastfed infant from VRAYLAR or from the underlying maternal condition. Reference ID: 5484584 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies of VRAYLAR have not been conducted. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.2)]. 8.5 Geriatric Use Clinical trials of VRAYLAR did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.3)]. 8.6 Hepatic Impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9) [see Clinical Pharmacology (12.3)]. Usage of VRAYLAR is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). VRAYLAR has not been evaluated in this patient population. 8.7 Renal Impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate (CrCL ≥ 30 mL/minute) renal impairment [see Clinical Pharmacology (12.3)]. Usage of VRAYLAR is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). VRAYLAR has not been evaluated in this patient population. 8.8 Smoking No dosage adjustment for VRAYLAR is needed for patients who smoke. VRAYLAR is not a substrate for CYP1A2; smoking is not expected to have an effect on the pharmacokinetics of VRAYLAR. 8.9 Other Specific Populations No dosage adjustment is required based on patient’s age, sex, or race. These factors do not affect the pharmacokinetics of VRAYLAR [see Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance VRAYLAR is not a controlled substance. 9.2 Abuse VRAYLAR has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance. 9.3 Dependence VRAYLAR has not been systematically studied in animals or humans for its potential for physical dependence. Reference ID: 5484584 -0'""'"'\_ I\ ~ =< \_/ )=(- / 10 OVERDOSAGE 10.1 Human Experience In pre-marketing clinical trials involving VRAYLAR in approximately 5000 patients or healthy subjects, accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. 10.2 Management of Overdosage No specific antidotes for VRAYLAR are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. 11 DESCRIPTION The active ingredient of VRAYLAR is cariprazine, an atypical antipsychotic, in hydrochloride salt form. The chemical name is trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’ dimethylurea hydrochloride; its empirical formula is C21H32Cl2N4O•HCl and its molecular weight is 463.9 g/mol. The chemical structure is: . HCl O N N H Cl Cl N N VRAYLAR capsules are intended for oral administration only. Each hard gelatin capsule contains a white to off-white powder of cariprazine HCl, which is equivalent to 1.5, 3, 4.5, or 6 mg of cariprazine base. In addition, capsules include the following inactive ingredients: gelatin, magnesium stearate, pregelatinized starch, shellac, and titanium dioxide. Colorants include black iron oxide (1.5, 3, and 6 mg), FD&C Blue 1 (3, 4.5, and 6 mg), FD&C Red 3 (6 mg), FD&C Red 40 (3 and 4.5 mg), or yellow iron oxide (3 and 4.5 mg). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of cariprazine is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug. 12.2 Pharmacodynamics Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity (Ki values 0.085 nM, and 0.49 nM (D2L) and 0.69 nM (D2S), respectively) and at the serotonin 5-HT1A receptors (Ki value 2.6 nM). Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity (Ki values 0.58 nM and 18.8 nM respectively) as well as it binds to the histamine H1 receptors (Ki value 23.2 nM). Cariprazine shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors (Ki values 134 nM and 155 nM, respectively) and has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM). Reference ID: 5484584 Effect on QTc Interval At a dose three-times the maximum recommended dose, cariprazine does not prolong the QTc interval to clinically relevant extent. 12.3 Pharmacokinetics VRAYLAR activity is thought to be mediated by cariprazine and its two major active metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which are pharmacologically equipotent to cariprazine. After multiple dose administration of VRAYLAR, mean cariprazine and DCAR concentrations reached steady state at around Week 1 to Week 2 and mean DDCAR concentrations appeared to be approaching steady state at around Week 4 to Week 8 in a 12-week study (Figure 1). The half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2 to 4 days for cariprazine, about 1 to 2 days for DCAR, and approximately 1 to 3 weeks for DDCAR. The time to reach steady state for the major active metabolite DDCAR was variable across patients, with some patients not achieving steady state at the end of the 12 week treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.6)]. Mean concentrations of DCAR and DDCAR are approximately 30% and 400%, respectively, of cariprazine concentrations by the end of 12-week treatment. After discontinuation of VRAYLAR, cariprazine, DCAR, and DDCAR plasma concentrations declined in a multi-exponential manner. Mean plasma concentrations of DDCAR decreased by about 50% 1 week after the last dose, and mean cariprazine and DCAR concentration dropped by about 50% in about 1 day. There was an approximately 90% decline in plasma exposure within 1 week for cariprazine and DCAR, and at about 4 weeks for DDCAR. Following a single dose of 1 mg of cariprazine administration, DDCAR remained detectable 8 weeks post-dose. After multiple dosing of VRAYLAR, plasma exposure of cariprazine, DCAR, and DDCAR increases approximately proportionally over the therapeutic dose range. Reference ID: 5484584 Figure 1. Plasma Concentration (Mean ± SE)-Time Profile During and Following 12-weeks of Treatment with Cariprazine 6 mg/daya Plasma Concentration (nM) 140 120 100 80 60 40 20 0 TOTAL CAR DDCAR CAR DCAR 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Weeks) a Trough concentrations shown during treatment with cariprazine 6 mg/day. SE: standard error; TOTAL CAR: sum concentration of cariprazine, DCAR and DDCAR; CAR: cariprazine Absorption After single dose administration of VRAYLAR, the peak plasma cariprazine concentration occurred in approximately 3-6 hours. Administration of a single dose of 1.5 mg VRAYLAR capsule with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or DCAR. Distribution Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins. Elimination Metabolism Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. Excretion Following administration of 12.5 mg/day cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose excreted in urine as unchanged cariprazine. Reference ID: 5484584 Studies in Specific Populations Hepatic Impairment Compared to healthy subjects, exposure (Cmax and AUC) in patients with either mild or moderate hepatic impairment (Child-Pugh score between 5 and 9) was approximately 25% higher for cariprazine and 20% to 30% lower for the major metabolites (DCAR and DDCAR) following daily doses of 0.5 mg cariprazine for 14 days [see Use in Specific Populations (8.6)]. Renal Impairment Cariprazine and its major active metabolites are minimally excreted in urine. Pharmacokinetic analyses indicated no significant relationship between plasma clearance and creatinine clearance [see Use in Specific Populations (8.7)]. CYP2D6 Poor Metabolizers CYP2D6 poor metabolizer status does not have clinically relevant effect on pharmacokinetics of cariprazine, DCAR, or DDCAR. Age, Sex, Race Age, sex, or race does not have clinically relevant effect on pharmacokinetics of cariprazine, DCAR, or DDCAR. Drug Interaction Studies In vitro studies Cariprazine and its major active metabolites did not induce CYP1A2 and CYP3A4 enzymes and were weak inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 in vitro. Cariprazine was also a weak inhibitor of CYP2C19, CYP2A6, and CYP2E1 in vitro. Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), or the breast cancer resistance protein (BCRP). Cariprazine and its major active metabolites were poor or non-inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. The major active metabolites were also poor or non-inhibitors of transporter P-gp although cariprazine was probably a P-gp inhibitor based on the theoretical GI concentrations at high doses in vitro. Based on in vitro studies, VRAYLAR is unlikely to cause clinically significant pharmacokinetic drug interactions with substrates of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E, and CYP3A4, or OATP1B1, OATP1B3, BCRP, OCT2, OAT1 and OAT3. In vivo studies and Model-based Approaches CYP3A4 inhibitors In the clinical drug-drug interaction studies, co-administration of ketoconazole (400 mg/day for four days), a strong CYP3A4 inhibitor, with VRAYLAR (0.5 mg/day) increased total cariprazine (the sum of cariprazine, DCAR and DDCAR) Cmax and AUC0-24h by approximately 100%. Co-administration of erythromycin (500 mg twice daily for 21 days), a moderate CYP3A4 inhibitor, with VRAYLAR (1.5 mg/day) increased total cariprazine Cmax and AUC0-24h by approximately 50%. Reference ID: 5484584 Physiologically based pharmacokinetic model-based analyses suggest that co-administration of ketoconazole (400 mg/day) with VRAYLAR (0.5 mg/day) at steady state is predicted to result in up to about 5.5-fold and 6-fold increase in Cmax and AUC0-24h, respectively, of total cariprazine. Co- administration of fluconazole (200 mg/day), a moderate CYP3A inhibitor, with VRAYLAR (0.5 mg/day) at steady state is predicted to result in up to about 3-fold increase in Cmax and AUC0-24h of total cariprazine. CYP3A4 inducers CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the plasma exposure of cariprazine and its major active metabolites has not been evaluated, and the net effect is unclear. CYP2D6 inhibitors CYP2D6 inhibitors are not expected to influence pharmacokinetics of cariprazine, DCAR, or DDCAR based on the observations in CYP2D6 poor metabolizers. Proton pump inhibitors Co-administration of pantoprazole (40 mg/day), a proton pump inhibitor, with VRAYLAR (6 mg/day) in patients with schizophrenia for 15 days did not affect cariprazine exposure at steady-state, based on Cmax and AUC0-24. Similarly, no significant change in exposure to DCAR and DDCAR was observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in the incidence of tumors following daily oral administration of cariprazine to rats for 2 years and to Tg.rasH2 mice for 6 months at doses which are up to 4 and 19 times respectively, the MRHD of 6 mg/day based on AUC of total cariprazine, (i.e. sum of AUC values of cariprazine, DCAR and DDCAR). Rats were administered cariprazine at oral doses of 0.25, 0.75, and 2.5 (males)/1, 2.5, and 7.5 mg/kg/day (females) which are 0.2 to 1.8 (males)/ 0.8 to 4.1 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. Tg.rasH2 mice were administered cariprazine at oral doses of 1, 5, and 15 (males)/5, 15, and 50 mg/kg/day (females) which are 0.2 to 7.9 (males)/2.6 to 19 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. Mutagenesis Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay, nor clastogenic in the in vitro human lymphocyte chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay. However, cariprazine increased the mutation frequency in the in vitro mouse lymphoma assay under conditions of metabolic activation. The major human metabolite DDCAR was not mutagenic in the in vitro bacterial reverse mutation assay, however, it was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay. Reference ID: 5484584 Impairment of Fertility Cariprazine was administered orally to male and female rats before mating, through mating, and up to day 7 of gestation at doses of 1, 3, and 10 mg/kg/day which are 1.6 to 16 times the MRHD of 6 mg/day based on mg/m2. In female rats, lower fertility and conception indices were observed at all dose levels which are equal to or higher than 1.6 times the MRHD of 6 mg/day based on mg/m2. No effects on male fertility were noted at any dose up to 4.3 times the MRHD of 6 mg/day based on AUC of total cariprazine. 13.2 Animal Toxicology and/or Pharmacology Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Cataract in the dog was observed at 4 mg/kg/day which is 7.1 (male) and 7.7 (female) times the MRHD of 6 mg/day based on AUC of total cariprazine. The NOEL for cataract and retinal toxicity in the dog is 2 mg/kg/day which is 5 (males) to 3.6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. Increased incidence and severity of retinal degeneration/atrophy in the rat occurred at all doses tested, including the low dose of 0.75 mg/kg/day, at total cariprazine plasma levels less than clinical exposure (AUC) at the MRHD of 6 mg/day. Cataract was not observed in other repeat dose studies in pigmented mice or albino rats. Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total cariprazine. Phospholipidosis was not reversible at the end of the 1-2 month drug-free periods. Inflammation was observed in the lungs of dogs dosed daily for 1 year with a NOEL of 1 mg/kg/day which is 2.7 (males) and 1.7 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. No inflammation was observed at the end of 2-month drug free period following administration of 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine; however, inflammation was still present at higher doses. Hypertrophy of the adrenal gland cortex was observed at clinically relevant total cariprazine plasma concentrations in rats (females only) and mice following daily oral administration of cariprazine for 2 years and 6 months, respectively. Reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed following daily oral administration of cariprazine to dogs for 1 year. The NOEL was 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. The relevance of these findings to human risk is unknown. 14 CLINICAL STUDIES 14.1 Schizophrenia The efficacy of VRAYLAR for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials in patients (mean age of 37 years, aged 18 to 60 years; 31% were female; and 45% were Caucasian) who met Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity. In all three trials, VRAYLAR was superior to placebo. Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: Reference ID: 5484584 • PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). The PANSS total score may range from 30 to 210 with the higher score reflecting greater severity. • The CGI-S is a validated clinician-related scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was change from baseline in PANSS total score at the end of week 6. The change from baseline for VRAYLAR and active control groups was compared to placebo. The results of the trials are shown in Table 16. The time course of efficacy results of Study 2 is shown in Figure 2. Study 1: In a 6-week, placebo-controlled trial (N = 711) involving three fixed doses of VRAYLAR (1.5, 3, or 4.5 mg/day) and an active control (risperidone), all VRAYLAR doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 2: In a 6-week, placebo-controlled trial (N = 604) involving two fixed doses of VRAYLAR (3 or 6 mg/day) and an active control (aripiprazole), both VRAYLAR doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 3: In a 6-week, placebo-controlled trial (N = 439) involving two flexible-dose range groups of VRAYLAR (3 to 6 mg/day or 6 to 9 mg/day), both VRAYLAR groups were superior to placebo on the PANSS total score and the CGI-S. The efficacy of VRAYLAR was demonstrated at doses ranging from 1.5 to 9 mg/day compared to placebo. There was, however, a dose-related increase in certain adverse reactions, particularly above 6 mg. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. Reference ID: 5484584 Table 16. Primary Analysis Results from Schizophrenia Trials Study Treatment Group Primary Efficacy Endpoint: PANSS Total Number (# ITT patients) Mean LS Mean Placebo-subtracted Baseline Change from Differencea (95% CI) Score (SD) Baseline (SE) Study 1 VRAYLAR (1.5 mg/day)* 97.1 (9.1) -19.4 (1.6) -7.6 (-11.8, -3.3) (n=140) VRAYLAR (3 mg/day)* 97.2 (8.7) -20.7 (1.6) -8.8 (-13.1, -4.6) (n=140) VRAYLAR (4.5 mg/day)* 96.7 (9.0) -22.3 (1.6) -10.4 (-14.6, -6.2) (n=145) Placebo 97.3 (9.2) -11.8 (1.5) - (n=148) Study 2 VRAYLAR (3 mg/day)* 96.1 (8.7) -20.2 (1.5) -6.0 (-10.1, -1.9) (n=151) VRAYLAR (6 mg/day)* 95.7 (9.4) -23.0 (1.5) -8.8 (-12.9, -4.7) (n=154) Placebo 96.5 (9.1) -14.3 (1.5) - (n=149) Study 3 VRAYLAR (3-6 mg/day)* 96.3 (9.3) -22.8 (1.6) -6.8 (-11.3, -2.4) (n=147) VRAYLAR (6-9 mg/day)b 96.3 (9.0) -25.9 (1.7) -9.9 (-14.5, -5.3) (n=147) Placebo 96.6 (9.3) -16.0 (1.6) - (n=145) ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval aDifference (drug minus placebo) in least-squares mean change from baseline Doses that are statistically significantly superior to placebo bThe maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Reference ID: 5484584 Q) C Q) en ro en E 0 ,._ '+ Q) OJ C ro ..s:::: (_) 0 -5 -10 -15 -20 -25 0 2 3 Weeks 4 ------ ........ --- - Placebo Vraylar 3 mg/day Vraylar 6 mg/day ... .... .... ■ 5 6 Figure 2. Change from Baseline in PANSS total score by weekly visits (Study 2) The safety and efficacy of VRAYLAR as maintenance treatment in adults with schizophrenia were demonstrated in a randomized withdrawal trial that included 200 patients meeting DSM-IV criteria for schizophrenia who were clinically stable following 20 weeks of open-label cariprazine at doses of 3 to 9 mg/day. Patients were randomized to receive either placebo or cariprazine at the same dose for up to 72 weeks for observation of relapse. The primary endpoint was time to relapse. Relapse during the double- blind phase (DBP) was defined as meeting any one of the following criteria: hospitalization due to worsening of schizophrenia, increase in the PANSS total score by ≥ 30%, increase in CGI-S score by ≥ 2 points, deliberate self-injury, aggressive or violent behavior, clinically significant suicidal or homicidal ideation, or score >4 on one or more of the following PANSS items: delusions (P1), conceptual disorganization (P2), hallucination (P3), suspiciousness or persecution (P6), hostility (P7), uncooperativeness (G8), or poor impulse control (G14). The efficacy of VRAYLAR was demonstrated at doses ranging from 3 to 9 mg/day compared to placebo. There was, however, a dose-related increase in certain adverse reactions, particularly above 6 mg. Therefore, the maximum recommended dose is 6 mg/day. The Kaplan-Meier curves of the time to relapse during the double-blind, placebo-controlled, randomized withdrawal phase of the long-term trial are shown in Figure 3. Time to relapse was statistically significantly longer in the VRAYLAR-treated group compared to the placebo group. Reference ID: 5484584 60 50 ,...._ C Q) 40 u C Q) ,:, ·u -~ 30 Q) 1/) C. "' ~ Q) 20 > :;:; "' :5 E 10 :, (.) 0 0 .. • 50 .... -· .. -- .--. -··. ..! •••••• • • ■I 100 150 • • • • • • • • • • • •••••••I -_ ... • .... ,. -· 200 250 300 350 Duration of DB Treatment (days) 400 ■ ■ Placebo Cariprazine 3-9 mg* 450 500 550 Figure 3. Kaplan-Meier Curves of Cumulative Rate of Relapse During the Double-Blind Treatment Period DB = double-blind The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. 14.2 Manic or Mixed Episodes Associated with Bipolar I Disorder The efficacy of VRAYLAR in the acute treatment of bipolar mania was established in three, 3-week placebo-controlled trials in patients (mean age of 39 years, range 18 to 65 years; 40% were female; and 48% were Caucasian) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. In all three trials, VRAYLAR was superior to placebo. Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity scale (CGI-S) were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: • The YMRS is an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology. YMRS total score may range from 0 to 60 with a higher score reflecting greater severity. • The CGI-S is validated clinician-related scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was decrease from baseline in YMRS total score at the end of week 3. The change from baseline for each VRAYLAR dose group was compared to placebo. The results of the trials are shown in Table 17. The time course of efficacy results is shown in Figure 4. Reference ID: 5484584 Study 4: In a 3-week, placebo-controlled trial (N = 492) involving two flexible-dose range groups of VRAYLAR (3 to 6 mg/day or 6 to 12 mg/day), both VRAYLAR dose groups were superior to placebo on the YMRS total score and the CGI-S. The 6 to 12 mg/day dose group showed no additional advantage. Study 5: In a 3-week, placebo-controlled trial (N = 235) involving a flexible-dose range of VRAYLAR (3 to 12 mg/day), VRAYLAR was superior to placebo on the YMRS total score and the CGI-S. Study 6: In a 3-week, placebo-controlled trial (N = 310) involving a flexible-dose range of VRAYLAR (3 to 12 mg/day), VRAYLAR was superior to placebo on the YMRS total score and the CGI-S. The efficacy of VRAYLAR was established at doses ranging from 3 to 12 mg/day. Doses above 6 mg did not appear to have additional benefit over lower doses (Table 17), and there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. Table 17. Primary Analysis Results from Manic or Mixed Episodes Associated with Bipolar I Disorder Trials Study Treatment Group Primary Efficacy Endpoint: YMRS Total Number (# ITT patients) Mean LS Mean Placebo-subtracted Baseline Change from Differencea (95% CI) Score (SD) Baseline (SE) Study 4 VRAYLAR (3-6 mg/day) 33.2 (5.6) -18.6 (0.8) -6.1 (-8.4, -3.8) (n=165) VRAYLAR (6-12 mg/day)b 32.9 (4.7) -18.5 (0.8) -5.9 (-8.2, -3.6) (n=167) Placebo 32.6 (5.8) -12.5 (0.8) - (n=160) Study 5 VRAYLAR (3-12 mg/day)b 30.6 (5.0) -15.0 (1.1) -6.1 (-8.9, -3.3) (n=118) Placebo 30.2 (5.2) -8.9 (1.1) - (n=117) Study 6 VRAYLAR (3-12 mg/day)b 32.3 (5.8) -19.6 (0.9) -4.3 (-6.7, -1.9) (n=158) Placebo 32.1 (5.6) -15.3 (0.9) - (n=152) ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval aDifference (drug minus placebo) in least-squares mean change from baseline Doses that are statistically significantly superior to placebo bThe maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Reference ID: 5484584 Q) C 0 Q) -5 en cu (l) E 0 .... '+- Q) -10 CJ) C cu ..c u -15 -20 0 3 5 7 10 Days 14 _._ Placebo ···•··· Vraylar 3-6 mg/day - • - Vraylar 6-12 mg/day* 21 Figure 4. Change from Baseline in YMRS total score by study visit (Study 4) * The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. 14.3 Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) The efficacy of VRAYLAR in the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) was established in one 8-week and two 6-week placebo-controlled trials in patients (mean age of 43 years, range 18 to 65 years; 61% were female; and 75% were Caucasian) who met DSM IV-TR or DSM-5 criteria for depressive episodes associated with bipolar I disorder. In each study, the primary endpoint was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of Week 6. The MADRS is a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The MADRS total score change from baseline for VRAYLAR compared to placebo is shown in Table 18. The time course of efficacy results of Study 8 is shown in Figure 5. In each study, the VRAYLAR 1.5 mg dose demonstrated statistical significance over placebo. The secondary endpoint was change from baseline to Week 6 in CGI-S. The CGI-S is validated clinician-related scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. Study 7: In an 8-week, placebo-controlled trial (N = 571) involving three-fixed doses of VRAYLAR (0.75 mg/day, 1.5 mg/day, and 3 mg/day), VRAYLAR 1.5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S. Study 8: In a 6-week, placebo-controlled trial (N = 474) involving two-fixed doses of VRAYLAR (1.5 mg/day and 3 mg/day), VRAYLAR 1.5 mg and 3 mg were superior to placebo at end of Week 6 on the MADRS total score. Reference ID: 5484584 Study 9: In a 6-week, placebo-controlled trial (N = 478) involving two-fixed doses of VRAYLAR (1.5 mg/day and 3 mg/day), VRAYLAR 1.5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. Table 18. Primary Analysis Results from Bipolar Depression Trials Study Number Treatment Group (# ITT patients) Primary Efficacy Endpoint: MADRS Total LS Mean Mean Baseline Score (SD) Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study 7 VRAYLAR (1.5 mg/day)* (n=145) VRAYLAR (3 mg/day) (n=145) Placebo (n=141) 30.3 (4.4) -15.1 (0.8) -4.0 (-6.3, -1.6) 30.6 (4.7) -13.7 (0.9) -2.5 (-4.9, -0.1) 30.4 (4.6) -11.1 (0.9) Study 8 VRAYLAR (1.5 30.7 (4.3) -15.1 (0.8) -2.5 (-4.6, -0.4) mg/day)* (n=154) VRAYLAR (3 mg/day)* 31.0 (4.9) -15.6 (0.8) -3.0 (-5.1, -0.9) (n=164) Placebo 30.2 (4.4) -12.6 (0.8) (n=156) Study 9 VRAYLAR (1.5 31.5 (4.3) -14.8 (0.8) -2.5 (-4.6, -0.4) mg/day)* (n=162) VRAYLAR (3 mg/day) 31.5 (4.8) -14.1 (0.8) -1.8 (-3.9, 0.4) (n=153) Placebo 31.4 (4.5) -12.4 (0.8) (n=163) ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval aDifference (drug minus placebo) in least-squares mean change from baseline Doses that are statistically significantly superior to placebo Reference ID: 5484584 0 Q) '- 0 u U) co +-' ~ U) -6 0::: 0 <( ~ C Q) 0) C co -12 .c () C co Q) ~ U) __J -18 Week 1 Week2 - Placebo ···• ··· Vraylar 1.5 mg/day - • - Vraylar 3 mg/day Week4 Week6 Figure 5. LS Mean Change from Baseline in MADRS Total Score by Visits (Study 8) LS Mean: least-squares mean 14.4 Adjunctive Treatment of Major Depressive Disorder The efficacy of VRAYLAR as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) was evaluated in 2 trials in adult patients (mean age of 45 years, range 18 to 65 years; 72% were female; and 85% were Caucasian) who met DSM-IV-TR or DSM-5 criteria for MDD, with or without symptoms of anxiety, who had an inadequate response to 1 to 3 courses of prior antidepressant (ADT) therapy. Inadequate response during antidepressant treatment was defined as less than 50% improvement to antidepressant treatment of adequate dose and adequate duration. In each study, the primary endpoint was change from baseline to Week 6 (Study 10) or Week 8 (Study 11) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score, a 10-item clinician-rated scale used to assess the degree of depressive symptomatology, with 0 representing no symptoms and 60 representing worst symptoms. Study 10: In a 6-week, placebo-controlled trial (N = 751) involving two fixed doses of VRAYLAR (1.5 mg per day or 3 mg per day) + ADT, VRAYLAR 1.5 mg + ADT was superior to placebo + ADT at end of Week 6 on the MADRS total score. The treatment effect in the VRAYLAR 3 mg per day + ADT group (vs. placebo + ADT) was not statistically significant. Study 11: An 8-week, placebo-controlled trial (N = 808) involved flexible doses of VRAYLAR 1 to 2 mg per day + ADT or 2 to 4.5 mg per day + ADT. VRAYLAR 2 to 4.5 mg (mean dose was 2.6 mg) + ADT was superior to placebo + ADT at end of Week 8 on the MADRS total score. The treatment effect in the VRAYLAR 1 to 2 mg per day + ADT group (vs. placebo + ADT) was not statistically significant. Reference ID: 5484584 Results from the primary efficacy parameters for both trials (Studies 10 and 11) are shown below in Table 19. Figure 6 below shows the time course of response based on the primary efficacy measure (MADRS total score) in Study 10. Table 19: Primary Analysis Results from Adjunctive Treatment of Major Depressive Disorder Trials Study Number Treatment Group (# ITT patients) Primary Efficacy Endpoint: MADRS Total Score LS Mean Study 10 VRAYLAR (1.5 mg/day) + ADT (n=250) VRAYLAR (3 mg/day) + ADT Mean Baseline Score (SD) 32.8 (5.0) 32.7 (4.9) Change from Baseline (SE) -14.1 (0.7) -13.1 (0.7) Placebo-subtracted Differencea (95% CI) -2.5(-4.2, -0.9) -1.5 (-3.2, 0.1) (n=252) Placebo + ADT (n=249) 31.9 (5.7) -11.5 (0.7) Study 11 VRAYLAR (1 to 2 mg/day) + ADT (n=273) VRAYLAR (2 to 4.5 mg/day) + ADT* (n=271) Placebo + ADT (n=264) 29.0 (4.3) 29.3 (4.1) 28.9 (4.3) -13.4 (0.5) -14.6 (0.6) -12.5 (0.5) -0.9 (-2.4, 0.6) -2.2 (-3.7, -0.6) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval * Dosages statistically significantly superior to placebo a Difference (drug minus placebo) in least-squares mean change from baseline Examination of population subgroups based on age, sex, and race did not suggest any clear evidence of differential responsiveness. Reference ID: 5484584 0 G) ... -2 8 II) iii -4 ... ~ lQ C -6 <( ~ -8 .!: G) ~ -10 ,a .c u C -12 ,a G) ~ ~ -14 -16 Placebo+ ADT (N) Vraylar 1.5 mg/day+ADT (N) Vraylar 3 mg/day+ADT* (N) 0 249 250 252 Weekl 246 250 252 Week2 246 242 245 --+- Placebo+ ADT (N=249) ••• ,. ••• Vraylar 1.5 mg/day + ADT (N =250) - ■ - Vraylar 3 mg/day+ ADT* (N =2 52) ............................. •••··· ••••·· ············& Week4 238 237 235 Week6 231 231 223 Figure 6. LS Mean‡ Change from Baseline to Week 6 in MADRS Total Score in Adjunctive Treatment of Major Depressive Disorder (Study 10) ‡ LS Mean: least-squares mean * Dose was not statistically significant. 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VRAYLAR (cariprazine) capsules are supplied as follows: Capsule Strength Imprint Codes Capsule Color Package Configuration NDC Code 1.5 mg FL 1.5 White cap and body Blister pack of 7 61874-115-17 Bottle of 30 61874-115-30 Bottle of 90 61874-115-90 Box of 20 (Hospital Unit Dose) 61874-115-20 3 mg FL 3 Green to blue- green cap and white body Bottle of 30 61874-130-30 Bottle of 90 61874-130-90 Box of 20 (Hospital Unit Dose) 61874-130-20 4.5 mg FL 4.5 Green to blue- green cap and body Bottle of 30 61874-145-30 Bottle of 90 61874-145-90 6 mg FL 6 Purple cap and white body Bottle of 30 61874-160-30 Bottle of 90 61874-160-90 (1) 1.5 mg, (6) 3 mg FL 1.5, FL 3 Mixed Blister pack of 7 61874-170-08 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect 3 mg and 4.5 mg capsules from light to prevent potential color fading. Reference ID: 5484584 17. PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to their healthcare provider [see Box Warning and Warnings and Precautions (5.2)]. Dosage and Administration Advise patients that VRAYLAR can be taken with or without food. Counsel them on the importance of following dosage escalation instructions [see Dosage and Administration (2)]. Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.4)]. Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.5)]. Late-Occurring Adverse Reactions Counsel patients that adverse reactions may not appear until several weeks after the initiation of VRAYLAR treatment [see Warnings and Precautions (5.6)]. Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.7)]. Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking VRAYLAR [see Warnings and Precautions (5.8)]. Orthostatic Hypotension and Syncope Counsel patients on the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.9)]. Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that VRAYLAR therapy does not affect them adversely [see Warnings and Precautions (5.12)]. Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)]. Reference ID: 5484584 Concomitant Medications Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the counter drugs since there is a potential for interactions [see Drug Interactions (7.1)]. Pregnancy Advise patients that third trimester use of VRAYLAR may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy [see Use in Specific Populations (8.1)]. Licensed from Gedeon Richter Plc. Manufactured by: Forest Laboratories Ireland Limited Dublin, IE. Distributed by: AbbVie Inc. North Chicago, IL 60064, USA VRAYLAR and its design are trademarks of Allergan Pharmaceuticals International Limited, an AbbVie company. © 2024 AbbVie. All rights reserved. Reference ID: 5484584 MEDICATION GUIDE VRAYLAR® (VRAY-lar) (cariprazine) capsules What is the most important information I should know about VRAYLAR? VRAYLAR may cause serious side effects, including: • Increased risk of death in elderly people with dementia related psychosis. Medicines like VRAYLAR can raise the risk of death in elderly who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). VRAYLAR is not approved for the treatment of patients with dementia-related psychosis. • Increased risk of suicidal thoughts and actions. VRAYLAR and antidepressant medicines may increase suicidal thoughts or actions in some children and young adults especially within the first few months of treatment or when the dose is changed. o Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when VRAYLAR or the antidepressant medicine is started or when the dose is changed. o Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. o Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking • other unusual changes in behavior or mood (mania) What is VRAYLAR? VRAYLAR is a prescription medicine used in adults: • to treat schizophrenia • for short-term (acute) treatment of manic or mixed episodes that happen with bipolar I disorder • to treat depressive episodes that happen with bipolar I disorder (bipolar depression) • along with antidepressant medicines to treat major depressive disorder (MDD) It is not known if VRAYLAR is safe and effective in children. Do not take VRAYLAR if you are allergic to cariprazine. See the end of this Medication Guide for a complete list of ingredients in VRAYLAR. Before taking VRAYLAR, tell your healthcare provider about all of your medical conditions, including if you: • have or have had heart problems or a stroke • have or have had low or high blood pressure • have or have had diabetes or high blood sugar, or a family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start and during treatment with VRAYLAR. • have or have had high levels of total cholesterol, LDL cholesterol, or triglycerides or low levels of HDL cholesterol. • have or had seizures (convulsions) • have or have had kidney or liver problems • have or had a low white blood cell count • are pregnant or plan to become pregnant. VRAYLAR may harm your unborn baby. Taking VRAYLAR during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal Reference ID: 5484584 symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take VRAYLAR during pregnancy. o Tell your healthcare provider if you become pregnant or think you are pregnant during treatment with VRAYLAR. o If you become pregnant during treatment with VRAYLAR, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research programs/pregnancyregistry/. • are breastfeeding or plan to breastfeed. It is not known if VRAYLAR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with VRAYLAR. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VRAYLAR and other medicines may affect each other causing possible serious side effects. VRAYLAR may affect the way other medicines work, and other medicines may affect how VRAYLAR works. Your healthcare provider can tell you if it is safe to take VRAYLAR with your other medicines. Do not start or stop any medicines while taking VRAYLAR without talking to your healthcare provider first. Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. How should I take VRAYLAR? • Take VRAYLAR exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking VRAYLAR without first talking to your healthcare provider. • Take VRAYLAR 1 time each day with or without food. • If you take too much VRAYLAR, call your healthcare provider or Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room, right away. What should I avoid while taking VRAYLAR? • Do not drive, operate machinery, or do other dangerous activities until you know how VRAYLAR affects you. VRAYLAR may make you drowsy. • Do not become too hot or dehydrated during treatment with VRAYLAR. o Do not exercise too much. o In hot weather, stay inside in a cool place if possible. o Stay out of the sun. o Do not wear too much clothing or heavy clothing. o Drink plenty of water. What are the possible side effects of VRAYLAR? VRAYLAR may cause serious side effects, including: • See “What is the most important information I should know about VRAYLAR?” • Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. • Neuroleptic malignant syndrome (NMS) is a serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: o high fever o stiff muscles o confusion o increased sweating o changes in your breathing, heart rate, and blood pressure • Uncontrolled body movements (tardive dyskinesia). VRAYLAR may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking VRAYLAR. Tardive dyskinesia may also start after you stop taking VRAYLAR. • Late occurring side effects. VRAYLAR stays in your body for a long time. Some side effects may not happen right away and can start a few weeks after you start taking VRAYLAR, or if your dose of VRAYLAR increases. Your healthcare provider should monitor you for side effects for several weeks after you start and after any increase in your dose of VRAYLAR. • Problems with your metabolism such as: o high blood sugar (hyperglycemia) and diabetes. Increases in blood sugar can happen in some people who take VRAYLAR. Extremely high blood sugar can lead to coma or death. Your healthcare Reference ID: 5484584 provider should check your blood sugar before you start, or soon after you start VRAYLAR, and then regularly during long-term treatment with VRAYLAR. Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with VRAYLAR: • feel very thirsty • need to urinate more than usual • feel very hungry • feel weak or tired • feel sick to your stomach • feel confused, or your breath smells fruity o increased fat levels (cholesterol and triglycerides) in your blood. Your healthcare provider should check the fat levels in your blood before you start, or soon after you start VRAYLAR, and then periodically during treatment with VRAYLAR. o weight gain. You and your healthcare provider should check your weight before you start and often during treatment with VRAYLAR. • Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with VRAYLAR. • Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. • Falls. VRAYLAR may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. • Seizures (convulsions). • Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. See “What should I avoid while taking VRAYLAR?” • Problems controlling your body temperature so that you feel too warm. See “What should I avoid while taking VRAYLAR?” • Difficulty swallowing that can cause food or liquid to get into your lungs. The most common side effects of VRAYLAR include: difficulty moving or slow movements, tremors, uncontrolled body movements, restlessness and feeling like you need to move around, sleepiness, nausea, vomiting, indigestion, constipation, feeling tired, trouble sleeping, increased appetite, and dizziness These are not all the possible side effects of VRAYLAR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VRAYLAR? • Store VRAYLAR at room temperature, between 68°F to 77°F (20°C to 25°C). Keep VRAYLAR and all medicines out of the reach of children. General information about the safe and effective use of VRAYLAR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VRAYLAR for a condition for which it was not prescribed. Do not give VRAYLAR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VRAYLAR that is written for healthcare professionals. What are the ingredients in VRAYLAR? Active ingredient: cariprazine Inactive ingredients: gelatin, magnesium stearate, pregelatinized starch, shellac, and titanium dioxide. Colorants include: black iron oxide, FD&C Blue 1, FD&C Red 3, FD&C Red 40, or yellow iron oxide. Manufactured by: Forest Laboratories Ireland Limited, Dublin, IE. Distributed by: AbbVie Inc. North Chicago, IL 60064, USA ©2024 AbbVie. All rights reserved. VRAYLAR and its design are trademarks of Allergan Pharmaceuticals International Limited, an AbbVie company. For more information, go to www.VRAYLAR.com or call 1-800-678-1605. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 2/2024 20084074 Reference ID: 5484584	custom-source	2025-02-12T15:47:03.812942	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/204370s012lbl.pdf', 'application_number': 204370, 'submission_type': 'SUPPL ', 'submission_number': 12}
80,357	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PHESGO safely and effectively. See full prescribing information for PHESGO. PHESGO® (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection, for subcutaneous use Initial U.S. Approval: 2020 WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete boxed warning. Cardiomyopathy: PHESGO administration can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue PHESGO for cardiomyopathy. (2.3, 5.1) Embryo-fetal Toxicity: Exposure to PHESGO can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception. (5.2, 8.1, 8.3) Pulmonary Toxicity: Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. (5.3) INDICATIONS AND USAGE PHESGO is a combination of pertuzumab and trastuzumab, HER2/neu receptor antagonists, and hyaluronidase, an endoglycosidase, indicated for: • Use in combination with chemotherapy as: o neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. (1.1) o adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence (1.1) • Use in combination with docetaxel for treatment of patients with HER2 positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. (1.2) DOSAGE AND ADMINISTRATION • For subcutaneous use in the thigh only. (2.2) • PHESGO has different dosage and administration instructions than intravenous pertuzumab and trastuzumab products. (2.2) • Do not administer intravenously. (2.2) • Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.1) • The initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes. (2.2) • Neoadjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion preoperatively for 3 to 6 cycles. (2.2) • Adjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion postoperatively for a total of 1 year (up to 18 cycles). (2.2) • MBC: administer PHESGO by subcutaneous injection and docetaxel by intravenous infusion every 3 weeks. (2.2) DOSAGE FORMS AND STRENGTHS Injection: • 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in a single-dose vial. (3) • 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in a single-dose vial. (3) CONTRAINDICATIONS PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients. (4) WARNINGS AND PRECAUTIONS • Exacerbation of Chemotherapy-Induced Neutropenia. (5.4) • Hypersensitivity and Administration-Related Reactions (ARRs): Monitor patients for systemic hypersensitivity reactions. Permanently discontinue PHESGO in patients who experience anaphylaxis or severe hypersensitivity reactions. (5.5) ADVERSE REACTIONS Neoadjuvant and Adjuvant Treatment of Breast Cancer • The most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia. (6.1) Metastatic Breast Cancer (based on intravenous pertuzumab) • The most common adverse reactions (>30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of PHESGO. (8.3) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 Reference ID: 5484217 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, AND PULMONARY TOXICITY 1 INDICATIONS AND USAGE 1.1 Early Breast Cancer (EBC) 1.2 Metastatic Breast Cancer (MBC) 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Important Dosage and Administration Information 2.3 Recommended Doses and Schedules 2.4 Dose Modification 2.5 Preparation for Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy 5.2 Embryo-Fetal Toxicity 5.3 Pulmonary Toxicity 5.4 Exacerbation of Chemotherapy-Induced Neutropenia 5.5 Hypersensitivity and Administration-Related Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Neoadjuvant and Adjuvant Breast Cancer 14.2 Metastatic Breast Cancer 14.3 Patient Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5484217 FULL PRESCRIBING INFORMATION WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY Cardiomyopathy PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity were highest in patients receiving PHESGO with anthracycline containing chemotherapy regimens. Evaluate cardiac function prior to and during treatment with PHESGO. Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Embryo-fetal Toxicity Exposure to PHESGO can result in embryo-fetal death and birth defects, including oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1), (8.3)]. Pulmonary Toxicity PHESGO administration can result in serious and fatal pulmonary toxicity. Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Monitor patients until symptoms completely resolve [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Early Breast Cancer (EBC) PHESGO is indicated for use in combination with chemotherapy for • the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer [see Dosage and Administration (2.2) and Clinical Studies (14.2)]. • the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.2)]. Select patients for therapy based on an FDA-approved companion diagnostic test [see Dosage and Administration (2.1)]. 1.2 Metastatic Breast Cancer (MBC) PHESGO is indicated for use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease [see Dosage and Administration (2.2) and Clinical Studies (14.1)]. Select patients for therapy based on an FDA-approved companion diagnostic test [see Dosage and Administration (2.1)]. Reference ID: 5484217 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.2 Important Dosage and Administration Information PHESGO is for subcutaneous use only in the thigh. Do not administer intravenously. PHESGO has different dosage and administration instructions than intravenous pertuzumab, intravenous trastuzumab, and subcutaneous trastuzumab when administered alone. Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan. PHESGO must always be administered by a healthcare professional. In patients receiving an anthracycline-based regimen for early breast cancer, administer PHESGO following completion of the anthracycline. In patients receiving PHESGO for early breast cancer with docetaxel or paclitaxel, administer docetaxel or paclitaxel after PHESGO. In patients receiving PHESGO for metastatic breast cancer with docetaxel, administer docetaxel after PHESGO. Observe patients for a minimum of 30 minutes after initial dose of PHESGO and 15 minutes after each maintenance dose of PHESGO for signs or hypersensitivity symptoms or administration-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use [see Warnings and Precautions (5.5)]. 2.3 Recommended Doses and Schedules The recommended dosage and administration schedule for PHESGO are shown in Table 1. Table 1: Recommended Dosage and Administration Schedule Dose Strength Administration Instructions Initial dose 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase in 15 mL (1,200 mg, 600 mg, and 30,000 units/15 mL) Administer subcutaneously over approximately 8 minutes Maintenance dose (administer every 3 weeks) 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase in 10 mL (600 mg, 600 mg, and 20,000 units/10 mL) Administer subcutaneously over approximately 5 minutes every 3 weeks Reference ID: 5484217 No dose adjustments for PHESGO are required for patient body weight or for concomitant chemotherapy regimen. Patients currently receiving intravenous pertuzumab and trastuzumab can transition to PHESGO. In patients receiving intravenous pertuzumab and trastuzumab with <6 weeks since their last dose, administer PHESGO as a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every 3 weeks for subsequent administrations. In patients receiving intravenous pertuzumab and trastuzumab with ≥6 weeks since their last dose, administer PHESGO as an initial dose of 1,200 mg pertuzumab/600 mg trastuzumab, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations. Neoadjuvant Treatment of Breast Cancer Administer PHESGO every 3 weeks for 3 to 6 cycles as part of a treatment regimen for early breast cancer [see Clinical Studies (14.2)]. Refer to the prescribing information for pertuzumab, administered in combination with trastuzumab and chemotherapy, for recommended dose and dosage modifications. Following surgery, patients should continue to receive PHESGO to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as a part of a complete regimen for early breast cancer. Adjuvant Treatment of Breast Cancer Administer PHESGO every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as part of a complete regimen for early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy. Start PHESGO on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.2)]. Metastatic Breast Cancer (MBC) When administered with PHESGO, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated. Administer PHESGO until disease progression or unmanageable toxicity, whichever occurs first. 2.4 Dose Modification Dose Modification for Delayed or Missed Doses For delayed or missed doses of PHESGO, if the time between two sequential injections is less than 6 weeks, administer the maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL. Do not wait until the next planned dose. If the time between two sequential injections is 6 weeks or more, re-administer the initial dose of 1,200 mg, 600 mg, and 30,000 units/15 mL, followed every 3 weeks thereafter by a maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL. For chemotherapy dose modifications, see relevant prescribing information. Cardiomyopathy [see Boxed Warning, Warnings and Precautions (5.1)] Assess left ventricular ejection fraction (LVEF) prior to initiation of PHESGO and at regular intervals during treatment as indicated in Table 2. The recommendations on dose modifications in the event of LVEF dysfunction are indicated in Table 2 [see Warnings and Precautions (5.1)]. Reference ID: 5484217 Table 2: Dose Modifications for Left Ventricular Dysfunction Pre treatment LVEF: Monitor LVEF every: Withhold PHESGO for at least 3 weeks for an LVEF decrease to: Resume PHESGO after 3 weeks if LVEF has recovered to: Early Breast Cancer ≥55%* ~12 weeks (once during neoadju vant therapy) <50% with a fall of ≥10%-points below pre treatment value Either ≥50% <10% points below pre treatment value Metastatic Breast Cancer ≥50% ~12 weeks Either Either <40% 40%-45% with a fall of ≥10% points below pre-treatment value >45% 40%-45% with a fall of <10%-points below pre treatment value * For patients receiving anthracycline-based chemotherapy, a LVEF of ≥50% is required after completion of anthracyclines, before starting PHESGO If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO [see Warnings and Precautions (5.1)]. Hypersensitivity and Administration-Related Reactions Discontinue the injection immediately if the patient experiences a serious hypersensitivity reaction (e.g. anaphylaxis) [see Warnings and Precautions (5.5)]. 2.5 Preparation for Administration To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is PHESGO and not intravenous pertuzumab, or intravenous trastuzumab, or subcutaneous trastuzumab. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if particulates or discoloration is present. Do not shake. Discard any unused portion remaining in the vial. For both the initial and maintenance dose, each corresponding PHESGO vial is ready-to-use for one subcutaneous injection and should not be diluted. A syringe, a transfer needle, and an injection needle are needed to withdraw PHESGO solution from the vial and inject it subcutaneously. PHESGO may be injected using 25G-27G (3/8”-5/8”) hypodermic injection needles. To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration followed by volume adjustment to 15 mL (initial dose) and 10 mL (maintenance dose). If the dose is not to be administered immediately, and the solution of PHESGO has been withdrawn from the vial into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe with the peel-off sticker and store the syringe in the refrigerator [2°C to 8°C (36°F to 46°F)] for up to 24 hours and at room temperature [20°C to 25°C (68°F to 77°F)] for up to 4 hours and avoid unnecessary storage. Reference ID: 5484217 PHESGO is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride and fluorinated ethylene polypropylene. Administration • Administer PHESGO 1,200 mg, 600 mg, 30,000 units/15 mL subcutaneously over approximately 8 minutes • Administer PHESGO 600 mg, 600 mg, 20,000 units/10 mL subcutaneously over approximately 5 minutes The subcutaneous injection site should be alternated between the left and right thigh only. New injections should be given at least 1 inch (2.5 cm) from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. Do not split the dose between two syringes or between two sites of administration. During the treatment course with PHESGO, other medications for subcutaneous administration should preferably be injected at different sites. 3 DOSAGE FORMS AND STRENGTHS Injection: PHESGO is a clear to opalescent, and colorless to slightly brownish solution provided as: • 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in a single-dose vial • 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in a single-dose vial 4 CONTRAINDICATIONS PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients. 5 Warnings and Precautions 5.1 Cardiomyopathy PHESGO can cause hypertension, arrhythmias, left ventricular cardiac dysfunction, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. PHESGO can cause asymptomatic decline in LVEF. An increased incidence of LVEF decline has been observed in patients treated with intravenous pertuzumab, intravenous trastuzumab, and docetaxel. A 4-6-fold increase in the incidence of symptomatic myocardial dysfunction has been reported among patients receiving trastuzumab, with the highest absolute incidence occurring when trastuzumab was administered with an anthracycline. Patients who receive anthracycline after stopping PHESGO may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. Cardiac Monitoring Prior to initiation of PHESGO, conduct a thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. During treatment with PHESGO, assess LVEF at regular intervals [see Dosage and Administration (2.4)]. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO. Reference ID: 5484217 Following completion of PHESGO, continue to monitor for cardiomyopathy and assess LVEF measurements every 6 months for at least 2 years as a component of adjuvant therapy. PHESGO In the FeDeriCa trial, the percentage of patients with at least one cardiac disorder was 22% in the PHESGO arm. The most frequent cardiac adverse reaction in the PHESGO arm was ejection fraction decreased. The incidence of cardiac failure (NYHA Class III/IV) with a LVEF decline ≥10% and a drop to less than 50% was 0.8% in the PHESGO arm. Confirmed asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF ≥10% and a drop to less than 50% was 1.2% in the PHESGO arm [see Adverse Reactions (6.1)]. PHESGO and/or intravenous pertuzumab and trastuzumab have not been studied in patients with a pretreatment LVEF value of <55% (EBC) or <50% (MBC); a prior history of CHF, conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to >360 mg/m2 of doxorubicin or its equivalent. 5.2 Embryo-Fetal Toxicity PHESGO can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of intravenous trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In an animal reproduction study, administration of intravenous pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on Cmax. Verify the pregnancy status of females of reproductive potential prior to the initiation of PHESGO. Advise pregnant women and females of reproductive potential that exposure to PHESGO during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PHESGO [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)]. 5.3 Pulmonary Toxicity PHESGO can cause serious and fatal pulmonary toxicity. These adverse reactions have been reported with intravenous trastuzumab. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. 5.4 Exacerbation of Chemotherapy-Induced Neutropenia PHESGO may exacerbate chemotherapy-induced neutropenia. In randomized controlled clinical trials with intravenous trastuzumab, Grade 3-4 neutropenia and febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not. 5.5 Hypersensitivity and Administration-Related Reactions Severe administration-related reactions (ARRs), including hypersensitivity, anaphylaxis, and events with fatal outcomes, have been associated with intravenous pertuzumab and trastuzumab. Patients experiencing dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or of a fatal ARR. Reference ID: 5484217 In the FeDeriCatrial, the incidence of hypersensitivity was 1.2% in the PHESGO arm. Administration-related reactions occurred in 21% of patients who received PHESGO. In the PHESGO arm, the most common administration-related reactions were injection site reaction (15%) and injection site pain (2%). Closely monitor patients during and for 30 minutes after the injection of initial dose and during and for 15 minutes following subsequent injections of maintenance dose of PHESGO. If a significant injection-related reaction occurs, slow down or pause the injection and administer appropriate medical therapies. Evaluate and carefully monitor patients until complete resolution of signs and symptoms. Permanently discontinue with PHESGO in patients who experience anaphylaxis or severe injection-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. For patients experiencing reversible Grade 1 or 2 hypersensitivity reactions, consider pre-medication with an analgesic, antipyretic, or an antihistamine prior to readministration of PHESGO [see Adverse Reactions (6.1)]. PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab, hyaluronidase or to any of its excipients [see Contraindications (4)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] • Pulmonary Toxicity [see Warnings and Precautions (5.3)] • Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.4)] • Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Neoadjuvant and Adjuvant Treatment of Breast Cancer The safety of PHESGO was evaluated in an open-label, multicenter, randomized trial (FeDeriCa) conducted in 500 patients with HER2 overexpressing early breast cancer [see Clinical Studies (14.2)]. Patients were randomized to receive either PHESGO (1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL) followed every 3 weeks by a maintenance dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL or the recommended dosages for intravenous pertuzumab and intravenous trastuzumab. Patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Following surgery, patients continued therapy with PHESGO alone or intravenous pertuzumab and trastuzumab (intravenous or subcutaneously administered) as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles. The median duration of treatment for PHESGO was 24 weeks (range: 0-42 weeks). Serious adverse reactions occurred in 16% of patients who received PHESGO. Serious adverse reactions in >1% of patients included febrile neutropenia (4%), neutropenic sepsis (1%), and Reference ID: 5484217 neutrophil count decreased (1%). One fatal adverse reaction occurred in 1/248 (0.4%) of patients, which was due to acute myocardial infarction, and occurred prior to the start of HER2 targeted treatment with PHESGO. Adverse reactions resulting in permanent discontinuation of any study drug occurred in 8% of patients on the PHESGO arm. Adverse reactions which resulted in permanent discontinuation of PHESGO were ejection fraction decreased (1.2%), cardiac failure (0.8%), and pneumonitis/pulmonary fibrosis (0.8%). Dosage interruptions due to an adverse reaction occurred in 40% of patients who received PHESGO. Adverse reactions which required dosage interruption in >1% of patients who received PHESGO included neutropenia (8%), neutrophil count decreased (4%) and diarrhea (7%). Table 3 summarizes the adverse reactions in FeDeriCa. Table 3: Adverse Reactions (≥5%) in Patients Who Received PHESGO in FeDeriCa Adverse Reactions PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Skin and subcutaneous tissue disorders Alopecia 77 0 71 0.4 Dry skin 15 0.4 13 0 Rash 16 0.4 21 0 Nail discoloration 9 0 6 0 Erythema 9 0 5 0 Dermatitis 7 0 6 0 Nail disorder 7 0 7 0.4 Palmar-plantar erythrodysaesthesia syndrome 6 0.8 5 0.4 Gastrointestinal disorders Nausea 60 2 61 1.6 Diarrhea 60 7 57 4.8 Stomatitis 25 0.8 24 0.8 Constipation 22 0 21 0 Vomiting 20 0.8 19 1.2 Dyspepsia 14 0 12 0 Hemorrhoids 9 0 4.0 0 Abdominal pain upper 8 0 6 0 Abdominal pain 9 0.4 6 0 Blood and lymphatic system disorders Anemia 36 1.6 43 4.4 Neutropenia 22 14 27 14 Leukopenia 9 2.4 14 2 Febrile neutropenia 7 7 6 6 General disorders and administration site conditions Reference ID: 5484217 Adverse Reactions PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Asthenia 31 0.4 32 2.4 Fatigue 29 2 24 2 Mucosal inflammation 15 0.8 20 1.2 Injection site reaction 15 0 0.8 0 Pyrexia 13 0 16 0.4 Edema peripheral 8 0 10 0 Malaise 7 0 6 0.4 Influenza-like illness 5 0 3.6 0 Nervous system disorders Dysgeusia 17 0 14 0 Peripheral sensory neuropathy 16 0.8 14 0.4 Headache 17 0 25 0.8 Neuropathy peripheral 12 0.4 15 2 Paresthesia 10 0.8 8 0 Dizziness 13 0 11 0 Investigations Weight decreased 11 0.8 6 0.8 Musculoskeletal and connective tissue disorders Myalgia 25 0.4 19 0.4 Arthralgia 24 0 28 0.4 Back pain 10 0 4.8 0 Bone pain 7 0 5 0 Pain in extremity 6 0 8 0 Muscle spasms 6 0 7 0 Musculoskeletal pain 6 0.4 8 0 Respiratory, thoracic and mediastinal disorder Cough 15 0.4 13 0 Epistaxis 12 0 14 0.4 Dyspnea 10 1.2 5 0 Rhinorrhea 7 0 4.4 0 Infections and infestations Upper respiratory tract infection 11 0 8 0.8 Nasopharyngitis 9 0 10 0 Paronychia 7 0.4 3.6 0 Urinary tract infection 7 0.4 5 0 Injury, poisoning and procedural complications Procedural pain 13 0 10 0 Radiation skin injury 19 0.4 19 0.4 Infusion related reaction 3.6 0 15 0.8 Metabolism and nutrition disorders Reference ID: 5484217 Adverse Reactions PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Decreased appetite 17 0.8 19 0.4 Hypokalemia 7 1.6 8 0 Psychiatric disorders Insomnia 17 0 13 0.4 Eye disorders Lacrimation increased 5 0.4 6 0 Dry eye 5 0.4 3.2 0 Vascular disorders Hot flush 12 0 13 0 Clinically relevant adverse reactions in <5% of patients who received PHESGO include ejection fraction decreased (3.6%) and pruritus (3.2%). In the FeDeriCa trial, when PHESGO was administered alone, adverse reactions occurred in <10% of patients with the exception of radiation skin injury (20%), arthralgia (19%), diarrhea (17%), injection site reaction (13%), dyspepsia (12%), asthenia (11%), hot flush (11%), and pruritus (10%). Table 4 summarizes the laboratory abnormalities in FeDeriCa. Table 4: Select Laboratory Abnormalities (>5%) that Worsened from Baseline in Patients Who Received PHESGO in FeDeriCa 1 Laboratory Abnormality PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Hematology Hemoglobin (low) 90 2.8 92 4.4 Lymphocytes, Absolute (low) 89 37 88 36 Total Leukocyte Count (low) 82 25 78 25 Neutrophils, Total Absolute (low) 68 30 67 33 Platelet (low) 27 0 28 0.4 Chemistry Creatinine (high) 84 0 87 0.4 Alanine aminotransferase (high) 58 1.6 68 2.4 Aspartate aminotransferase (high) 50 0.8 58 0.8 Reference ID: 5484217 Laboratory Abnormality PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Potassium (low) 17 5.2 17 2.8 Albumin (low) 16 0 20 0.4 Potassium (high) 13 1.2 9 0 Sodium (low) 13 0.4 10 1.6 Bilirubin (high) 9 0 9 0.4 Glucose (low) 9 0 9 0.4 Sodium (high) 7 0.8 10 0.8 1 The denominator used to calculate the rate varied from 163 to 252 based on the number of patients with a baseline value and at least one post-treatment value. Other Clinical Trials Experience The safety of the addition of intravenous pertuzumab to trastuzumab in combination with chemotherapy has been established in studies conducted in patients with HER2 overexpressing early breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, nausea, fatigue, neutropenia, vomiting, peripheral neuropathy, constipation, anemia, asthenia, mucosal inflammation, myalgia, and thrombocytopenia. Refer to the Prescribing Information for pertuzumab for more information. The safety of intravenous pertuzumab, trastuzumab and docetaxel has been established in patients with HER2 overexpressing metastatic breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. Refer to the Prescribing Information for pertuzumab for more information. 6.2 Postmarketing Experience The following adverse reactions have been identified with the use of intravenous pertuzumab and trastuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Glomerulopathy • Immune thrombocytopenia • Tumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated. 7 DRUG INTERACTIONS Patients who receive anthracycline after stopping PHESGO may be at increased risk of cardiac dysfunction because of PHESGO’s long washout period [see Clinical Pharmacology (12.3)]. If possible, avoid anthracycline-based therapy for up to 7 months after stopping PHESGO. If anthracyclines are used, carefully monitor the patient’s cardiac function. Reference ID: 5484217 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Pharmacovigilance Program There is a pregnancy pharmacovigilance program for PHESGO. If PHESGO is administered during pregnancy, or if a patient becomes pregnant while receiving PHESGO or within 7 months following the last dose of PHESGO, health care providers and patients should immediately report PHESGO exposure to Genentech at 1-888-835-2555. Risk Summary PHESGO can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of intravenous trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data). In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures that were 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on Cmax (see Data). Apprise the patient of the potential risks to a fetus. There are clinical considerations if PHESGO is used during pregnancy or within 7 months prior to conception (see Clinical Considerations). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received PHESGO during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data In post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after amniotic index improved and oligohydramnios recurred. Animal Data PHESGO for subcutaneous injection contains pertuzumab, trastuzumab, and hyaluronidase [see Description (11)]. Pertuzumab: Pregnant cynomolgus monkeys were treated on Gestational Day (GD) 19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases Reference ID: 5484217 in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85%. At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. Trastuzumab: In studies where intravenous trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects. Hyaluronidase: In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is >2,400 and 3,600, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is >400 and 600, based on loading and maintenance doses, respectively, times higher than the human dose. In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is >1,200 and 1,800, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring. 8.2 Lactation Risk Summary There is no information regarding the presence of pertuzumab, trastuzumab or hyaluronidase in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest that human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating cynomolgus monkeys but not associated with neonatal toxicity (see Data). Consider the developmental and health benefits of breast feeding along with the mother’s clinical need for PHESGO treatment and any potential adverse effects on the breastfed child from PHESGO or from the underlying maternal condition. This consideration should also take into account the elimination half-life of pertuzumab and the trastuzumab wash out period of 7 months [see Clinical Pharmacology (12.3)]. Data In lactating cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of intravenous trastuzumab). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age. 8.3 Females and Males of Reproductive Potential PHESGO can cause embryo-fetal harm when administered during pregnancy. Reference ID: 5484217 Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of PHESGO. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PHESGO [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PHESGO in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients in the FeDeriCa trial (n=500) treated with PHESGO, 11% were 65 and over, while 1.6% were 75 and over. Clinical studies of PHESGO did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients. In the intravenous trastuzumab trials, the risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients, in both those receiving treatment for adjuvant therapy or metastatic disease. Other differences in safety or effectiveness were not observed between elderly patients and younger patients. In the intravenous pertuzumab in combination with trastuzumab trials, the risk of decreased appetite, anemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral and hypomagnesemia was increased in patients 65 years of age and older compared to patients less than 65 years of age. 11 DESCRIPTION PHESGO is a combination of pertuzumab, trastuzumab, and hyaluronidase. Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2). Pertuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. Pertuzumab has an approximate molecular weight of 148 kDa. Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. Trastuzumab has a molecular weight of approximately 148 kDa. Hyaluronidase (recombinant human) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is a glycosylated single-chain protein produced by mammalian (Chinese Hamster Ovary) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa. PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection is a sterile, preservative- free, clear to opalescent, and colorless to slightly brownish solution supplied in single-dose vials for subcutaneous administration. PHESGO injection is supplied as two different configurations: • PHESGO is supplied in a 15 mL single-dose vial containing 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase, and α,α-trehalose (397 mg), Reference ID: 5484217 L-histidine (6.75 mg), L-histidine hydrochloric monohydrate (53.7 mg), L-methionine (22.4 mg), polysorbate 20 (6 mg), and sucrose (685 mg) with a pH of 5.5. • PHESGO is supplied in a 10 mL single-dose vial containing 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase, and α,α-trehalose (397 mg), L- histidine (4.4 mg), L-histidine hydrochloric monohydrate (36.1 mg), L-methionine (14.9 mg), polysorbate 20 (4 mg), and sucrose (342 mg) with a pH of 5.5. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling pathway in human tumor cells that overexpress HER2. Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in PHESGO acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into the systemic circulation when given in the subcutis of Göttingen Minipigs. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of pertuzumab and trastuzumab in PHESGO have not been fully characterized. Cardiac Electrophysiology The effect of intravenous pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2-positive breast cancer (NCT00567190). No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial. A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design. The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship Reference ID: 5484217 between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors. 12.3 Pharmacokinetics The pharmacokinetics (PK) of pertuzumab and trastuzumab were characterized in the FeDeriCa trial following subcutaneous administration of PHESGO (1200 mg pertuzumab/600 mg trastuzumab initial dose followed by 600 mg pertuzumab/600 mg trastuzumab every 3 weeks) and intravenous administration of pertuzumab and trastuzumab (840 mg pertuzumab/8 mg/kg trastuzumab initial dose followed by 420 mg pertuzumab/6 mg/kg trastuzumab every 3 weeks). Trastuzumab is estimated to reach concentrations that are <1 mcg/mL by 7 months in at least 95% patients. Pertuzumab Cycle 7 Ctrough was 88.7 mcg/mL for PHESGO and 72.4 mcg/mL for intravenous pertuzumab with a geometric mean ratio (GMR) of 1.22 (90% CI: 1.14–1.31). Trastuzumab Cycle 7 Ctrough was 57.5 mcg/mL for PHESGO and 43.2 mcg/mL for intravenous trastuzumab with a GMR of 1.33 (90% CI: 1.24–1.43) [see Clinical Studies (14.2)]. Following subcutaneous administration of PHESGO, the pertuzumab median Cycle 7 Cmax was 34% lower and AUC0-21days was 5% higher than that following intravenous administration of pertuzumab. The median trastuzumab Cycle 7 Cmax was 31% lower and AUC0-21days was 10% higher, than that following intravenous administration of trastuzumab. Absorption The mean absolute bioavailability (CV%) was 0.71 (18%) for pertuzumab and 0.77 (13%) for trastuzumab after subcutaneous administration of the approved recommended dosage of PHESGO. The median time to reach Cmax was 3.8 days for both pertuzumab and trastuzumab. Distribution The volume of distribution of pertuzumab and trastuzumab at steady state was 2.8 L and 2.9 L, respectively. Elimination For pertuzumab, the clearance (CV%) was 0.2 L/day (24%). For trastuzumab, the linear clearance was 0.1 L/day (30%); the non-linear elimination Vmax (CV%) was 12 mg/day (20%) and Km (CV%) was 34 mg/L (39%). The terminal half-life of pertuzumab and trastuzumab was 24 days and 22 days, respectively. Steady state concentration was achieved at Cycle 7 for pertuzumab and at Cycle 11 for trastuzumab. Specific Populations No dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant. In patients with a body weight <58 kg, mean Cycle 7 AUC0-21days of trastuzumab was about 33% higher after PHESGO than after intravenous trastuzumab treatment, whereas in the highest BW group (>77 kg) Cycle 7 AUC0-21days was 24% lower after PHESGO than after intravenous trastuzumab treatment. However, no body weight-based dose adjustments are needed, as the exposure changes are not considered clinically relevant. No clinically significant differences in the pharmacokinetics of pertuzumab and trastuzumab were observed based on age (25 to 80 years), race (Asian and non-Asian), and renal impairment (creatinine clearance 30 mL/min or greater determined by Cockcroft-Gault). The effects of hepatic impairment on the pharmacokinetics of pertuzumab and trastuzumab are unknown. Drug Interaction Studies There have been no formal clinical drug interaction studies performed with PHESGO. Reference ID: 5484217 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the trial described below, including those of PHESGO or of other pertuzumab or trastuzumab products. During treatment and post-treatment with subcutaneous administration of PHESGO and concurrent administration with neoadjuvant chemotherapy in the FeDeriCa trial [see Clinical Studies (14.1)], the incidence of anti-pertuzumab and anti-trastuzumab antibodies was 12.9% (31/241) and 2.1% (5/241), respectively. During treatment and post-treatment with intravenous pertuzumab and trastuzumab and concurrent administration with neoadjuvant chemotherapy, the incidence of anti-pertuzumab and anti-trastuzumab antibodies was 10.6 % (26/245) and 0.4% (1/245), respectively. The incidence of neutralizing antibodies (NAb) to pertuzumab and to trastuzumab was 6% (2/31) and 20% (1/5), respectively, in patients treated with PHESGO. The corresponding incidences of NAb were 11.5% (3/26) and 0% (0/1), respectively, in patients treated with intravenous pertuzumab and trastuzumab. Because of limited immunogenicity data, the effect of anti-pertuzumab and anti-trastuzumab antibodies on the pharmacokinetics and effectiveness of PHESGO is unknown. There was no identified clinically significant effect of anti-pertuzumab and anti-trastuzumab antibodies on the safety of PHESGO. In the FeDeriCa trial, the incidence of anti-rHuPH20 antibodies was 6.3% (15/238) and the incidence of NAb was 0% (0/15) in patients treated with PHESGO. Because of limited immunogenicity data, the clinical impact of anti-rHuPH20 antibodies is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility PHESGO contains pertuzumab, trastuzumab, and hyaluronidase. Pertuzumab Studies have not been performed to evaluate the carcinogenicity or mutagenic potential of pertuzumab. No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six months duration in cynomolgus monkeys. Trastuzumab Trastuzumab has not been tested for carcinogenicity potential. No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab. A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg of intravenous trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. Hyaluronidase Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when Reference ID: 5484217 subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is >223 and 335, based on loading and maintenance doses, respectively, times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data. 14 CLINICAL STUDIES 14.1 Neoadjuvant and Adjuvant Treatment of Breast Cancer The effectiveness of PHESGO for use in combination with chemotherapy has been established for the treatment of patients with HER2-positive early breast cancer. Use of PHESGO for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing early breast cancer (NCT00545688, NCT00976989, NCT02132949, NCT01358877) and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between PHESGO and intravenous pertuzumab and intravenous trastuzumab in FeDeriCa [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. FeDeriCa The FeDeriCa trial (NCT03493854) was an open-label, multicenter, randomized trial conducted in 500 patients with operable or locally advanced (including inflammatory) HER2-positive breast cancer with a tumor size >2 cm or node-positive. HER2 overexpression was defined as IHC 3+ in >10% of immunoreactive cells or HER2 gene amplification by ISH (ratio of HER2 gene signals to centromere 17 signals >2.0) using an FDA-approved test. Patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Investigators selected one of two of the following neoadjuvant chemotherapy regimens for individual patients: • 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks followed by paclitaxel (80 mg/m2) weekly for 12 weeks • 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks followed by 4 cycles of docetaxel (75 mg/m2 for the first cycle and then 100 mg/m2 at subsequent cycles at the investigator’s discretion) every 3 weeks Following surgery, patients continued therapy with PHESGO or intravenous pertuzumab and trastuzumab as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles of anti HER2 therapy. Patients also received adjuvant radiotherapy and endocrine therapy as per investigator’s discretion. In adjuvant period, substitution of intravenous trastuzumab for subcutaneous trastuzumab was permitted at investigator discretion. Patients received HER2 targeted therapy every 3 weeks according to Table 5 as follows: Table 5: Dosing and Administration of PHESGO, Intravenous Pertuzumab, Intravenous Trastuzumab, and Subcutaneous Trastuzumab Medication Administration Dose Initial Maintenance PHESGO Subcutaneously 1200 mg/600 mg 600mg/600 mg Pertuzumab Intravenously 840 mg 420 mg Reference ID: 5484217 Trastuzumab Intravenously 8 mg/kg 6 mg/kg Trastuzumab-oysk Subcutaneously* 600 mg * In adjuvant period substitution of intravenous trastuzumab for subcutaneous trastuzumab was permitted at investigator discretion FeDeriCa was designed to demonstrate non-inferiority of the Cycle 7 (i.e., pre-dose Cycle 8) pertuzumab serum Ctrough from PHESGO pertuzumab to the intravenous pertuzumab (major efficacy outcome measure) [see Clinical Pharmacology 12.3]. Additional outcome measures included Cycle 7 serum trastuzumab Ctrough, efficacy (pathological complete response [pCR], defined as the absence of invasive neoplastic cells in the breast and in the axillary lymph nodes), and safety. The median age of patients was 51 years (range: 25-81); 99% were female; 66% were White, 21% were Asian, 4% were American Indian or Alaska Native, 1.2% were Black or African American, 15% were Hispanic or Latino. The majority of patients had hormone receptor-positive disease (61%) or node-positive disease (58%). Table 6: Summary of Pathological Complete Response (pCR) (FeDeriCa) PHESGO n=248 Intravenous pertuzumab + trastuzumab n=252 pCR: ypT0/is, ypN0 148 (59.7%) 150 (59.5%) Exact 95% CI for pCR Rate1 (53.3%, 65.8%) (53.2%, 65.6%) Difference in pCR rate (SC minus IV arm) 0.15% 95% CI for the difference in pCR2 rate (-8.7%; 9.0%) 1 Confidence interval for one sample binomial using Pearson-Clopper method 2 Hauck-Anderson continuity correction has been used in this calculation 14.2 Metastatic Breast Cancer The effectiveness of PHESGO for use in combination with docetaxel has been established for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Use of PHESGO for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing metastatic breast cancer (NCT00567190) and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between PHESGO and intravenous pertuzumab and intravenous trastuzumab in FeDeriCa [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. 14.3 Patient Experience The PHranceSCa trial (NCT03674112) was a randomized, multi-center, open-label cross-over trial conducted in 160 patients with HER2-positive breast cancer undergoing adjuvant treatment. All patients completed neoadjuvant treatment with pertuzumab, trastuzumab and chemotherapy and had surgery before randomization. Following randomization, 80 patients in arm A received 3 cycles of intravenous pertuzumab and trastuzumab followed by 3 cycles of PHESGO and 80 patients in arm B received 3 cycles of PHESGO followed by 3 cycles of intravenous pertuzumab and trastuzumab. All patients received 18 total cycles of HER2-targeted therapy. After Cycle 6, Reference ID: 5484217 136 out of 160 patients (85%) reported preferring subcutaneous administration of PHESGO over intravenous pertuzumab and trastuzumab and the most common reason was that administration required less time in the clinic. After Cycle 6, 22 out of 160 patients (14%) reported preferring intravenous pertuzumab and trastuzumab over PHESGO and the most common reason was feels more comfortable during administration. Two out of 160 patients (1%) had no preference for the route of administration. All 160 patients (100%) completed the preference questionnaire. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection is a sterile, preservative- free, clear to opalescent, and colorless to slightly brownish solution in single-dose vials for subcutaneous administration supplied as each carton containing one single-dose vial: • 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) (NDC 50242-245-01). • 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, 2,000 units/mL) (NDC 50242-260-01). Storage and Handling Store PHESGO vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Cardiomyopathy • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential that exposure to PHESGO during pregnancy or within 7 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. • Advise women who are exposed to PHESGO during pregnancy or within 7 months prior to conception that there is a pregnancy pharmacovigilance program that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Genentech [see Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PHESGO [see Use in Specific Populations (8.3)]. Hypersensitivity and Administration-Related Reactions • Advise patients to contact their healthcare provider immediately and to report any symptoms of hypersensitivity and administration-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.5)]. Reference ID: 5484217 PHESGO® [pertuzumab, trastuzumab, and hyaluronidase-zzxf] PHESGO® is a trademark of Genentech, Inc. ©2024 Genentech, Inc. Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 Reference ID: 5484217	custom-source	2025-02-12T15:47:04.081674	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761170s007lbl.pdf', 'application_number': 761170, 'submission_type': 'SUPPL ', 'submission_number': 7}
80,358	------------------------WARNINGS AND PRECAUTIONS---------------------- HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IMKELDI safely and effectively. See full prescribing information for IMKELDI. IMKELDI (imatinib) oral solution Initial U.S. Approval: 2001 ---------------------------INDICATIONS AND USAGE---------------------------- Imkeldi is a kinase inhibitor indicated for the treatment of: • Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. (1.1) • Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy. (1.2) • Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). (1.3) • Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. (1.4) • Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. (1.5) • Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. (1.6) • Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. (1.7) • Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). (1.8) • Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). (1.9) • Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. (1.10) -----------------------DOSAGE AND ADMINISTRATION---------------------- • Adults with Ph+ CML CP (2.2): 400 mg/day • Adults with Ph+ CML AP or BC (2.2): 600 mg/day • Pediatrics with Ph+ CML CP (2.3): 340 mg/m2/day • Adults with Ph+ ALL (2.4): 600 mg/day • Pediatrics with Ph+ ALL (2.5): 340 mg/m2/day • Adults with MDS/MPD (2.6): 400 mg/day • Adults with ASM (2.7): 100 mg/day or 400 mg/day • Adults with HES/CEL (2.8): 100 mg/day or 400 mg/day • Adults with DFSP (2.9): 800 mg/day • Adults with metastatic and/or unresectable GIST (2.10): 400 mg/day • Adjuvant treatment of adults with GIST (2.11): 400 mg/day • Patients with mild to moderate hepatic impairment (2.12): 400 mg/day • Patients with severe hepatic impairment (2.12): 300 mg/day All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device. A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose. (2.1, 5.15) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Oral solution: 80 mg/mL of imatinib (3) -------------------------------CONTRAINDICATIONS----------------------------- None. (4) • Fluid Retention and Edema: Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics. (5.1, 6.1) • Hematologic Toxicity: Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter. (5.2) • Congestive Heart Failure and Left Ventricular Dysfunction: Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure. (5.3) • Hepatotoxicity: Severe hepatotoxicity, including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. (5.4) • Hemorrhage: Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST. (5.5) • Gastrointestinal Disorders: Gastrointestinal (GI) perforations, some fatal, have been reported. (5.6) • Hypereosinophilic Cardiac Toxicity: Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Imkeldi in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM). (5.7) • Dermatologic Toxicities: Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Imkeldi. (5.8) • Hypothyroidism: Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients. (5.9) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to use effective contraception. (5.10, 8.1) • Growth Retardation in Children and Adolescents: Growth retardation occurring in children and pre-adolescents receiving Imkeldi has been reported. Close monitoring of growth in children under Imkeldi treatment is recommended. (5.11, 6.2) • Tumor Lysis Syndrome: Close monitoring is recommended. (5.12) • Impairments Related to Driving and Using Machinery: Motor vehicle accidents have been reported in patients receiving imatinib. Caution patients about driving a car or operating machinery. (5.13) • Renal Toxicity: A decline in renal function may occur in patients receiving Imkeldi. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction. (5.14) • Measuring Device: Advise patients to measure IMKELDI with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions. Advise patients to ask their pharmacist to recommend an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring the correct dose. (5.15) -------------------------------ADVERSE REACTIONS----------------------------- The most frequently reported adverse reactions (≥30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Shorla Oncology at 844-9-SHORLA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS----------------------------- • CYP3A4 inducers: Avoid or increase imatinib dosage if unavoidable. (7.1) • CYP3A4 inhibitors: Use caution. Avoid grapefruit juice. (7.2) • CYP3A4 substrates: Use caution. Patients who require anticoagulation should receive other anticoagulants instead of warfarin. (7.3) • CYP2D6 substrates: Use caution. (7.4) -----------------------USE IN SPECIFIC POPULATIONS----------------- • Lactation: Advise not to breastfeed.(8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 Reference ID: 5484208 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 5.11 Growth Retardation in Children and Adolescents 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid 5.12 Tumor Lysis Syndrome Leukemia (Ph+ CML) 5.13 Impairments Related to Driving and Using Machinery 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or 5.14 Renal Toxicity Chronic Phase (CP) After Interferon-alpha (IFN) Therapy 5.15 Measuring Device 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) 6 ADVERSE REACTIONS 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia 6.1 Clinical Trials Experience (ALL) 6.2 Postmarketing Experience 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) 7 DRUG INTERACTIONS 1.6 Aggressive Systemic Mastocytosis (ASM) 7.1 Agents Inducing CYP3A Metabolism 1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic 7.2 Agents Inhibiting CYP3A Metabolism Leukemia (CEL) 7.3 Interactions With Drugs Metabolized by CYP3A4 1.8 Dermatofibrosarcoma Protuberans (DFSP) 7.4 Interactions With Drugs Metabolized by CYP2D6 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) 8 USE IN SPECIFIC POPULATIONS 1.10 Adjuvant Treatment of GIST 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 2.1 Important Administration Instructions 8.3 Females and Males of Reproductive Potential 2.2 Adult Patients With Ph+ CML CP, AP, or BC 8.4 Pediatric Use 2.3 Pediatric Patients With Ph+ CML CP 8.5 Geriatric Use 2.4 Adult Patients With Ph+ ALL 8.6 Hepatic Impairment 2.5 Pediatric Patients With Ph+ ALL 8.7 Renal Impairment 2.6 Adult Patients With MDS/MPD 10 OVERDOSAGE 2.7 Adult Patients With ASM 11 DESCRIPTION 2.8 Adult Patients With HES/CEL 12 CLINICAL PHARMACOLOGY 2.9 Adult Patients With DFSP 12.1 Mechanism of Action 2.10 Adult Patients With Metastatic and/or Unresectable GIST 12.3 Pharmacokinetics 2.11 Adult Patients With Adjuvant GIST 13 NONCLINICAL TOXICOLOGY 2.12 Dosage Modification Guidelines for Drug Interactions, Hepatic 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Impairment, and Renal Impairment 13.2 Animal Toxicology and/or Pharmacology 2.13 Dosage Modifications for Hepatotoxicity and Non- 14 CLINICAL STUDIES Hematologic Adverse Reactions 14.1 Chronic Myeloid Leukemia 2.14 Dosage Modifications for Hematologic Adverse Reactions 14.2 Pediatric CML 3 DOSAGE FORMS AND STRENGTHS 14.3 Acute Lymphoblastic Leukemia 4 CONTRAINDICATIONS 14.4 Pediatric ALL 5 WARNINGS AND PRECAUTIONS 14.5 Myelodysplastic/Myeloproliferative Diseases 5.1 Fluid Retention and Edema 14.6 Aggressive Systemic Mastocytosis 5.2 Hematologic Toxicity 14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia 5.3 Congestive Heart Failure and Left Ventricular Dysfunction 14.8 Dermatofibrosarcoma Protuberans 5.4 Hepatotoxicity 14.9 Gastrointestinal Stromal Tumors 5.5 Hemorrhage 15 REFERENCES 5.6 Gastrointestinal Disorders 16 HOW SUPPLIED/STORAGE AND HANDLING 5.7 Hypereosinophilic Cardiac Toxicity 17 PATIENT COUNSELING INFORMATION 5.8 Dermatologic Toxicities Sections or subsections omitted from the full prescribing information are not 5.9 Hypothyroidism listed. 5.10 Embryo-Fetal Toxicity Reference ID: 5484208 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. 1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions All doses of Imkeldi should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, and a dose of 800 mg should be administered as 400 mg twice a day. If a dose is missed, the patient should wait until the next scheduled dose and not take two doses at the same time. Imkeldi is intended for oral use only. It is important that Imkeldi be measured with an accurate measuring device [see Warnings and Precautions (5.15), Instructions for Use]. A household teaspoon is not an accurate measuring device. A pharmacist can provide a press-in bottle adapter and oral dispensing syringe and can provide instructions for measuring the correct dose. Recommendations for Dose Rounding Round each dose to the nearest measurable graduation mark on the oral syringe, if necessary [see Instructions for Use]. Continue treatment until disease progression or unacceptable toxicity. Imkeldi is a hazardous drug. Follow applicable special handling and disposal procedures1. Reference ID: 5484208 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dosage of Imkeldi is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dosage of Imkeldi for pediatric patients with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose or the daily dose may be split into two–one portion doses in the morning and one portion in the evening. There is no experience with Imkeldi treatment in children under 1 year of age. Follow recommendations for dose rounding [see Dosage and Administration (2.1)]. 2.4 Adult Patients With Ph+ ALL The recommended dosage of Imkeldi is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dosage of Imkeldi to be given in combination with chemotherapy to pediatric patients with newly diagnosed Ph+ ALL is 340 mg/m2/day (not to exceed 600 mg). Imkeldi treatment can be given as a once daily dose. Follow recommendations for dose rounding [see Dosage and Administration (2.1)]. 2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dosage of Imkeldi is 400 mg/day for adult patients with MDS/MPD. 2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment. The recommended dosage of Imkeldi is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c- Kit mutational status is not known or unavailable, treatment with Imkeldi 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.8 Adult Patients With HES/CEL The recommended dosage of Imkeldi is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.9 Adult Patients With DFSP The recommended dosage of Imkeldi is 800 mg/day for adult patients with DFSP. 2.10 Adult Patients With Metastatic and/or Unresectable GIST The recommended dosage of Imkeldi is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. 2.11 Adult Patients With Adjuvant GIST The recommended dosage of Imkeldi is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of imatinib and three years of imatinib were studied. In the patient population Reference ID: 5484208 defined in Study 2, three years of Imkeldi is recommended [see Clinical Studies (14.8)]. The optimal treatment duration with Imkeldi is not known. Reference ID: 5484208 2.12 Dosage Modifications for Drug Interactions, Hepatic Impairment, and Renal Impairment Drug Interactions Concomitant Strong CYP3A4 inducers Avoid concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital) with Imkeldi. If concomitant use with a strong CYP3A4 inducer cannot be avoided the Imkeldi dosage should be increased by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1)]. Hepatic Impairment A 25% decrease in the approved recommended Imkeldi dosage should be used for patients with severe hepatic impairment (total bilirubin ˃3 to 10 times upper limit of normal [ULN] and any value for AST) [see Use in Specific Populations (8.6)]. Patients with mild hepatic impairment (total bilirubin ≤ ULN and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) do not require a dose adjustment and should be treated per the approved recommended dosage. Renal Impairment Imkeldi should be used with caution in patients with severe renal impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.7)]. Patients with moderate renal impairment (creatinine clearance [CLcr] = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CLcr = 40-59 mL/min). Doses greater than 400 mg are not recommended for patients with moderate renal impairment. 2.13 Dosage Modifications for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, Imkeldi should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN. In adults, treatment with Imkeldi may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day. If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imkeldi should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the reaction. 2.14 Dosage Modifications for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1. Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia ASM associated with eosinophilia ANC less than 1 x 109/L 1. Stop Imkeldi until ANC greater than or equal to (starting dose 100 mg) and/or 1.5 x 109/L and platelets greater than or equal to platelets less than 50 x 109/L 75 x 109/L 2. Resume treatment with Imkeldi at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα ANC less than 1 x 109/L 1. Stop Imkeldi until ANC greater than or equal to fusion kinase (starting dose 100 mg) and/or 1.5 x 109/L and platelets greater than or equal to platelets less than 50 x 109/L 75 x 109/L 2. Resume treatment with Imkeldi at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose ANC less than 1 x 109/L 1. Stop Imkeldi until ANC greater than or equal to 400 mg) and/or 1.5 x 109/L and platelets greater than or equal to platelets less than 50 x 109/L 75 x 109/L MDS/MPD, ASM and HES/CEL 2. Resume treatment with Imkeldi at the original (starting dose 400 mg) starting dose of 400 mg 3. If recurrence of ANC less than 1 x 109/L and/or GIST (starting dose 400 mg) platelets less than 50 x 109/L, repeat step 1 and resume Imkeldi at a reduced dose of 300 mg Reference ID: 5484208 1. Check if cytopenia is related to leukemia (marrow Ph+ CML: Accelerated Phase and ANC less than 0.5 x 109/L aspirate or biopsy) Blast Crisis (starting dose 600 mg) and/or 2. If cytopenia is unrelated to leukemia, reduce dose Ph+ ALL platelets less than 10 x 109/L of Imkeldi to 400 mg (starting dose 600 mg) 3. If cytopenia persists 2 weeks, reduce further to 300 mg 4. If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Imkeldi until ANC greater than or equal to 1 x 109/L and platelets greater than or equal to 20 x 109/L and then resume treatment at 300 mg 1. Stop Imkeldi until ANC greater than or equal to DFSP 1.5 x 109/L and platelets greater than or equal to (starting dose 800 mg) ANC less than 1 x 109/L 75 x 109/L and/or 2. Resume treatment with Imkeldi at 600 mg platelets less than 50 x 109/L 3. In the event of recurrence of ANC less than 1 x 109/L and/or platelets less than 50 x 109/L, repeat step 1 and resume Imkeldi at reduced dose of 400 mg 1. Stop Imkeldi until ANC greater than or equal to Pediatric newly diagnosed chronic ANC less than 1 x 109/L 1.5 x 109/L and platelets greater than or equal to phase CML and/or 75 x 109/L (starting dose 340 mg/m2) platelets less than 50 x 109/L 2. Resume treatment with Imkeldi at previous dose (i.e., dose before severe adverse reaction) 3. In the event of recurrence of ANC less than 1 x 109/L and/or platelets less than 50 x 109/L, repeat step 1 and resume Imkeldi at reduced dose of 260 mg/m2 Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia. 3 DOSAGE FORMS AND STRENGTHS Oral solution: 80 mg/mL imatinib as 140 mL of a clear yellow to brownish yellow colored solution with a strawberry flavor. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Imatinib can cause edema and occasionally serious fluid retention [see Adverse Reactions (6.1)]. Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib, and in 2% to 6% of other adult CML patients taking imatinib. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking imatinib, and in 2% to 6% of other adult CML patients taking imatinib. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib for GIST [see Adverse Reactions (6.1)]. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none Reference ID: 5484208 were Grade 3 or 4) of patients in the imatinib arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm. 5.2 Hematologic Toxicity Treatment with imatinib can cause anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.14)]. 5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure. 5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Imkeldi [see Adverse Reactions (6.1)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with Imkeldi interruption and/or dose reduction [see Dosage and Administration (2.13)]. When imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended. 5.5 Hemorrhage In a trial of imatinib versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience. 5.6 Gastrointestinal Disorders Imatinib can cause GI irritation. Imkeldi should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation. 5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Imkeldi therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imkeldi. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imkeldi at the initiation of therapy. Reference ID: 5484208 5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib therapy after resolution or improvement of the bullous reaction. In these instances, imatinib was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines. 5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib. Monitor TSH levels in such patients. 5.10 Embryo-Fetal Toxicity Imkeldi can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area (BSA). Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on BSA. Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Imkeldi and for 14 days after stopping Imkeldi. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1)]. 5.11 Growth Retardation in Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving imatinib. The long-term effects of prolonged treatment with Imkeldi on growth in children are unknown. Therefore, monitor growth in children under Imkeldi treatment [see Adverse Reactions (6.1)]. 5.12 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving imatinib. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of Imkeldi. 5.13 Impairments Related to Driving and Using Machinery Motor vehicle accidents have been reported in patients receiving imatinib. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Imkeldi. Recommend caution when driving a car or operating machinery. 5.14 Renal Toxicity A decline in renal function may occur in patients receiving Imkeldi. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m2 (N = 1190) to 75 mL/min/1.73 m2 at 12 months (N = 1082) and 69 mL/min/1.73 m2 at 60 months (N = 549). Evaluate renal function prior to initiating Imkeldi and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure. 5.15 Measuring Device Advise patients to measure Imkeldi with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions. Advise patients to ask their pharmacist to recommend an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring the correct dose [see Instructions for Use]. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Fluid Retention and Edema [see Warnings and Precautions (5.1)] • Hematologic Toxicity [see Warnings and Precautions (5.2)] Reference ID: 5484208 6 • Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] • Hepatotoxicity [see Warnings and Precautions (5.4)] • Hemorrhage [see Warnings and Precautions (5.5)] • Gastrointestinal Disorders [see Warnings and Precautions (5.6)] • Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7)] • Dermatologic Toxicities [see Warnings and Precautions (5.8)] • Hypothyroidism [see Warnings and Precautions (5.9)] • Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.12)] • Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13)] • Renal Toxicity [see Warnings and Precautions (5.14)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Myeloid Leukemia The majority of imatinib-treated patients experienced adverse reactions at some time. Imatinib was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib versus IFN+Ara-C, and in 12.5% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib and nilotinib. Imatinib was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of imatinib [see Dosage and Administration (2.13)]. The frequency of severe superficial edema was 1.5%-6%. A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib-treated patients are shown in Tables 2, 3, and 4. Reference ID: 5484208 Table 2: Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Imatinib Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib-Treated Patients)(1) All Grades CTC Grades 3/4 Imatinib IFN+Ara−C Imatinib IFN+Ara−C Preferred term N = 551 (%) N = 533 (%) N = 551 (%) N = 533 (%) Fluid retention 61.7 11.1 2.5 0.9 − Superficial edema 59.9 9.6 1.5 0.4 − Other fluid retention reactions2 6.9 1.9 1.3 0.6 Nausea 49.5 61.5 1.3 5.1 Muscle cramps 49.2 11.8 2.2 0.2 Musculoskeletal pain 47.0 44.8 5.4 8.6 Diarrhea 45.4 43.3 3.3 3.2 Rash and related terms 40.1 26.1 2.9 2.4 Fatigue 38.8 67.0 1.8 25.1 Headache 37.0 43.3 0.5 3.8 Joint pain 31.4 38.1 2.5 7.7 Abdominal pain 36.5 25.9 4.2 3.9 Nasopharyngitis 30.5 8.8 0 0.4 Hemorrhage 28.9 21.2 1.8 1.7 - GI hemorrhage 1.6 1.1 0.5 0.2 - CNS hemorrhage 0.2 0.4 0 0.4 Myalgia 24.1 38.8 1.5 8.3 Vomiting 22.5 27.8 2.0 3.4 Dyspepsia 18.9 8.3 0 0.8 Cough 20.0 23.1 0.2 0.6 Pharyngolaryngeal pain 18.1 11.4 0.2 0 Upper respiratory tract infection 21.2 8.4 0.2 0.4 Dizziness 19.4 24.4 0.9 3.8 Pyrexia 17.8 42.6 0.9 3.0 Weight increased 15.6 2.6 2.0 0.4 Insomnia 14.7 18.6 0 2.3 Depression 14.9 35.8 0.5 13.1 Influenza 13.8 6.2 0.2 0.2 Bone pain 11.3 15.6 1.6 3.4 Constipation 11.4 14.4 0.7 0.2 Sinusitis 11.4 6.0 0.2 0.2 Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. NCI Common Terminology Criteria for Adverse Events, version 3.0. (1)All adverse reactions occurring in greater than or equal to 10% of imatinib-treated patients are listed regardless of suspected relationship to treatment. (2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Reference ID: 5484208 Table 3: Most Frequently Reported Non-Hematologic Adverse Reactions (regardless of relationship to study drug) in Patients With Newly Diagnosed Ph+ CML-CP in the Imatinib Versus Nilotinib Study (Greater Than or Equal to 10% in Imatinib 400 mg Once Daily or Nilotinib 300 mg Twice Daily Groups) 60-Month Analysisa Patients with newly diagnosed Ph+ CML-CP Imatinib Nilotinib Imatinib Nilotinib 400 mg 300 mg 400 mg 300 mg once daily twice daily once daily twice daily N = 280 N = 279 N = 280 N = 279 Body system and preferred term All Grades (%) CTC Gradesb 3/4 (%) Skin and subcutaneous tissue disorders Rash 19 38 2 < 1 Pruritus 7 21 0 < 1 Alopecia 7 13 0 0 Dry skin 6 12 0 0 Gastrointestinal disorders Nausea 41 22 2 2 Constipation 8 20 0 < 1 Diarrhea 46 19 4 1 Vomiting 27 15 < 1 < 1 Abdominal pain 14 18 < 1 1 upper Abdominal pain 12 15 0 2 Dyspepsia 12 10 0 0 Nervous system disorders Headache 23 32 < 1 3 Dizziness 11 12 < 1 < 1 General disorders and administration-site conditions Fatigue 20 23 1 1 Pyrexia 13 14 0 < 1 Asthenia 12 14 0 < 1 Peripheral edema 20 9 0 < 1 Face edema 14 < 1 < 1 0 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 17 22 < 1 < 1 Muscle spasms 34 12 1 0 Pain in extremity 16 15 < 1 < 1 Back pain 17 19 1 1 Respiratory, thoracic and mediastinal disorders Cough 13 17 0 0 Oropharyngeal pain 6 12 0 0 Dyspnea 6 11 < 1 2 Infections and infestations Nasopharyngitis 21 27 0 0 Upper respiratory tract infection 14 17 0 < 1 Influenza 9 13 0 0 Gastroenteritis 10 7 < 1 0 Eye disorders Eyelid edema 19 1 < 1 0 Periorbital edema 15 < 1 0 0 Psychiatric disorders Insomnia 9 11 0 0 Vascular disorder Hypertension 4 10 < 1 1 Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. aExcluding laboratory abnormalities. bNCI Common Terminology Criteria for Adverse Events, version 3.0. Reference ID: 5484208 Table 4: Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (Greater Than or Equal to 10% of All Patients in Any Trial)(1) Myeloid blast Crisis Accelerated phase Chronic phase, IFN failure (n = 260) (n = 235) (n = 532) % % % All Preferred term Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Fluid retention 72 11 76 6 69 4 -Superficial edema 66 6 74 3 67 2 -Other fluid retention reactions (2) 22 6 15 4 7 2 Nausea 71 5 73 5 63 3 Muscle cramps 28 1 47 0.4 62 2 Vomiting 54 4 58 3 36 2 Diarrhea 43 4 57 5 48 3 Hemorrhage 53 19 49 11 30 2 - CNS hemorrhage 9 7 3 3 2 1 - GI hemorrhage 8 4 6 5 2 0.4 Musculoskeletal pain 42 9 49 9 38 2 Fatigue 30 4 46 4 48 1 Skin rash 36 5 47 5 47 3 Pyrexia 41 7 41 8 21 2 Arthralgia 25 5 34 6 40 1 Headache 27 5 32 2 36 0.6 Abdominal pain 30 6 33 4 32 1 Weight increased 5 1 17 5 32 7 Cough 14 0.8 27 0.9 20 0 Dyspepsia 12 0 22 0 27 0 Myalgia 9 0 24 2 27 0.2 Nasopharyngitis 10 0 17 0 22 0.2 Asthenia 18 5 21 5 15 0.2 Dyspnea 15 4 21 7 12 0.9 Upper respiratory tract infection 3 0 12 0.4 19 0 Anorexia 14 2 17 2 7 0 Night sweats 13 0.8 17 1 14 0.2 Constipation 16 2 16 0.9 9 0.4 Dizziness 12 0.4 13 0 16 0.2 Pharyngitis 10 0 12 0 15 0 Insomnia 10 0 14 0 14 0.2 Pruritus 8 1 14 0.9 14 0.8 Hypokalemia 13 4 9 2 6 0.8 Pneumonia 13 7 10 7 4 1 Anxiety 8 0.8 12 0 8 0.4 Liver toxicity 10 5 12 6 6 3 Rigors 10 0 12 0.4 10 0 Chest pain 7 2 10 0.4 11 0.8 Influenza 0.8 0.4 6 0 11 0.2 Sinusitis 4 0.4 11 0.4 9 0.4 Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha. (1)All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment. (2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Hematologic and Biochemistry Laboratory Abnormalities Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively. Reference ID: 5484208 These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but may require permanent discontinuation of treatment. Table 5: Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Imatinib Versus IFN+Ara-C) Imatinib IFN+Ara-C N = 551 N = 533 % % CTC Grades Grade 3 Grade Grade 3 Grade 4 4 Hematology parameters − Neutropenia* 13.1 3.6 20.8 4.5 − Thrombocytopenia* 8.5 0.4 15.9 0.6 − Anemia 3.3 1.1 4.1 0.2 Biochemistry parameters − Elevated creatinine 0 0 0.4 0 − Elevated bilirubin 0.9 0.2 0.2 0 − Elevated alkaline phosphatase 0.2 0 0.8 0 − Elevated SGOT (AST)/SGPT (ALT) 4.7 0.5 7.1 0.4 Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups). Table 6: Percent Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Imatinib Versus Nilotinib) Imatinib 400 mg Nilotinib 300 mg once daily twice daily N = 280 N = 279 (%) (%) Hematologic parameters Thrombocytopenia 9 10 Neutropenia 22 12 Anemia 6 4 Biochemistry parameters Elevated lipase 4 9 Hyperglycemia < 1 7 Hypophosphatemia 10 8 Elevated bilirubin (total) < 1 4 Elevated SGPT (ALT) 3 4 Hyperkalemia 1 2 Hyponatremia < 1 1 Hypokalemia 2 < 1 Elevated SGOT (AST) 1 1 Decreased albumin < 1 0 Hypocalcemia < 1 < 1 Elevated alkaline phosphatase < 1 0 Elevated creatinine < 1 0 Abbreviations: CML, chronic myeloid leukemia; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). NCI Common Terminology Criteria for Adverse Events, version 3.0. Reference ID: 5484208 Table 7: Laboratory Abnormalities in Other CML Clinical Trials Myeloid blast crisis Accelerated phase Chronic phase, IFN failure (n = 260) (n = 235) (n = 532) 600 mg n = 223 600 mg n = 158 400 mg n = 37 400 mg n = 77 400 mg % % % CTC Grades (1) Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters − Neutropenia 16 48 23 36 27 9 − Thrombocytopenia 30 33 31 13 21 < 1 − Anemia 42 11 34 7 6 1 Biochemistry parameters − Elevated creatinine 1.5 0 1.3 0 0.2 0 − Elevated bilirubin 3.8 0 2.1 0 0.6 0 − Elevated alkaline phosphatase 4.6 0 5.5 0.4 0.2 0 − Elevated SGOT (AST) 1.9 0 3.0 0 2.3 0 − Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0 Abbreviations: CML, chronic myeloid leukemia; CTC, common terminology criteria; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). (1)CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (hemoglobin greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5– 20 x ULN, Grade 4 greater than 20 x ULN). Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients. Adverse Reactions in Pediatric Population Single-Agent Therapy The overall safety profile of pediatric patients treated with imatinib in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression. In Combination with Multi-Agent Chemotherapy Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were White, 7% were Black, and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n = 92) were assigned to receive imatinib and treated in 5 successive cohorts. Imatinib exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration. The safety of imatinib given in combination with intensive chemotherapy was evaluated by comparing the incidence of Grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive imatinib. The Reference ID: 5484208 safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with imatinib, and 647 without imatinib. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included imatinib are presented in Table 8. Table 8: Adverse Reactions Reported More Frequently in Patients Treated With Study Drug (Greater Than 5%) or in Cycles With Study Drug (Greater Than 1%) Per patient Per patient Per patient Per patient incidence incidence per cycle per cycle incidence Ph+ ALL Ph- ALL incidence with with no no Imatinib Imatinib Imatinib Imatinib** N = 778 N = 92 N = 65 N = 647 Adverse event n (%) n (%) n (%) n (%) Grade 3 and 4 adverse events Nausea and/or vomiting 15 (16) 6 (9) 28 (4) 8 (1) Hypokalemia 31 (34) 16 (25) 72 (9) 32 (5) Pneumonitis 7 (8) 1 (1) 7 (1) 1 (< 1) Pleural effusion 6 (7) 0 6 (1) 0 Abdominal pain 8 (9) 2 (3) 9 (1) 3 (< 1) Anorexia 10 (11) 3 (5) 19 (2) 4 (1) Hemorrhage 11 (12) 4 (6) 17 (2) 8 (1) Hypoxia 8 (9) 2 (3) 12 (2) 2 (< 1) Myalgia 5 (5) 0 4 (1) 1 (< 1) Stomatitis 15 (16) 8 (12) 22 (3) 14 (2) Diarrhea 8 (9) 3 (5) 12 (2) 3 (< 1) Rash/Skin disorder 4 (4) 0 5 (1) 0 Infection 49 (53) 32 (49) 131 (17) 92 (14) Hepatic (transaminase and/or bilirubin) 52 (57) 38 (58) 172 (22) 113 (17) Hypotension 10 (11) 5 (8) 16 (2) 6 (1) Myelosuppression Neutropenia (< 750/mcL) 92 (100) 63 (97) 556 (71) 218 (34) Thrombocytopenia (< 75,000/mcL) 90 (92) 63 (97) 431 (55) 329 (51) Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia. Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib (includes patients with Ph+ ALL that received cycles with imatinib). Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib (includes patients with Ph+ ALL that received cycles without imatinib as well as all patients with Ph- ALL who did not receive imatinib in any treatment cycle). Adverse Reactions in Other Subpopulations In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation. Acute Lymphoblastic Leukemia The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps, and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of imatinib. Reference ID: 5484208 Myelodysplastic/Myeloproliferative Diseases Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib for MDS/MPD in the Phase 2 study, are shown in Table 9. Table 9: Adverse Reactions Regardless of Relationship to Study Drug Reported (More Than One Patient) in MPD Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades N = 7 Preferred term n (%) Nausea 4 (57.1) Diarrhea 3 (42.9) Anemia 2 (28.6) Fatigue 2 (28.6) Muscle cramp 3 (42.9) Arthralgia 2 (28.6) Periorbital edema 2 (28.6) Abbreviation: MPD, myeloproliferative disease. Aggressive Systemic Mastocytosis All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued imatinib due to drug-related adverse reactions or abnormal laboratory values. Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of imatinib observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being GI, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia. Dermatofibrosarcoma Protuberans Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib for DFSP in the Phase 2 study are shown in Table 10. Table 10: Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades N = 12 Preferred term n (%) Nausea 5 (41.7) Diarrhea 3 (25.0) Vomiting 3 (25.0) Periorbital edema 4 (33.3) Face edema 2 (16.7) Rash 3 (25.0) Fatigue 5 (41.7) Peripheral edema 4 (33.3) Pyrexia 2 (16.7) Eye edema 4 (33.3) Lacrimation increased 3 (25.0) Dyspnea exertional 2 (16.7) Anemia 3 (25.0) Rhinitis 2 (16.7) Anorexia 2 (16.7) Abbreviation: DFSP, dermatofibrosarcoma protuberans. Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib for DFSP in the Phase 2 study are presented in Table 11. Reference ID: 5484208 Table 11: Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study N = 12 CTC Grades (1) Grade 3 Grade 4 % % Hematology parameters - Anemia 17 0 - Thrombocytopenia - Neutropenia Biochemistry parameters - Elevated creatinine 17 0 0 0 8 8 Abbreviation: CTC, common terminology criteria. (1)CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN). Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials, the majority of imatinib-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of imatinib [see Dosage and Administration (2.13)]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib are shown in Table 12. Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. Table 12: Number (%) of Patients With Adverse Reactions Regardless of Relationship to Study Drug Where Frequency is Greater Than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N = 818 N = 822 All Grades Grades 3/4/5 All Grades Grades 3/4/5 Reported or specified term % % % % Edema 76.7 9.0 86.1 13.1 Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2 Nausea 58.1 9.0 64.5 7.8 Abdominal pain/cramping 57.2 13.8 55.2 11.8 Diarrhea 56.2 8.1 58.2 8.6 Rash/desquamation 38.1 7.6 49.8 8.9 Vomiting 37.4 9.2 40.6 7.5 Myalgia 32.2 5.6 30.2 3.8 Anemia 32.0 4.9 34.8 6.4 Anorexia 31.1 6.6 35.8 4.7 Other GI toxicity 25.2 8.1 28.1 6.6 Headache 22.0 5.7 19.7 3.6 Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0 Other dermatology/skin toxicity 17.6 5.9 20.1 5.7 Leukopenia 17.0 0.7 19.6 1.6 Other constitutional symptoms 16.7 6.4 15.2 4.4 Cough 16.1 4.5 14.5 3.2 Reference ID: 5484208 Imatinib 400 mg Imatinib 800 mg N = 818 N = 822 All Grades Grades 3/4/5 All Grades Grades 3/4/5 Reported or specified term % % % % Infection (without neutropenia) 15.5 6.6 16.5 5.6 Pruritus 15.4 5.4 18.9 4.3 Other neurological toxicity 15.0 6.4 15.2 4.9 Constipation 14.8 5.1 14.4 4.1 Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2 Arthralgia (joint pain) 13.6 4.8 12.3 3.0 Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6 Fever in absence of neutropenia (ANC < 1.0 x 109/L) 13.2 4.9 12.9 3.4 Sweating 12.7 4.6 8.5 2.8 Other hemorrhage 12.3 6.7 13.3 6.1 Weight gain 12.0 1.0 10.6 0.6 Alopecia 11.9 4.3 14.8 3.2 Dyspepsia/heartburn 11.5 0.6 10.9 0.5 Neutropenia/granulocytopenia 11.5 3.1 16.1 4.1 Rigors/chills 11.0 4.6 10.2 3.0 Dizziness/lightheadedness 11.0 4.8 10.0 2.8 Creatinine increase 10.8 0.4 10.1 0.6 Flatulence 10.0 0.2 10.1 0.1 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3 Lymphopenia 6.0 0.7 10.1 1.9 Abbreviations: ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors. Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13. Table 13: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg 600 mg (n = 73) % (n = 74) % CTC Grades1 Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters − Anemia 3 0 8 1 − Thrombocytopenia 0 0 1 0 − Neutropenia 7 3 8 3 Biochemistry parameters − Elevated creatinine 0 0 3 0 − Reduced albumin 3 0 4 0 − Elevated bilirubin 1 0 1 3 − Elevated alkaline phosphatase 0 0 3 0 − Elevated SGOT (AST) 4 0 3 3 − Elevated SGPT (ALT) 6 0 7 1 Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). 1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), albumin (Grade 3 less than 20 g/L). Reference ID: 5484208 Adjuvant Treatment of GIST In Study 1, the majority of both imatinib and placebo-treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST-treatment setting that had not been previously reported in other patient populations, including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the imatinib and placebo-treated patients, respectively. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation. In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the imatinib 12-month, and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with imatinib are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to imatinib treatment in either trial. Table 14: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (Greater Than or Equal to 5% of Imatinib-Treated Patients)(1) All CTC Grades CTC Grade 3 and Above Imatinib Placebo Imatinib Placebo (n = 337) (n = 345) (n = 337) (n = 345) Preferred term % % % % Diarrhea 59.3 29.3 3.0 1.4 Fatigue 57.0 40.9 2.1 1.2 Nausea 53.1 27.8 2.4 1.2 Periorbital edema 47.2 14.5 1.2 0 Hemoglobin decreased 46.9 27.0 0.6 0 Peripheral edema 26.7 14.8 0.3 0 Rash (Exfoliative) 26.1 12.8 2.7 0 Vomiting 25.5 13.9 2.4 0.6 Abdominal pain 21.1 22.3 3.0 1.4 Headache 19.3 20.3 0.6 0 Dyspepsia 17.2 13.0 0.9 0 Anorexia 16.9 8.7 0.3 0 Weight increased 16.9 11.6 0.3 0 Liver enzymes (ALT) increased 16.6 13.0 2.7 0 Muscle spasms 16.3 3.3 0 0 Neutrophil count decreased 16.0 6.1 3.3 0.9 Arthralgia 15.1 14.5 0 0.3 White blood cell count decreased 14.5 4.3 0.6 0.3 Constipation 12.8 17.7 0 0.3 Dizziness 12.5 10.7 0 0.3 Liver enzymes (AST) increased 12.2 7.5 2.1 0 Myalgia 12.2 11.6 0 0.3 Blood creatinine increased 11.6 5.8 0 0.3 Cough 11.0 11.3 0 0 Pruritus 11.0 7.8 0.9 0 Weight decreased 10.1 5.2 0 0 Hyperglycemia 9.8 11.3 0.6 1.7 Insomnia 9.8 7.2 0.9 0 Lacrimation increased 9.8 3.8 0 0 Alopecia 9.5 6.7 0 0 Flatulence 8.9 9.6 0 0 Rash 8.9 5.2 0.9 0 Abdominal distension 7.4 6.4 0.3 0.3 Reference ID: 5484208 All CTC Grades CTC Grade 3* and Above Imatinib Placebo Imatinib Placebo (n = 337) (n = 345) (n = 337) (n = 345) Preferred term % % % % Back pain 7.4 8.1 0.6 0 Pain in extremity 7.4 7.2 0.3 0 Hypokalemia 7.1 2.0 0.9 0.6 Depression 6.8 6.4 0.9 0.6 Facial edema 6.8 1.2 0.3 0 Blood alkaline phosphatase increased 6.5 7.5 0 0 Dry skin 6.5 5.2 0 0 Dysgeusia 6.5 2.9 0 0 Abdominal pain upper 6.2 6.4 0.3 0 Neuropathy peripheral 5.9 6.4 0 0 Hypocalcemia 5.6 1.7 0.3 0 Leukopenia 5.0 2.6 0.3 0 Platelet count decreased 5.0 3.5 0 0 Stomatitis 5.0 1.7 0.6 0 Upper respiratory tract infection 5.0 3.5 0 0 Vision blurred 5.0 2.3 0 0 Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). NCI Common Terminology Criteria for Adverse Events, version 3.0. (1)All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Table 15: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (Greater Than or Equal to 5% of Imatinib-Treated Patients) Study 2(1) Preferred term All CTC Grades CTC Grades 3 and above Imatinib Imatinib Imatinib Imatinib 12 Months 36 Months 12 Months 36 Months (N = 194) (N = 198) (N = 194) (N = 198) % % % % Patients with at least one AE 99.0 100.0 20.1 32.8 Hemoglobin decreased 72.2 80.3 0.5 0.5 Periorbital edema 59.3 74.2 0.5 1.0 Blood lactate dehydrogenase increased 43.3 60.1 0 0 Diarrhea 43.8 54.0 0.5 2.0 Nausea 44.8 51.0 1.5 0.5 Muscle spasms 30.9 49.0 0.5 1.0 Fatigue 48.5 48.5 1.0 0.5 White blood cell count decreased 34.5 47.0 2.1 3.0 Pain 25.8 45.5 1.0 3.0 Blood creatinine increased 30.4 44.4 0 0 Peripheral edema 33.0 40.9 0.5 1.0 Dermatitis 29.4 38.9 2.1 1.5 Aspartate aminotransferase increased 30.9 37.9 1.5 3.0 Alanine aminotransferase increased 28.9 34.3 2.1 3.0 Neutrophil count decreased 24.2 33.3 4.6 5.1 Hypoproteinemia 23.7 31.8 0 0 Infection 13.9 27.8 1.5 2.5 Weight increased 13.4 26.8 0 0.5 Pruritus 12.9 25.8 0 0 Flatulence 19.1 24.7 1.0 0.5 Vomiting 10.8 22.2 0.5 1.0 Reference ID: 5484208 Preferred term All CTC Grades CTC Grades 3 and above Imatinib Imatinib Imatinib Imatinib 12 Months 36 Months 12 Months 36 Months (N = 194) (N = 198) (N = 194) (N = 198) % % % % Dyspepsia 17.5 21.7 0.5 1.0 Hypoalbuminemia 11.9 21.2 0 0 Edema 10.8 19.7 0 0.5 Abdominal distension 11.9 19.2 0.5 0 Headache 8.2 18.2 0 0 Lacrimation increased 18.0 17.7 0 0 Arthralgia 8.8 17.2 0 1.0 Blood alkaline phosphatase increased 10.8 16.7 0 0.5 Dyspnea 6.2 16.2 0.5 1.5 Myalgia 9.3 15.2 0 1.0 Platelet count decreased 11.3 14.1 0 0 Blood bilirubin increased 11.3 13.1 0 0 Dysgeusia 9.3 12.6 0 0 Paresthesia 5.2 12.1 0 0.5 Vision blurred 10.8 11.1 1.0 0.5 Alopecia 11.3 10.6 0 0 Decreased appetite 9.8 10.1 0 0 Constipation 8.8 9.6 0 0 Pyrexia 6.2 9.6 0 0 Depression 3.1 8.1 0 0 Abdominal pain 2.6 7.6 0 0 Conjunctivitis 5.2 7.6 0 0 Photosensitivity reaction 3.6 7.1 0 0 Dizziness 4.6 6.6 0.5 0 Hemorrhage 3.1 6.6 0 0 Dry skin 6.7 6.1 0.5 0 Nasopharyngitis 1.0 6.1 0 0.5 Palpitations 5.2 5.1 0 0 Abbreviations: AE, adverse event; CTC, common terminology criteria. (1)All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Adverse Reactions from Multiple Clinical Trials Cardiac Disorders: Estimated 1%-10%: palpitations, pericardial effusion Estimated 0.1%-1%: congestive cardiac failure, tachycardia, pulmonary edema Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma Investigations: Estimated 1%-10%: blood creatine phosphokinase (CPK) increased, blood amylase increased Estimated 0.1%-1%: blood lactate dehydrogenase (LDH) increased Reference ID: 5484208 Skin and Subcutaneous Tissue Disorders: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme, panniculitis (including erythema nodosum) Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis Gastrointestinal Disorders: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration-Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Blood and Lymphatic System Disorders: Estimated 1%-10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia Estimated 0.1%-1%: thrombocythemia, bone marrow depression, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary Disorders: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Immune System Disorders: Estimated 0.01%-0.1%: angioedema Infections and Infestations: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolism and Nutrition Disorders: Estimated 1%-10%: weight decreased, decreased appetite Estimated 0.1%-1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia Musculoskeletal and Connective Tissue Disorders: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness, muscular weakness, arthritis Nervous System/Psychiatric Disorders: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis Reference ID: 5484208 Renal and Urinary Disorders: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive System and Breast Disorders: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory, Thoracic and Mediastinal Disorders: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Endocrine Disorders: Estimated 0.1%-1%: hypothyroidism, hyperthyroidism Eye, Ear, and Labyrinth Disorders: Estimated 1%-10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract Estimated 0.01%-0.1%: papilledema1, glaucoma 1Including some fatalities. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of imatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: thrombotic microangiopathy Cardiac Disorders: pericarditis, cardiac tamponade1 Eye Disorders: vitreous hemorrhage Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation1 [see Warnings and Precautions (5.6)], diverticulitis, gastric antral vascular ectasia Infections: hepatitis B virus reactivation1 Musculoskeletal and Connective Tissue Disorders: osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthralgia, bone pain) Nervous System Disorders: cerebral edema1 Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure1, interstitial lung disease Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus Vascular Disorders: thrombosis/embolism, anaphylactic shock 1Including some fatalities. DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other strong CYP3A4 inducers are indicated for concomitant use with Imkeldi. The dosage of Imkeldi should be increased if concomitant use with a strong CYP3A4 inducer is required [see Dosage and Administration (2.12)]. Reference ID: 5484208 7 Imatinib is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases imatinib exposure [see Clinical Pharmacology (12.3)], which may reduce imatinib efficacy. Reference ID: 5484208 8 7.2 Agents Inhibiting CYP3A Metabolism Caution is recommended when administering Imkeldi with strong CYP3A4 inhibitors. Grapefruit juice should be avoided. Imatinib is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor increases imatinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Imkeldi adverse reactions. 7.3 Interactions With Drugs Metabolized by CYP3A4 Use caution when administering Imkeldi with CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions. Because warfarin is metabolized by both CYP2C9 and CYP3A4, use other anti-coagulants instead of warfarin in patients receiving Imkeldi who require anticoagulation. Imatinib is a CYP3A inhibitor. Imatinib increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. 7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering Imkeldi with CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions. Imatinib is a CYP2D6 inhibitor. Imatinib increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Imkeldi can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Imkeldi in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes. In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 Reference ID: 5484208 generation was 15 mg/kg/day. Reference ID: 5484208 8.2 Lactation Risk Summary Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed children from Imkeldi, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose. Human Data Based on data from 3 breastfeeding women taking imatinib, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed child could receive up to 10% of the maternal therapeutic dose based on body weight. 8.3 Females and Males of Reproductive Potential Based on human postmarketing reports and animal studies, Imkeldi can cause fetal harm [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females with reproductive potential prior to the initiation of treatment with Imkeldi. Contraception Females Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Imkeldi during treatment and for fourteen days after stopping treatment with Imkeldi [see Use in Specific Populations (8.1)]. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [see Nonclinical Toxicology (13)]. 8.4 Pediatric Use The safety and effectiveness of Imkeldi have been established in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2, 14.4)]. There are no data in pediatric patients under 1 year of age. The safety and efficacy of Imkeldi have not been established in pediatric patients for all other indications [see Indications and Usage (1)]. 8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1)]. The efficacy of imatinib was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of imatinib was similar in patients older than 65 years and younger patients. 8.6 Hepatic Impairment Reduce the dose by 25% for patients with severe hepatic impairment [see Dosage and Administration (2.12)]. Patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) do not require a dose adjustment. The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Mild hepatic impairment (total bilirubin ≤ ULN and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN and any value for AST) and moderate hepatic impairment (total bilirubin ˃1.5 to 3 times ULN and Reference ID: 5484208 any value for AST) do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, (total bilirubin ˃ 3 to 10 times ULN and any value for AST), the imatinib Cmax and area under curve (AUC) increased by 63% and 45% and the CGP74588 Cmax and AUC increased by 56% and 55%, relative to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Dose reductions are necessary for patients with moderate and severe renal impairment [see Dosage and Administration (2.12)]. The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild (CLcr = 40-59 mL/min) and moderate renal impairment (CLcr = 20-39 mL/min) increased 1.5- to 2-fold compared to patients with normal renal function. There are not sufficient data in patients with severe renal impairment (CLcr = less than 20 mL/min) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of imatinib overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and GI pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of imatinib daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of imatinib on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea. 11 DESCRIPTION Imkeldi oral solution contains imatinib mesylate, a kinase inhibitor. Imatinib mesylate is designated chemically as 4-[(4 Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Reference ID: 5484208 ·Cli>SO,H 0 12 The molecular formula is C29H31N7O • CH4SO3 and its molecular weight is 589.7 g/mol. Imatinib mesylate is soluble in aqueous buffers less than or equal to pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile. Imatinib oral solution is a clear, yellow to brownish yellow colored solution. Each mL of Imkeldi contains the equivalent of 80 mg imatinib present as 95.57 mg imatinib mesylate. Inactive Ingredients: acesulfame potassium, citric acid monohydrate, glycerine, liquid maltitol, purified water, sodium benzoate, strawberry flavor (artificial flavors, lactic acid, triacetin). CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation. 12.2 Pharmacodynamics Imatinib exposure-response relationships and the time course of pharmacodynamic response are unknown. 12.3 Pharmacokinetics The pharmacokinetics of imatinib have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. No clinically significant difference in imatinib pharmacokinetics were observed between CML and GIST patients. Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1000 mg (0.06 to 1.25 times the approved recommended dosage of 400 mg). Imatinib accumulation is 1.5- to 2.5- fold at steady state when imatinib is dosed once daily. Absorption Imatinib mean absolute bioavailability is 98%. Imatinib is well absorbed after oral administration with maximum concentration (Cmax ) achieved within 2-4 hours post-dose. Distribution Imatinib and the N-demethylated metabolite (CGP74588) plasma protein binding is approximately 95% in vitro, mostly to albumin and α1-acid glycoprotein. Elimination Reference ID: 5484208 The elimination half-life is approximately 18 hours for imatinib and 40 hours for the N-demethyl derivative metabolite (CGP74588), following oral administration in healthy volunteers. Typical imatinib clearance in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity. Metabolism CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative (CGP74588), formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. Excretion Imatinib elimination is predominately in the feces, mostly as metabolites. Following an oral radio-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Specific Populations Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer and varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or total bilirubin ˃1 to 1.5 times ULN) and moderately (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) hepatically-impaired groups and the normal group. Patients with severe hepatic impairment (Total bilirubin ˃ 3 to 10 times ULN and any value for AST) tend to have higher exposure to both imatinib and CGP74588 than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (AUC/dose) in patients with mild (CLcr = 40-59 mL/min) and moderate (CLcr = 20-39 mL/min) renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment (CLcr = less than 20 mL/min) were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Pediatric Use Dosing in a limited number of children at both 260 mg/m2 and 340 mg/m2 (0.76 and 1 times the approved recommended dosage) achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose. Another analysis suggested that exposure of imatinib in pediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily. Imatinib time to Cmax is 2-4 hours in pediatric patients which is similar to adult patients. Apparent oral clearance was also similar to adult values (11.0 L/hr/m2 in children vs 10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs 17.1 hours in adults). Imatinib clearance increases with increasing BSA in pediatric patients with hematological disorders (CML, Ph+ ALL, or Reference ID: 5484208 other hematological disorders treated with imatinib). After correcting for this BSA effect, other demographics, such as age, body weight, and body mass index did not have clinically significant effects on the exposure of imatinib. Reference ID: 5484208 13 Drug Interactions Clinical Studies Agents Inducing CYP3A Metabolism Imatinib oral-dose clearance increased by 3.8-fold, which significantly (p less than 0.05) decreased mean Cmax and AUC, following pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib. Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of imatinib and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Agents Inhibiting CYP3A Metabolism There was a significant increase in imatinib exposure (mean Cmax increased by 26% and mean AUC increased by 40%) in healthy subjects following concomitant use of imatinib with a single dose of ketoconazole (CYP3A4 inhibitor). Interactions with Drugs Metabolized by CYP3A4 Simvastatin (CYP3A4 substrate) mean Cmax increased 2-fold and AUC 3.5-fold, following concomitant use with imatinib. Interactions with Drugs Metabolized by CYP2D6 Metoprolol (CYP2D6 substrate) mean Cmax and AUC increased by approximately 23% following concomitant use with imatinib. Interactions with Acetaminophen Imatinib inhibits the acetaminophen O-glucuronidate pathway in vitro. No clinically significant differences in the pharmacokinetics of acetaminophen or imatinib were observed when acetaminophen (1,000 mg single dose on Day 8) was used concomitantly with imatinib (400 mg/day for 8 days) in patients with CML. There is no pharmacokinetic or safety data on the concomitant use of imatinib at doses greater than 400 mg/day or the chronic use of concomitant acetaminophen and imatinib. In vitro Studies CYP450 Metabolism: Imatinib is a substrate of CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Imatinib is a competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at greater than or equal to 30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure Reference ID: 5484208 14 in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on BSA. This was not seen at doses less than or equal to 20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib mesylate. 13.2 Animal Toxicology and/or Pharmacology Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39 week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. CLINICAL STUDIES 14.1 Chronic Myeloid Leukemia Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (imatinib versus IFN+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent imatinib or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the imatinib arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m2/day for 10 days/month. A total of 1106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range, 18 to 70 years), with 21.9% of patients greater than or equal to 60 years of age. There were 59% males and 41% females; 89.9% White and 4.7% Black patients. At the Reference ID: 5484208 100 • ' 90 80 70 - C 0 60 ,; w f! 50 .. 0 ct 40 ;; 0 30 - ~ i 'II, 20 10 0 0 ' ' Nurottr Of BlUt:01$ • 'Mth progrn-slon • CC11$0(Cd at (li$ClOf'ltiAl.liUOf'l • ceniOftO at I.Ht lolow·Up Hazard Ratio (95% CII Loo·rank TC$1 GleeV9C"'arm l~N•Atu·C aun 12 24 ---- -- ~ - - -•FN•M:C - - - - - - 86 ISS 94 192 373 206 0.378 10.2$1. 0.4931 P<il.0001 36 48 60 Monlhs Since Randomization 72 cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the imatinib and IFN arm, respectively. The median duration of second-line treatment with imatinib was 64 months. Sixty percent of patients randomized to imatinib are still receiving first-line treatment. In these patients, the average dose of imatinib was 403 mg ± 57 mg. Overall, in patients receiving first line imatinib, the average daily dose delivered was 406 mg ± 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the imatinib arm was severe intolerance to treatment (26%) and progression (14%). The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive imatinib were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81.2% [95% CI: 78, 85] in the imatinib arm and 60.6% [56, 65] in the IFN arm (p less than 0.0001, log-rank test), (Figure 1). With 7 years follow up there were 93 (16.8%) progression events in the imatinib arm: 37 (6.7%) progression to AP/BC, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C. The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5% [90, 95] in the imatinib arm compared to the 85.1%, [82, 89] (p less than or equal to 0.001) in the IFN arm, (Figure 2). The annual rates of any progression events have decreased with time on therapy. The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in CCyR but without a major molecular response and 70% in patients who were not in CCyR at this time point (p less than 0.001). Figure 1: Progression Free Survival (ITT Principle) Reference ID: 5484208 100 90 - 80 W · 70 ~ I 60 s !:a 0 Q. - ,,,, 40 Cl• ~ ct; 3 30 ,#, 20 10 0 0 -- Nlf{l)betor PaUet!IS, • w1t progriau.lGn to Ill' or oc • censor~ al iilSOOflUni,a M • cansorfll al la.st folow•up ttmrd Am [95, Clj L~ an Tesl l,l@i!II r111 IFt.11.Ata•C: ami '12 24 ~ 36 137 381 ~ 58 228 287 0.4:M 10.312.0.72:2) p~J)()1 36 48 IM'onths Slnte 1nandomltalloni 60 72 Figure 2: Time to Progression to AP or BC (ITT Principle) A total of 71 (12.8%) and 85 (15.4%) patients died in the imatinib and IFN+Ara-C group, respectively. At 84 months the estimated overall survival is 86.4% (83, 90) vs 83.3% (80, 87) in the randomized imatinib and the IFN+Ara-C group, respectively (p = 0.073 log-rank test). The hazard ratio is 0.750 with 95% CI 0.547-1.028. This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to imatinib. Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints. Response data are shown in Table 18. Complete hematologic response, major cytogenetic response and CCyR were also statistically significantly higher in the imatinib arm compared to the IFN + Ara- C arm (no cross-over data considered for evaluation of responses). Median time to CCyR in the 454 responders was 6 months (range, 2 to 64 months, 25th to 75th percentiles = 3 to 11 months) with 10% of responses seen only after 22 months of therapy. Table 18: Response in Newly Diagnosed CML Study (84-Month Data) Imatinib IFN+Ara-C Best response rate n = 553 n = 553 Hematologic response1 CHR rate n (%) 534 (96.6%) 313 (56.6%)* [95% CI] [94.7%, 97.9%] [52.4%, 60.8%] Cytogenetic response2 Major cytogenetic response n (%) 472 (85.4%)* 93 (16.8%)* [95% CI] [82.1%, 88.2%] [13.8%, 20.2%] Unconfirmed3 88.6%* 23.3%* Complete cytogenetic response n (%) 413 (74.7%)* 36 (6.5%)* [95% CI] [70.8, 78.3] [4.6, 8.9] Unconfirmed3 82.5%* 11.6%* p less than 0.001, Fischer’s exact test. 1Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): WBC less than 10 x 109/L, platelet less than 450 x 109/L, myelocyte + metamyelocyte less than 5% in blood, no blasts and promyelocytes in blood, no extramedullary involvement. 2Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1% 35%). A major response (0%-35%) combines both complete and partial responses. 3Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation. Reference ID: 5484208 Molecular response was defined as follows: in the peripheral blood, after 12 months of therapy, reduction of greater than or equal to 3 logarithms in the amount of BCR-ABL transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline. Molecular response was only evaluated in a subset of patients who had a CCyR by 12 months or later (N = 333). The molecular response rate in patients who had a CCyR in the imatinib arm was 59% at 12 months and 72% at 24 months. Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase. After one month of therapy to 6 months of therapy, there was a 13% to 21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity. There was no apparent change from baseline in median index for patients treated with imatinib. An open-label, multicenter, randomized trial (imatinib versus nilotinib) was conducted to determine the efficacy of imatinib versus nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group. Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56%, and 62% in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice-daily treatment groups, respectively). More than 60% of all patients were White, and 25% were Asian. The primary data analysis was performed when all 846 patients completed 12 months of treatment or discontinued earlier. Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment or discontinued earlier. The median time on treatment was approximately 61 months in all three treatment groups. The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 19. Twelve patients in the imatinib arm progressed to either accelerated phase or blast crises (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months) while two patients on the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment). Table 19: Efficacy (MMR and CCyR) of Imatinib Compared to Nilotinib in Newly Diagnosed Ph+ CML-CP Imatinib 400 mg once daily Nilotinib 300 mg twice daily N = 283 N = 282 MMR at 12 months (95% CI) 22% (17.6, 27.6) 44% (38.4, 50.3) P-Valuea < 0.0001 CCyRb by 12 months (95% CI) 65% (59.2, 70.6) 80% (75.0, 84.6) MMR at 24 months (95% CI) 38% (31.8, 43.4) 62% (55.8, 67.4) CCyRb by 24 months (95% CI) 77% (71.7, 81.8) 87% (82.4, 90.6) Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. aCMH test stratified by Sokal risk group. bCCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample. Reference ID: 5484208 By 60 months, MMR was achieved by 60% of patients on imatinib and 77% of patients on nilotinib. Median overall survival was not reached in either arm. At the time of the 60-month final analysis, the estimated survival rate was 91.7% for patients on imatinib and 93.7% for patients on nilotinib. Late Chronic Phase CML and Advanced Stage CML: Three international, open-label, single-arm Phase 2 studies were conducted to determine the safety and efficacy of imatinib in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis. About 45% of patients were women and 6% were Black. In clinical studies, 38% to 40% of patients were greater than or equal to 60 years of age and 10% to 12% of patients were greater than or equal to 70 years of age. Chronic Phase, Prior Interferon-Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed. The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN therapy at doses greater than or equal to 25 x 106 units/week and were all in late chronic phase, with a median time from diagnosis of 32 months. Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or CCyR (0% Ph+ metaphases). Median duration of treatment was 29 months with 81% of patients treated for greater than or equal to 24 months (maximum = 31.5 months). Efficacy results are reported in Table 20. Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%). Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients. Accelerated Phase: 235 patients with accelerated phase disease were enrolled. These patients met one or more of the following criteria: greater than or equal to 15% - less than 30% blasts in PB or BM; greater than or equal to 30% blasts + promyelocytes in PB or BM; greater than or equal to 20% basophils in PB; and less than 100 x 109/L platelets. The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg. Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for greater than or equal to 24 months (maximum = 35 months). Efficacy results are reported in Table 20. Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs 64%), confirmed and unconfirmed major cytogenetic response (31% vs 19%). Myeloid Blast Crisis: 260 patients with myeloid blast crisis were enrolled. These patients had greater than or equal to 30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg. Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase. Cytogenetic responses were also assessed. Median duration of treatment was 4 months with 21% of patients treated for greater than or equal to 12 months and 10% for greater than or equal to 24 months (maximum = 35 months). Efficacy results are reported in Table 20. The hematologic response rate was higher in untreated patients than in treated patients (36% vs 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs 16%). The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600-mg dose group than for the 400-mg dose group (17% vs 8%). Reference ID: 5484208 Table 20: Response in Chronic Myeloid Leukemia Studies Chronic phase IFN failure Accelerated phase Myeloid blast crisis (n = 532) (n = 235) (n = 260) 600 mg n = 158 600 mg n = 223 400 mg 400 mg n = 77 400 mg n = 37 % of patients [CI 95%] Hematologic response1 95% [92.3−96.3] 71% [64.8−76.8] 31% [25.2−36.8] Complete hematologic response (CHR) 95% 38% 7% No evidence of leukemia (NEL) Not applicable 13% 5% Return to chronic phase (RTC) Not applicable 20% 18% Major cytogenetic response2 60% [55.3−63.8] 21% [16.2−27.1] 7% [4.5−11.2] (Unconfirmed3) (65%) (27%) (15%) Complete4 (Unconfirmed3) 39% (47%) 16% (20%) 2% (7%) Abbreviations: BM, bone marrow; PB, peripheral blood. 1Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): CHR: Chronic phase study [WBC less than 10 x 109/L, platelet less than 450 x 109/L, myelocytes + metamyelocytes less than 5% in blood, no blasts and promyelocytes in blood, basophils less than 20%, no extramedullary involvement] and in the accelerated and blast crisis studies [absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, platelets greater than or equal to 100 x 109/L, no blood blasts, BM blasts less than 5% and no extramedullary disease]. NEL: Same criteria as for CHR but ANC greater than or equal to 1 x 109/L and platelets greater than or equal to 20 x 109/L (accelerated and blast crisis studies). RTC: less than 15% blasts BM and PB, less than 30% blasts + promyelocytes in BM and PB, less than 20% basophils in PB, no extramedullary disease other than spleen and liver (accelerated and blast crisis studies). 2Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1% 35%). A major response (0%-35%) combines both complete and partial responses. 3Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation. 4Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least 1 month after the initial bone marrow study. The median time to hematologic response was 1 month. In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2]. In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg). An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response. The median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not yet reached for the 600 mg group (p = 0.0097). An estimated 46.2% [34.7, 57.7] vs 65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400 mg vs 600 mg dose groups, respectively. In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response. Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study. Efficacy results were similar in men and women and in patients younger and older than age 65. Responses were seen in Black patients, but there were too few Black patients to allow a quantitative comparison. 14.2 Pediatric CML A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single-arm Phase 2 trial. Patients were treated with imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between Months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of Reference ID: 5484208 6.74 months. Patients were allowed to be removed from protocol therapy to undergo alternative therapy, including hematopoietic stem cell transplantation. Thirty-one children received stem cell transplantation. Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal. Twenty-five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range, 4 to 24). Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy. One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. These patients had not previously received imatinib and ranged in age from 3 to 20 years old; 3 were 3 to 11 years old, 9 were 12 to 18 years old, and 2 were greater than 18 years old. Patients were treated at doses of 260 mg/m2/day (n = 3) (approximately 0.8 times the recommended pediatric dosage of Imkeldi), 340 mg/m2/day (n = 4), 440 mg/m2/day (n = 5) (approximately 1.3 times the recommended pediatric dosage of Imkeldi) and 570 mg/m2/day (n = 2) (approximately 1.7 times the recommended pediatric dosage of Imkeldi). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a CCyR, and 2 had a minimal cytogenetic response. In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a CCyR at doses of 242 mg/m2/day and 257 mg/m2/day (0.7 and 0.8 times the recommended pediatric dosage of Imkeldi, respectively). 14.3 Acute Lymphoblastic Leukemia A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended imatinib dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received imatinib 600 mg/day in a Phase 1 study. Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ ALL Phase 2 study patients and for the 2 Phase 1 patients are shown in Table 21. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months. Table 21: Effect of Imatinib on Relapsed/Refractory Ph+ ALL Phase 1 study Phase 2 study (N = 2) (N = 43) n (%) n (%) CHR 8 (19) 2 (100) NEL 5 (12) RTC/PHR 11 (26) MCyR 15 (35) CCyR 9 (21) PCyR 6 (14) Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response; NEL, no evidence of leukemia; PCyR, partial cytogenic response; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; PHR, partial hematologic response; RTC, return to chronic phase. 14.4 Pediatric ALL Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5-year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The safety and effectiveness of imatinib (340 mg/m2/day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL. The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor. There were 92 eligible patients with Ph+ ALL enrolled. The median age was 9.5 years (1 to 21 years: 2.2% between 1 and less than 2 years, 56.5% between 2 and less than 12 years, 34.8% between 12 and less than 18 years, and 6.5% between 18 and 21 years). Sixty-four percent were male, 75% were White, 9% were Asian/Pacific Islander, and 5% were Black. In 5 successive cohorts of patients, imatinib exposure was systematically increased by earlier introduction and prolonged duration. Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of imatinib exposure. Reference ID: 5484208 There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received imatinib plus chemotherapy; 30 were treated exclusively with chemotherapy and imatinib and 20 received chemotherapy plus imatinib and then underwent hematopoietic stem cell transplant, followed by further imatinib treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to imatinib beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12, imatinib was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of imatinib prior to HSCT, and 28 weeks (196 days) of imatinib after the immediate post transplant period. The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months. 14.5 Myelodysplastic/Myeloproliferative Diseases An open-label, multicenter, Phase 2 clinical trial was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with imatinib 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received imatinib at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a CCyR). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8 to 26.7) in the 7 patients treated within the Phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 22. Response durations of Phase 2 study patients ranged from 141+ days to 457+ days. Table 22: Response in MDS/MPD Number Complete hematologic Major cytogenetic of patients response response N N (%) N (%) Overall population 31 14 (45) 12 (39) Chromosome 5 translocation 14 11 (79) 11 (79) Chromosome 4 translocation 2 2 (100) 1 (50) Others/no translocation 14 1 (7) 0 Molecular relapse 1 NE NE Abbreviations: NE, not evaluable; MDS/MPD, myelodysplastic/myeloproliferative disease. 14.6 Aggressive Systemic Mastocytosis One open-label, multicenter, Phase 2 study was conducted testing imatinib in diverse populations of patients with life- threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with ASM treated with 100 mg to 400 mg of imatinib daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of imatinib in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of imatinib daily. Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with imatinib from the published reports and in the Phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to imatinib), one with concomitant CML. Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (PHR) (61% overall response rate). Median duration of imatinib therapy for the 5 ASM patients in the Phase 2 study was 13 months (range, 1.4 to 22.3 months) and between 1 month and more than 30 months in the responding Reference ID: 5484208 patients described in the published medical literature. A summary of the response rates to imatinib in ASM is provided in Table 23. Response durations of literature patients ranged from 1+ to 30+ months. Table 23: Response in ASM Cytogenetic abnormality Number of patients Complete hematologic response Partial hematologic response N N (%) N (%) FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion) 7 7 (100) 0 Juxtamembrane mutation 2 0 2 (100) Unknown or no cytogenetic abnormality detected 15 0 7 (44) D816V mutation 4 1 (25) 0 Total 28 8 (29) 9 (32) Abbreviations: ASM, aggressive systemic mastocytosis; PDGFR, platelet-derived growth factor receptor. Patient had concomitant chronic myeloid leukemia CML and ASM. Imatinib has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Imkeldi is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to imatinib and should not receive imatinib. 14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia One open-label, multicenter, Phase 2 study was conducted testing imatinib in diverse populations of patients with life- threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1,000 mg (2.5 times the recommended dosage of Imkeldi) of imatinib daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received imatinib at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 44 months. Table 24: Response in HES/CEL Cytogenetic abnormality Number of patients Complete hematological response Partial hematological response N (%) N (%) Positive FIP1L1-PDGFRα fusion kinase 61 61 (100) 0 Negative FIP1L1-PDGFRα fusion kinase 56 12 (21) 9 (16) Unknown cytogenetic abnormality 59 34 (58) 7 (12) Total 176 107 (61) 23 (13) Abbreviations: CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; PDGFR, platelet-derived growth factor receptor. 14.8 Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene. An open-label, multicenter, Phase 2 study was conducted testing imatinib in a diverse population of patients with life- threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with imatinib 800 mg daily (age range, 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with imatinib are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. A single pediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/daily. Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 25. Reference ID: 5484208 Table 25: Response in DFSP Number of patients (n = 18) % Complete response 7 39 Partial response 8 44 Total responders 15 83 *5 patients made disease free by surgery. Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement, there were 4 complete and 6 partial responses. The median duration of response in the Phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months. 14.9 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant GIST. The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST. The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 26. Table 26: Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST Trials Imatinib 400mg Imatinib 800mg N = 818 N = 822 Progression-free survival (months) Median 18.9 23.2 95% CI 17.4–21.2 20.8–24.9 Overall survival (months) 49.0 48.7 95% CI 45.3–60.0 45.3–51.6 Best overall tumor response Complete response 43 (5.3%) 41 (5.0%) Partial response 377 (46.1%) 402 (48.9%) Abbreviation: GIST, gastrointestinal stromal tumors. Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p = 0.98). Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n = 347) had a 3.4 month median and a 7.7 month mean exposure to imatinib following crossover. One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally every day for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group. The median time to response was 12 weeks (range was 3 to 98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached). Reference ID: 5484208 1.0 '" ~ a, 0.9 '-' 0.8 C: e ~ 0.7 e " 0.6 C: .. '" -~ 0.5 '" C) C: 0.4 ·;; .c 0 0.3 -~ :s 0.2 .. .c e 0.1 Q. -- lmatinib 400mg a -censored 0.0 ------- Placebo + =censored 0 12 24 36 48 60 72 84 96 108 Patients at risk Survival time in months lmatinib : 359 292 258 221 169 90 30 11 Placebo: 354 276 242 215 156 79 30 6 Adjuvant Treatment of GIST In the adjuvant setting, imatinib was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to imatinib at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size greater than or equal to 3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration. Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month imatinib arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p less than 0.0001. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month imatinib arm. Seventy-two of these 79 patients subsequently crossed over to imatinib therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month imatinib arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month imatinib and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365). Figure 3: Study 1 Recurrence-Free Survival (ITT Population) A second randomized, multicenter, open-label, Phase 3 trial in the adjuvant setting (Study 2) compared 12 months of imatinib treatment to 36 months of imatinib treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter greater than 5 cm and mitotic count greater than 5/50 high power fields (HPF), or tumor diameter greater than 10 cm and any mitotic count, or tumor of any size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range, 22 to 84 years). RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of imatinib treatment significantly prolonged RFS compared to 12 months of imatinib treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p less than 0.0001 (Figure 4). The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of imatinib treatment significantly prolonged OS compared to 12 months of imatinib treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p = 0.0187 (Figure 5). Reference ID: 5484208 jij 100 > -~ 90 :::, 111 80 1 70 u 60 C: ~ 50 :::, ~ 40 'o 30 :,.. :!: 20 2i .. ..c 10 ~ IL 0 0 P < .0001 Hazard ratio 0.46 (95% Cl, 0 32-0.65) N -- (1) lmatinib 12 MO: 199 ---- (2) lmatinib 36 MO: 198 I I I Censored observations 6 12 18 24 At-risk : Events Evt Cen 84 115 50 148 30 36 42 48 54 Survival time in months (1) 199:0 182:8 177:12 163:25 137:46 105:65 88:72 61 :77 49:81 36:83 (2) 198:0 189:5 184:8 181 :11 173:18 152:22 133:25 102:29 82:35 54:46 60 27:84 39:47 66 14:84 21 :49 72 10:84 8:50 78 2:84 0:50 84 0:84 100 11111 I «Urz:lt I ~ 90 ·~ 80 • ?• I ll~W#:if ;~ll~lltll-+-+-11111-H-+Hll-1 •H--111111➔--tH llll l ldllll II ~I ll I 111111 1111 :::, Ill 70 ni 60 i 0 50 'o :,.. 40 :!: :C 30 .. .c e 20 0. 10 0 P = 0.0187 Hazard ratio 0.45 (95% Cl, 0.22-0.89) N -- (1) lmatinib 12 MO: 199 ---- (2) lmatinib 36 MO 198 I I I Censored observations 6 12 18 24 At-risk: Events Evt 25 12 30 Cen 174 186 36 42 48 Survival time in months 54 60 66 72 (1) 199:0 190:2 (2) 198:0 196:0 188:2 183:6 176:8 156:10 140:11 105:14 87:18 64:22 46:23 27:25 20:25 192:0 187:4 184:5 164:7 152:7 119:8 100:8 76:10 56:11 31:11 13:12 78 2:25 0:12 84 0:25 Figure 4: Study 2 Recurrence-Free Survival (ITT Population) Figure 5: Study 2 Overall Survival (ITT Population) 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Imkeldi oral solution 80 mg/mL is supplied as 140 mL of clear yellow to brownish yellow colored solution with a strawberry flavor in an amber PET bottle with a child resistant tamper-evident closure. NDC 81927-201-01 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Store and dispense in original container only. Any open bottle should be discarded after 30 days. Imkeldi is a hazardous drug. Follow applicable special handling and disposal procedures1. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Fluid Retention and Edema Inform patients of the possibility of developing edema and fluid retention. Advise patients to contact their health care provider if unexpected rapid weight gain occurs [see Warnings and Precautions (5.1)]. Reference ID: 5484208 Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding, or bruising [see Warnings and Precautions (5.4)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Imkeldi and for 14 days after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with Imkeldi and for 1 month after the last dose [see Use in Specific Populations (8.2)]. Drug Interactions Imkeldi and certain other medicines, such as warfarin, erythromycin, and phenytoin, including over-the-counter medications, such as herbal products, can interact with each other. Advise patients to tell their doctor if they are taking or plan to take iron supplements. Avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking Imkeldi [see Drug Interactions (7)]. Pediatric Advise patients that growth retardation has been reported in children and pre-adolescents receiving imatinib. The long term effects of prolonged treatment with Imkeldi on growth in children are unknown. Therefore, closely monitor growth in children under Imkeldi treatment [see Warnings and Precautions (5.11)]. Driving and Using Machines Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Imkeldi. Therefore, caution patients about driving a car or operating machinery [see Warnings and Precautions (5.13)]. Accurate Measuring Device and Dosing and Administration Advise patients and caregivers to measure Imkeldi with an accurate milliliter measuring device. A household teaspoon is not an accurate measuring device. Advise patients and caregivers to ask their pharmacist to recommend an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring the correct dose [see Warnings and Precautions (5.15)]. Advise patients to take Imkeldi with a meal and a large glass of water. Advise patients that, if a dose is missed, they should wait until the next scheduled dose and not take two doses at the same time. Advise patients to take Imkeldi exactly as prescribed, not to change their dose or to stop taking Imkeldi unless they are told to do so by their doctor [see Dosage and Administration (2.1)]. Manufactured for: Shorla Oncology Inc. Cambridge, MA 02142, USA Patent Information: U.S. Patent: 11,957,681 Version: IMAPI006 Reference ID: 5484208 Oral Dispensing Syringe (not Included, Bottle Bottle Adapter (not lrw;luded, Disposable Cloves {not lneJuded) INSTRUCTIONS FOR USE IMKELDI (IM-KELL-DEE) (imatinib) oral solution 80 mg/mL This Instructions for Use contains information on how to take (or give) IMKELDI. Read this Instructions for Use before you (or your child) start using IMKELDI oral solution and each time you get a refill. There may be new information. This important information does not take the place of talking to your (or your child’s) healthcare provider about your (or your child’s) medical condition or treatment. Supplies needed (Figure A) IMKELDI bottle with child resistant cap Oral dispensing syringe (not included with IMKELDI) Bottle adapter (not included with IMKELDI) Disposable gloves (not included with IMKELDI) Figure A Important Information You Need to Know Before Taking IMKELDI For oral use only (taken by mouth). Always use the oral dispensing syringe and bottle adapter provided by your pharmacist. If you did not receive the oral dispensing syringe and bottle adapter, contact your pharmacist. Ask your pharmacist to show you how to measure your prescribed doses. Take IMKELDI exactly as prescribed by your healthcare provider. Do not stop taking IMKELDI without first speaking with your healthcare provider. All doses of IMKELDI should be taken with a meal and a large glass of water. Taking IMKELDI with certain medicines and grapefruit juice may affect each other. Talk to your healthcare provider about all the medicines you take. If you miss a dose of IMKELDI, do not take the missed dose. Take your next dose at your regular time. IMKELDI is a hazardous drug. Do not prepare, withdraw, take, or give IMKELDI without wearing disposable gloves. IMKELDI may cause dizziness, blurred vision, or sleepiness during treatment. Reference ID: 5484208 Preparing a new bottle of IMKELDI before first time use 1. Wash hands thoroughly with soap and water (Figure B). Figure B 2. Wear disposable gloves while preparing, withdrawing, taking, or giving IMKELDI to avoid direct contact with the medicine. 3. Check the expiration date on the bottle. Do not use IMKELDI if the expiration date on the bottle has passed. Contact your healthcare provider or pharmacist. 4. Remove the child-resistant bottle cap by pushing it down firmly and twisting it counter-clockwise (to the left) (Figure C). Do not throw away the child-resistant bottle cap. Figure C 5. Place the open bottle upright on a clean flat surface. Hold the bottle firmly and push the ribbed end of the bottle adapter firmly into the neck of the bottle as far as it will go (Figure D). Do not remove the bottle adapter from the bottle after it is inserted. Figure D 6. Put the child-resistant cap back on the bottle by turning it clockwise (to the right) (Figure E). Make sure that the child-resistant cap is tightly closed. Figure E Reference ID: 5484208 --, ~~~--- \ \ \ '\ / 7. Write the date of first opening on the bottle label. Preparing and withdrawing a dose of IMKELDI 8. Repeat Step 1 to Step 4 above. 9. Place the IMKELDI bottle on a clean flat surface. 10. Check your prescription to find out the number of mL you are supposed to take. Find the number line on the oral dispensing syringe barrel that matches your dose. 11. Push the plunger of the oral dispensing syringe all the way up towards the tip of the oral dispensing syringe to remove air (Figure F). Figure F 12. While keeping the bottle in an upright position, insert the tip of the oral dispensing syringe into the opening of the bottle adapter and push down gently (Figure G). Do not force the oral dispensing syringe tip into the bottler adapter opening. Figure G 13. Hold the oral dispensing syringe tip firmly in the bottle and carefully turn the bottle upside down (Figure H). Slowly pull down the plunger of the oral dispensing syringe until the widest part of the oral dispensing syringe plunger lines up with the prescribed number of mL dose (Figure I). Figure H Reference ID: 5484208 Figure I 14. Leave the oral dispensing syringe tip in the bottle adapter. Check the oral dispensing syringe for air (Figure J). If you see air bubbles, push the plunger all the way back up to push the air into the bottle (Figure K). Then pull the plunger down again to withdraw the prescribed dose. Repeat this Step until all the air is gone from the oral dispensing syringe. Figure J Figure K 15. Leave the oral dispensing syringe tip in the bottle adapter. Turn the bottle back to an upright position and place the bottle on a clean flat surface (Figure L). Without touching the plunger, hold the oral dispensing syringe by the barrel and gently twist and pull the oral dispensing syringe out of the bottle adapter (Figure M). Figure L Reference ID: 5484208 \ \ \ Figure M 16. Inspect the oral dispensing syringe to make sure that it contains the correct dose as described in Step 13 (Figure N). Figure N Taking (or giving) IMKELDI 17. The child or adult should sit up straight or stand before taking IMKELDI. 18. Gently place the oral dispensing syringe tip in the mouth towards the inside of the cheek (Figure O). Figure O 19. Slowly and gently push the plunger down to gently squirt the medicine into the inside of the cheek until the plunger no longer moves and all the medicine is out of the oral dispensing syringe (Figure P). Do not push down too hard on the plunger or squirt the medicine to the back of the mouth or throat as this may cause choking. Remove the oral dispensing syringe from the mouth. Figure P 20. Swallow the medicine completely. Make sure that no medicine is left in the mouth. Reference ID: 5484208 21. After swallowing IMKELDI, eat a meal and drink a large glass of water (Figure Q). Note: If you do not eat a meal and drink a large glass of water right after swallowing IMKELDI, you may get stomach or intestine problems. Figure Q 22. Close the bottle by screwing the child-resistant cap back on the bottle in a clockwise direction (to the right) with the adapter left in place. Make sure that the cap is tightly closed (Figure R). Figure R Cleaning the oral dispensing syringe after use 23. Right after use, wash the oral dispensing syringe thoroughly with water. Hold the syringe under water and push the plunger in and out of the oral dispensing syringe several times to remove any medicine from the oral dispensing syringe including the tip (Figure S). Remove the plunger from the oral dispensing syringe barrel and wash both the plunger and oral dispensing syringe barrel thoroughly with cold water. Repeat this Step until the oral dispensing syringe is clean. Figure S 24. Shake off excess water from the plunger and the oral dispensing syringe barrel. Dry both the oral dispensing syringe and the oral dispensing syringe plunger with a clean paper towel. 25. Make sure that all oral dispensing syringe parts are fully dry before putting the plunger back in the oral dispensing syringe barrel and using it for the next dose. 26. Throw away (dispose of) the gloves after administration of IMKELDI and cleaning the oral dispensing syringe. 27. Wash hands thoroughly with soap and water. Reference ID: 5484208 Storing IMKELDI Store at room temperature between 68°F to 77°F (20°C to 25°C). IMKELDI comes in a child resistant tamper-evident bottle. Store and give in original bottle only. Keep out of the reach of children. Throwing away (disposing of) IMKELDI Any opened bottle should be thrown away (discarded) 30 days after first opening. Talk to your healthcare provider or pharmacist about the best way to throw away any unused IMKELDI. Follow all special handling and throw away (disposal) procedures provided by your healthcare provider and pharmacist. Additional Information Call your healthcare provider about side effects. You can report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Shorla Oncology at 844-9-SHORLA Manufactured for: Shorla Oncology Inc. Cambridge, MA 02142, USA This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved 11/2024 Version: IMAIFU002 Reference ID: 5484208	custom-source	2025-02-12T15:47:04.667817	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219097s000lbl.pdf', 'application_number': 219097, 'submission_type': 'ORIG ', 'submission_number': 1}
80,362	0 0 II )-l___ H 2 N ............... 0 ~ 0 _,, NH 2 H 3 c' ~ CH 3 ASPIRIN HO .,,,.:::;O H 3 C.........._..,O=c II I 0 .,,,.:::; EQUAGESIC® CIV (meprobamate and aspirin tablets) Rx only DESCRIPTION Each tablet of EQUAGESIC, for oral administration, contains 200 mg meprobamate and 325 mg aspirin. Chemically, meprobamate is 2-methyl-2-propyl-1,3- propanediol dicarbamate. Its molecular formula is C9H18N2O4 with a molecular weight of 218.25. Chemically, aspirin is benzoic acid 2-(acetyloxy). Its molecular formula is C9H8O4 with a molecular weight of 180.16. It occurs as an odorless white, needle like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water. The structural formulas of meprobamate and aspirin are: MEPROBAMATE The inactive ingredients present are cellulose, D&C Yellow 10, FD&C Red 3, FD&C Yellow 6, hydrogenated vegetable oil, magnesium stearate, polacrilin potassium, and starch. CLINICAL PHARMACOLOGY Meprobamate is a carbamate derivative which has been shown (in animal and/or human studies) to have effects at multiple sites in the central nervous system, including the thalamus and limbic system. Aspirin is a nonnarcotic analgesic with antipyretic and anti-inflammatory properties. INDICATIONS AND USAGE As an adjunct in the short-term treatment of pain accompanied by tension and/or anxiety in patients with musculoskeletal disease. Clinical trials have demonstrated that in these situations relief of pain is somewhat greater than with aspirin alone. EQUAGESIC is not intended for use longer than 10 days. CONTRAINDICATIONS Usage in Pregnancy and Lactation An increased risk of congenital malformations associated with the use of minor tranquilizers (meprobamate, chlordiazepoxide, and diazepam) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. Reference ID: 5482812 Because of the known effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system (closure of the ductus arteriosus), use during the third trimester of pregnancy should be avoided. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, and perinatal mortality. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug. Meprobamate passes the placental barrier. It is present both in umbilical-cord blood at or near maternal plasma levels and in breast milk of lactating mothers at concentrations two to four times that of maternal plasma. When use of meprobamate is contemplated in breast-feeding patients, the drug’s higher concentrations in breast milk as compared to maternal plasma levels should be considered. EQUAGESIC is contraindicated in patients with acute intermittent porphyria and in patients with allergic or idiosyncratic reactions to aspirin, meprobamate, or related compounds, such as carbromal, carisoprodol, mebutamate, nonsteroidal anti-inflammatory drug products, salicylates, or tybamate. EQUAGESIC is also contraindicated in patients with the syndrome of asthma, rhinitis, and nasal polyps. The aspirin component of EQUAGESIC may cause severe angioedema, bronchospasm (asthma), or urticaria. Reye’s syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’s syndrome with concomitant use of aspirin in certain viral illnesses. WARNINGS EQUAGESIC should be prescribed cautiously and in small quantities to patients with suicidal tendencies. Additive Effects Since CNS suppressant effects of meprobamate and alcohol or meprobamate and other psychotropic drugs may be additive, appropriate caution should be exercised with patients who take more than one of these agents simultaneously. Alcohol Warning Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. Gastrointestinal Side Effects (GI) GI side effects include gross GI bleeding, heartburn, nausea, stomach pain, and vomiting. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, Reference ID: 5482812 physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. Peptic Ulcer Disease Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. Potentially Hazardous Tasks Patients should be warned that meprobamate may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as driving a motor vehicle or operating machinery. Such tasks should be avoided while taking this product. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including EQUAGESIC, in pregnant women at about 30 weeks gestation and later. NSAIDs, including EQUAGESIC, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including EQUAGESIC, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit EQUAGESIC use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if EQUAGESIC treatment extends beyond 48 hours. Discontinue EQUAGESIC if oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS; Pregnancy]. Serious Skin Reactions NSAIDs, including aspirin, a component of EQUAGESIC, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life- threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of EQUAGESIC at the first appearance Reference ID: 5482812 of skin rash or any other sign of hypersensitivity. EQUAGESIC is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as EQUAGESIC. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue EQUAGESIC and evaluate the patient immediately. PRECAUTIONS General EQUAGESIC should be prescribed with caution in certain special-risk populations, such as elderly or debilitated patients and those with acute abdominal conditions, Addison’s disease, coagulation disorders, elevated intracranial pressure, head injuries, hypothyroidism, impairment of liver or kidney function, prostatic hypertrophy, or urethral stricture. Meprobamate is metabolized in the liver and excreted by the kidney. To avoid its excess accumulation, caution should be exercised in the administration to patients with compromised liver or kidney function. Meprobamate occasionally may precipitate seizures in epileptic patients. Information for Patients Patients should be informed that EQUAGESIC contains aspirin and should not be taken by patients with an aspirin allergy. Patients with a predisposition for gastrointestinal bleeding should be cautioned that concomitant use of medications containing aspirin and/or alcohol may have an additive effect in this regard. Serious Skin Reactions, including DRESS Advise patients to stop taking EQUAGESIC immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS]. Pregnancy Embryo-Fetal Toxicity Inform pregnant women to avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with EQUAGESIC is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy]. Reference ID: 5482812 Drug Interactions Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin angiotensin conversion pathway. Acetazolamide Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. Alcohol, General Anesthetics, Narcotic Analgesics, Sedative Hypnotics, Tranquilizers such as Chlordiazepoxide, or Other CNS Depressants: The effects of these substances may be enhanced, causing increased CNS depression. Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylates can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Corticosteroids: In patients receiving concomitant corticosteroids and chronic use of medications containing aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. 6-Mercaptopurine and Methotrexate: Bone marrow toxicity and blood dyscrasia may result from displacing these drugs from secondary binding sites, and in the case of methotrexate, also reducing its excretion. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. Oral Hypoglycemics: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia. Reference ID: 5482812 Uricosuric Agents (Probenicid and Sulfinpyrazone): Salicylates antagonize the uricosuric action, reducing their effectiveness in the treatment of gout. Aspirin competes with these agents for protein binding sites. Laboratory Test Interactions Aspirin may interfere with the following laboratory determinations in blood: blood urea nitrogen, cholesterol, elevated hepatic enzymes including aspartate aminotransferase (AST), fasting blood glucose, hyperkalemia, prolonged bleeding time, protein, prothrombin time, serum amylase, serum creatinine, and uric acid. Aspirin may interfere with the following laboratory determinations in urine: 5-hydroxyindoleacetic acid, diacetic acid, Gerhardt ketone, glucose, proteinuria, uric acid, spectrophotometric detection of barbiturates, and vanillylmandelic acid (VMA). Carcinogenesis, Mutagenesis, Impairment of Fertility Administration of aspirin for 68 weeks at 0.5 percent in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Pregnancy Risk Summary Use of NSAIDs, including EQUAGESIC, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of EQUAGESIC use between about 20 and 30 weeks of gestation, and avoid EQUAGESIC use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including EQUAGESIC, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Reference ID: 5482812 The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including EQUAGESIC, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If EQUAGESIC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue EQUAGESIC and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal Reference ID: 5482812 outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full- term infant exposed to NSAIDs through maternal use is uncertain. Nursing Mothers Nursing mothers should avoid using aspirin because salicylate is excreted in breast milk. Use of high doses may lead to rashes, platelet abnormalities, and bleeding in nursing infants. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (See also CONTRAINDICATIONS). Pediatric Use Safety and effectiveness have not been established for pediatric patients under the age of 12 years (See CONTRAINDICATIONS). Geriatric Use Clinical studies of meprobamate with aspirin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Body as a Whole: Fever, hypothermia, thirst. Allergic or Idiosyncratic: Severe hypersensitivity reactions, including anaphylaxis, angioneurotic edema, anuria, asthma, bronchospasm, bullous dermatitis, chills, erythema multiforme, exfoliative erythroderma, laryngeal edema, oliguria, proctitis, purpura, Stevens-Johnson syndrome, stomatitis, and urticaria. Milder reactions are characterized by an itchy, erythematous maculopapular, or urticarial rash which may be generalized or confined to the groin. Other reactions have included acute non thrombocytopenic purpura, adenopathy, cross-sensitivity between meprobamate/mebutamate and meprobamate/carbromal, ecchymoses, eosinophilia, fixed-drug eruption with cross-reaction to carisoprodol, leukopenia, peripheral edema, and petechiae. Cardiovascular: Various forms of arrhythmia, hypotension, palpitation, syncope, tachycardia, and transient ECG changes. Central Nervous System: Agitation, ataxia, cerebral edema, coma, confusion, dizziness, drowsiness, dysphoria, euphoria, fast EEG activity, headache, impairment of visual accommodation, lethargy, overstimulation, paradoxical excitement, paresthesias, sedation, slurred speech, subdural or intracranial hemorrhage, seizures, vertigo, and weakness. Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, and respiratory alkalosis. Reference ID: 5482812 Gastrointestinal Abdominal pain, constipation, diarrhea, dyspepsia, epigastric discomfort, gastric distress, gastrointestinal bleeding, heartburn, hepatitis, nausea, pancreatitis, Reye’s syndrome, transient elevations of hepatic enzymes, ulceration and perforation, and vomiting. Hematologic (see also “Allergic or Idiosyncratic”): Agranulocytosis and aplastic anemia have been reported, although no causal relationship has been established, coagulopathy, disseminated intravascular coagulation, exacerbation of porphyric symptoms, hemolytic anemia, iron deficiency anemia, occult blood loss, prolongation of the prothrombin time, thrombocytopenia, and thrombocytopenic purpura. Musculoskeletal: Rhabdomyolysis Metabolism: Hyperglycemia and hypoglycemia Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, and antepartum and postpartum bleeding. Respiratory: Acute airway obstruction, hyperpnea, pulmonary edema, and tachypnea. Special Senses: Hearing loss and tinnitus. Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, and renal insufficiency and failure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). DRUG ABUSE AND DEPENDENCE Physical dependence, psychological dependence, and abuse have occurred. Chronic intoxication from prolonged ingestion of, usually, greater-than-recommended doses is manifested by ataxia, slurred speech, and vertigo. Therefore, careful supervision of dose and amounts prescribed is advised, as well as avoidance of prolonged administration, especially for alcoholics and other patients with a known propensity for taking excessive quantities of drugs. Sudden withdrawal of the drug after prolonged and excessive use may precipitate recurrence of preexisting symptoms, such as anorexia, anxiety, or insomnia, or withdrawal reactions, such as ataxia, confusional states, hallucinosis, muscle twitching, tremors, vomiting, and, rarely, convulsive seizures. Such seizures are more likely to occur in persons with central nervous system damage or preexistent or latent convulsive disorders. Onset of withdrawal symptoms occurs usually within 12 to 48 hours after discontinuation of meprobamate; symptoms usually cease within the next 12- to 48-hour period. When excessive dosage has continued for weeks or months, dosage should be reduced gradually over a period of 1 to 2 weeks rather than abruptly stopped. Alternatively, a long-acting barbiturate may be substituted, then gradually withdrawn. OVERDOSAGE Treatment of overdose with EQUAGESIC is essentially symptomatic and supportive. In cases where excessive doses of EQUAGESIC have been taken, sleep ensues rapidly and blood pressure, pulse, and respiratory rates are reduced to basal levels. Any drug remaining in the stomach should be removed and symptomatic treatment given. After emesis and/or lavage, activated charcoal may reduce Reference ID: 5482812 absorption of both aspirin and meprobamate. Should respiration or blood pressure become compromised, respiratory assistance, central nervous system stimulants, and pressor agents should be administered cautiously as indicated. Diuresis, osmotic (mannitol) diuresis, peritoneal dialysis, and hemodialysis have been used successfully in removing both aspirin and meprobamate. Alkalinization of the urine increases the excretion of salicylates. Careful monitoring of urinary output is necessary, and caution should be taken to avoid over hydration. Relapse and death, after initial recovery, have been attributed to incomplete gastric emptying and delayed absorption. Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. Signs and symptoms include abdominal pain, acidbase disturbances with development of metabolic acidosis, convulsions, delirium, hyperpnea, hyperthermia, hypoprothrombinemia, restlessness, tinnitus (ringing in the ears), and vomiting. The early signs of salicylic overdose (salicylism), including tinnitus, occur at plasma concentrations approaching 200 μg/mL. Plasma concentrations of aspirin above 300 μg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 μg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. Careful medical management is essential. In acute aspirin overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Treatment of aspirin overdose consists primarily of supporting vital functions, increasing salicylate elimination, and correcting the acid-base disturbance. Gastric emptying and/or lavage is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis administration of activated charcoal, as a slurry, is beneficial, if less than 3 hours have passed since ingestion. Charcoal adsorption should not be employed prior to emesis and lavage. Severity of aspirin intoxication is determined by measuring the blood salicylate level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are the immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children. Suicidal attempts with meprobamate have resulted in ataxia, coma, drowsiness, lethargy, shock, stupor, and respiratory and vasomotor collapse. Some suicidal attempts have been fatal. The following data have been reported in the literature and from other sources. These data are not expected to correlate with each case (considering factors such as individual susceptibility and length of time from ingestion to treatment) but represent the usual ranges reported. Acute simple overdose (meprobamate alone): Death has been reported with ingestion of as little as 12 grams meprobamate and survival with as much as 40 grams. Reference ID: 5482812 Blood Levels 0.5 to 2 mg percent represents the usual blood-level range of meprobamate after therapeutic doses. 3 to 10 mg percent usually corresponds to findings of mild to moderate symptoms of overdosage, such as stupor or light coma. 10 to 20 mg percent usually corresponds to deeper coma, requiring more intensive treatment. Some fatalities occur. At levels greater than 20 mg percent, more fatalities than survivals can be expected. Acute combined overdose (meprobamate with other CNS psychotropic drugs or alcohol): Since effects can be additive, a history of ingestion of a low dose of meprobamate plus any of these compounds (or of a relatively low blood or tissue level) cannot be used as a prognostic indicator. DOSAGE AND ADMINISTRATION The usual dosage of EQUAGESIC is one or two tablets, each tablet containing meprobamate, 200 mg, and aspirin, 325 mg, orally 3 to 4 times daily as needed for the relief of pain when tension or anxiety is present. EQUAGESIC is not recommended for patients 12 years of age and under. HOW SUPPLIED The drug product is not being marketed. Distributed by: The drug product is not being marketed. Rev. 11/2024 Reference ID: 5482812	custom-source	2025-02-12T15:47:04.919016	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/011702s041lbl.pdf', 'application_number': 11702, 'submission_type': 'SUPPL ', 'submission_number': 41}
80,359	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use COMBOGESIC® IV safely and effectively. See full prescribing information for COMBOGESIC IV. COMBOGESIC IV (acetaminophen and ibuprofen) injection, for intravenous use. Initial U.S. Approval: 2023 WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK See full prescribing information for complete boxed warning. • Take care when prescribing, preparing, and administering COMBOGESIC IV to avoid dosing errors which could result in accidental overdose and death. (5.1) • COMBOGESIC IV contains acetaminophen, which has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4000 mg per day, and often involve more than one acetaminophen-containing product. (5.2) • Nonsteroidal anti-inflammatory drugs (NSAIDS), like the ibuprofen in COMBOGESIC IV, may cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.3). • COMBOGESIC IV is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.3) • NSAIDS, like the ibuprofen in COMBOGESIC IV, cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.4) -----------------------------RECENT MAJOR CHANGES-------------------------- Warnings and Precautions (5.10) 11/2024 -----------------------------INDICATIONS AND USAGE-------------------------- COMBOGESIC IV is indicated in adults where an intravenous route of administration is considered clinically necessary for: • the relief of mild to moderate pain • the management of moderate to severe pain as an adjunct to opioid analgesics Limitations of Use COMBOGESIC IV is indicated for short-term use of five days or less. ------------------------DOSAGE AND ADMINISTRATION---------------------- • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1). • Do not exceed the maximum total daily dose of COMBOGESIC IV (4,000 mg acetaminophen and 1,200 mg ibuprofen) in 24 hours. (2.1) • Do not exceed a total daily dose of 4,000 mg (4 g) of acetaminophen from all sources. (2.1) • Do not administer with other acetaminophen-containing products. (2.1) • For adult patients weighing greater than or equal to 50 kg (actual body weight): The recommended dosage is 1,000 mg of acetaminophen and 300 mg of ibuprofen administered as a 15-minute infusion, every 6 hours, as necessary (2.2). • For adult patients weighing less than 50 kg (actual body weight): The recommended dosage is 15 mg/kg acetaminophen and 4.5 mg/kg ibuprofen administered as a 15-minute infusion, every 6 hours, as necessary. (2.2) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Injection: 1,000 mg/100 mL (10 mg/mL) of acetaminophen and 300 mg/100 mL (3 mg/mL) of ibuprofen in single-dose vial. (3) -------------------------------CONTRAINDICATIONS------------------------------ COMBOGESIC IV is contraindicated in: • patients who have previously demonstrated hypersensitivity to acetaminophen, ibuprofen, other NSAIDs or to any of the excipients in the IV formulation (4) • patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (4, 5.9, 5.11) • the setting of coronary artery bypass graft (CABG) surgery (4, 5.3) • patients with severe hepatic impairment or severe active liver disease (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.5) • Heart Failure and Edema: Avoid use of COMBOGESIC IV in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.6) • Renal Toxicity: Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC IV, has resulted in renal papillary necrosis and other renal injury. (5.7) • Anaphylactic Reactions: Discontinue use immediately if symptoms occur. (5.8) • Exacerbation of Asthma Related to Aspirin Sensitivity: COMBOGESIC IV is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.9) • Serious Skin Reactions: Discontinue COMBOGESIC IV at first appearance of skin rash or other signs of hypersensitivity. (5.10) • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.11) • Fetal Toxicity: Limit use of NSAID-containing products, including COMBOGESIC IV, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAID- containing products, including COMBOGESIC IV, in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.12) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.13). -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions (greater than or equal to 3%) are infusion site pain, nausea, constipation, dizziness, infusion site extravasation, vomiting, headache, somnolence. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1- 800-FDA 1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- A number of known or potential interactions between COMBOGESIC IV and other drugs/drug classes exist. Please refer to the Drug Interactions section (7) for further information. --------------------------USE IN SPECIFIC POPULATIONS-------------------- • COMBOGESIC IV is not recommended in patients with renal impairment. (5.7, 8.7) • COMBOGESIC IV is not recommended in patients with hepatic impairment. (5.2, 8.6) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 Reference ID: 5482804 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Recommended Dosage: Adults 2.3 Instructions for Intravenous Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Medication Errors 5.2 Hepatotoxicity 5.3 Cardiovascular Thrombotic Events 5.4 Gastrointestinal Bleeding, Ulceration, and Perforation 5.5 Hypertension 5.6 Heart Failure and Edema 5.7 Renal Toxicity and Hyperkalemia 5.8 Hypersensitivity and Anaphylactic Reactions 5.9 Exacerbation of Asthma Related to Aspirin Sensitivity 5.10 Serious Skin Reactions 5.11 Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) 5.12 Fetal Toxicity 5.13 Hematologic Toxicity 5.14 Ophthalmological Effects 5.15 Aseptic Meningitis 5.16 Masking of Inflammation and Fever 5.17 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Phase 3 Clinical Efficacy Study 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5482804 FULL PRESCRIBING INFORMATION WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK RISK OF MEDICATION ERRORS: Take care when prescribing, preparing, and administering COMBOGESIC IV to avoid dosing errors which could result in accidental overdose and death (5.1). HEPATOTOXICITY: COMBOGESIC IV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4,000 mg per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.2)]. CARDIOVASCULAR RISK: COMBOGESIC IV contains ibuprofen, a nonsteroidal anti- inflammatory drug (NSAID). NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.3)]. COMBOGESIC IV is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.3)]. GASTROINTESTINAL RISK: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE COMBOGESIC IV is indicated in adults where an intravenous route of administration is considered clinically necessary for: • the relief of mild to moderate pain • the management of moderate to severe pain as an adjunct to opioid analgesics Limitations of Use COMBOGESIC IV is indicated for short-term use of five days or less. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.4)]. • Do not exceed the maximum total daily dose of COMBOGESIC IV (4,000 mg acetaminophen and 1,200 mg ibuprofen) in 24 hours. • Do not exceed a total daily dose of 4,000 mg (4 g) acetaminophen from all sources. Reference ID: 5482804 • Do not co-administer COMBOGESIC IV with other acetaminophen or ibuprofen containing products [see Warnings and Precautions (5.2)]. • Visually inspect for particulate matter and discoloration prior to administration. If visibly opaque particles, discoloration, or other foreign particulates are observed, do not use. • Use COMBOGESIC IV in one patient on one occasion only. It contains no antimicrobial preservative. Discard any unused solution. • Do not mix with diluents or with other medicines. 2.2 Recommended Dosage For adult patients weighing greater than or equal to 50 kg (actual body weight): The recommended dosage of COMBOGESIC IV is one vial (100 mL; acetaminophen 1,000 mg/ibuprofen 300 mg) administered as a 15-minute infusion every 6 hours, as necessary. For adult patients weighing less than 50 kg (actual body weight): The recommended dosage is 15 mg/kg acetaminophen and 4.5 mg/kg ibuprofen, administered as a 15-minute infusion every 6 hours, as necessary. This equates to a maximum single dose of 750 mg acetaminophen and 225 mg ibuprofen (discard remaining medicine in vial), and a total daily dose of 3,000 mg (3 g) acetaminophen and 900 mg ibuprofen. 2.3 Instructions for Intravenous Administration • Administer as a 15-minute intravenous infusion. • Do not mix other medications with the COMBOGESIC IV vial or infusion device. • As for all solutions for infusion presented in glass vials, monitor closely, particularly at the end of infusion, regardless of administration route, in order to avoid air embolism. This applies particularly for central route infusion. • To decrease the likelihood of bung fragmentation or the bung being forced into the vial, use a syringe or giving set with a diameter equal to or below 0.8 mm for solution sampling and ensure that the bung is pierced at the location specifically designed for needle introduction (where the thickness of the bung is the lowest). • The entire 100 mL container of COMBOGESIC IV is not intended for use in patients weighing less than 50 kg. For doses less than 1,000 mg acetaminophen and 300 mg ibuprofen, the appropriate dose must be withdrawn from the container and placed into a separate container prior to administration. Using aseptic technique, withdraw the appropriate dose (weight-based) from an intact sealed COMBOGESIC IV container and place the measured dose in a separate empty, sterile container (e.g., glass bottle, plastic intravenous container, or syringe) for intravenous infusion to avoid the inadvertent delivery and administration of the total volume of the commercially available container. COMBOGESIC IV is supplied in a single-dose container and the unused portion must be discarded. 3 DOSAGE FORMS AND STRENGTHS Injection: 1,000 mg/100 mL (10 mg/mL) of acetaminophen and 300 mg/100 mL (3 mg/mL) of ibuprofen in a clear, colorless solution in single-dose vial. Reference ID: 5482804 4 CONTRAINDICATIONS COMBOGESIC IV is contraindicated in: • patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to acetaminophen, ibuprofen, other NSAIDs or to any other components of this product [see Warnings and Precautions (5.8, 5.10, 5.11)] • patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.8, 5.9)] • in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.3)] • patients with severe hepatic impairment or severe active liver disease [see Warnings and Precautions (5.2)] 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Medications Errors Take care when prescribing, preparing, and administering COMBOGESIC IV in order to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: • the dose in milligrams (mg) and milliliters (mL) is not confused; • the dosing is based on weight for patients under 50 kg; • infusion pumps are properly programmed; and • the total daily dose of acetaminophen from all sources does not exceed maximum daily limits [see Dosage and Administration (2)]. 5.2 Hepatotoxicity Acetaminophen COMBOGESIC IV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 mg per day, and often involve more than one acetaminophen-containing product. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Ibuprofen COMBOGESIC IV contains ibuprofen, a NSAID. Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs, including ibuprofen. Reference ID: 5482804 Clinical Recommendations COMBOGESIC IV is contraindicated in patients with severe hepatic impairment or severe active liver disease. COMBOGESIC IV has not been studied in patients with impaired hepatic function. Use in these patients is not recommended [see Use in Specific Populations (8.6)]. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue COMBOGESIC IV immediately, and perform a clinical evaluation of the patient. 5.3 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, the lowest effective dose for the shortest duration possible should be used. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.4)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Reference ID: 5482804 Avoid the use of COMBOGESIC IV in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If COMBOGESIC IV is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.4 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. However, even short-term therapy is not without risk. Risk Factors for GI Bleeding, Ulceration and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10 fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most post-marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for getting an ulcer or bleeding. Strategies to Minimize the GI Risks in NSAID-treated Patients • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk, unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue COMBOGESIC IV until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.5 Hypertension NSAIDs, including the ibuprofen in COMBOGESIC IV, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.6 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Reference ID: 5482804 Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of COMBOGESIC IV in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If COMBOGESIC IV is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.7 Renal Toxicity and Hyperkalemia Renal Toxicity Use of COMBOGESIC IV is not recommended in patients with renal impairment. Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC IV, has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of COMBOGESIC IV in patients with advanced renal disease. The renal effects of COMBOGESIC IV may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating COMBOGESIC IV. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.8 Hypersensitivity and Anaphylactic Reactions Acetaminophen There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Discontinue COMBOGESIC IV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use COMBOGESIC IV in patients with acetaminophen allergy. Ibuprofen NSAIDS, including the ibuprofen in COMBOGESIC IV, has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.9)]. Discontinue COMBOGESIC IV immediately if symptoms associated with allergy or hypersensitivity occur. Reference ID: 5482804 5.9 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin- sensitive patients, COMBOGESIC IV is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When COMBOGESIC IV is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.10 Serious Skin Reactions COMBOGESIC IV contains acetaminophen and ibuprofen. Acetaminophen, or NSAIDs, including ibuprofen, may cause serious skin reactions such as exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and discontinued the use of the drug at the first appearance of skin rash or any other sign of hypersensitivity. COMBOGESIC IV is contraindicated in patients with previous serious skin reactions to acetaminophen or NSAIDs [see Contraindications (4)]. 5.11 Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as the ibuprofen in COMBOGESIC IV. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue COMBOGESIC IV and evaluate the patient immediately. 5.12 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAID-containing products, including COMBOGESIC IV, in pregnant women at about 30 weeks gestation and later. NSAID-containing products, including COMBOGESIC IV, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAID-containing products, including COMBOGESIC IV, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. Reference ID: 5482804 If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit COMBOGESIC IV use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if COMBOGESIC IV treatment extends beyond 48 hours. Discontinue COMBOGESIC IV if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.13 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient being treated with COMBOGESIC IV has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including the ibuprofen in COMBOGESIC IV, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.14 Ophthalmological Effects Blurred or diminished vision, scotomata, and/or changes in color vision have been reported with oral ibuprofen. If a patient develops such complaints while receiving COMBOGESIC IV, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing. 5.15 Aseptic Meningitis Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have underlying chronic disease. If signs or symptoms of meningitis develop in a patient on COMBOGESIC IV, the possibility of its being related to ibuprofen should be considered. 5.16 Masking of Inflammation and Fever The pharmacological activity of COMBOGESIC IV in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.17 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on NSAID treatment with a CBC and a chemistry profile as clinically indicated [see Warnings and Precautions (5.3,5.4,5.8)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions to ibuprofen or acetaminophen are described elsewhere in other sections of the labeling. • Hepatotoxicity [see Warnings and Precautions (5.2)] • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.3)] • Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] Reference ID: 5482804 • Heart Failure and Edema [see Warnings and Precautions (5.6)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.7)] • Hypersensitivity and Anaphylactic Reactions [see Warnings and Precautions (5.8)] • Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.9)] • Serious Skin Reactions [see Warnings and Precautions (5.10)] • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.11)] • Hematologic Toxicity [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical trials of COMBOGESIC IV have been conducted in patients with postoperative musculoskeletal pain and soft tissue pain models lasting between two to five days. Two Phase 3 clinical trials have been conducted with COMBOGESIC IV to assess efficacy and safety after multiple doses. In AFT-MXIV-07 participants were treated with COMBOGESIC IV, acetaminophen IV, ibuprofen IV or placebo for a treatment period of 48 hours. In AFT MXIV-11 participants were treated for between 48 hours and five days with COMBOGESIC IV. The study population for AFT-MXIV-07 was comprised of adults aged 18 to 65 years, mean age: 42 years. AFT-MXIV-11 included adults aged 19 – 87 years, mean age: 53 years. Safety data for the first 48 hours of both studies was pooled. Overall, 59.3% of the patients (N = 182/307) administered COMBOGESIC IV experienced one or more treatment-emergent adverse event (TEAE) during the first 48 hours of treatment, accounting for a total of 436 TEAEs (see Table 1). The most common TEAEs were related to the infusion site (infusion site pain, infusion site extravasation), or affected the gastrointestinal (nausea, vomiting, constipation) or nervous (dizziness, headache, somnolence) systems. Table 1: Common TEAEs (occurring in ≥ 3% of COMBOGESIC IV-treated participants) Adverse Reactions COMBOGESIC IV (N=307) % Acetaminophen (N=75) % Ibuprofen (N=76) % Placebo (N=50) % Gastrointestinal disorders Nausea 16.3 33.3 34.2 32.0 Vomiting 6.2 14.7 6.6 2.0 Constipation 7.2 5.3 5.3 8.0 Infusion Site Complications Infusion site pain 17.6 0.0 9.2 2.0 Infusion site extravasation 6.5 2.7 6.6 14.0 Nervous System Disorders Headache 5.5 6.7 6.6 20.0 Dizziness 7.2 9.3 9.2 18.0 Somnolence 3.9 8.0 7.9 6.0 Other skin and subcutaneous-related TEAEs (pruritis, hyperhidrosis) also affected around 2-3% of the study population, as did procedural nausea and polyuria. Reference ID: 5482804 AFT-MXIV-11 found no notable difference in the safety profile of COMBOGESIC IV in participants treated for 5 days compared to those treated for 48 hours. Additionally, the safety profile was comparable between older participants (aged 65-75 years and >75 years) and younger participants (aged <65 years); the type and incidence of treatment-emergent adverse events was comparable, and the incidence of clinically significant shifts in laboratory tests (hematocrit 1.3% (n=3/228), hemoglobin 1.3% (n=3/228) and erythrocytes 0.9% (n=2/218), was low in participants over the age of 65. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of acetaminophen and ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS Table 2. Drug Interactions with COMBOGESIC IV Drugs That Interfere with Hemostasis Clinical Impact: • Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of COMBOGESIC IV with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.13)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.3)]. Intervention: Concomitant use of COMBOGESIC IV and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.4, 5.13)]. COMBOGESIC IV is not a substitute for low dose aspirin for cardiovascular protection. Reference ID: 5482804 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of COMBOGESIC IV and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of COMBOGESIC IV and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.7)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COMBOGESIC IV with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.7)]. Digoxin Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of COMBOGESIC IV and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COMBOGESIC IV and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of COMBOGESIC IV and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NSAIDS and cyclosporine may increase cyclosporine’s nephrotoxicity. Reference ID: 5482804 Intervention: During concomitant use of COMBOGESIC IV and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.4)]. Intervention: The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NSAIDS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of COMBOGESIC IV and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAID-containing products, including COMBOGESIC IV, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of COMBOGESIC IV use between about 20 and 30 weeks of gestation and avoid COMBOGESIC IV use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus: Use of NSAID-containing products, including COMBOGESIC IV, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Use of NSAID-containing products, including COMBOGESIC IV, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimester of pregnancy are inconclusive. No adequate and well-controlled studies have been conducted using COMBOGESIC IV in pregnant women. Animal reproduction studies have also not been conducted with COMBOGESIC IV. Reference ID: 5482804 The following describes animal reproduction studies for Acetaminophen and Ibuprofen: Acetaminophen: Reproductive and developmental studies in rats and mice from the published literature have identified adverse events at clinically relevant doses of acetaminophen. Fetotoxicity, increases in bone variations in the fetuses, and necrosis in the fetus liver and kidney have been noted in studies in rats. In mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation (see Data). Ibuprofen: Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities after ibuprofen exposure. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women and ibuprofen should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses (see Data). The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAID-containing products, including COMBOGESIC IV, in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including COMBOGESIC IV, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If, after consideration of alternative treatments for pain management, an NSAID-containing product, including COMBOGESIC IV, is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If COMBOGESIC IV treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue COMBOGESIC IV and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of COMBOGESIC IV during labor or delivery. In animal studies, NSAIDS, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Reference ID: 5482804 Data Human Data Acetaminophen: The results from a large population-based prospective cohort, including data from 26,424 women with live born singletons who were exposed to oral acetaminophen during the first trimester, indicate no increased risk for congenital malformations, compared to a control group of unexposed children. The rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study showed that 11,610 children with prenatal exposure to acetaminophen during the first trimester had no increased risk of major birth defects compared to 4,500 children in the control group. Other epidemiological data showed similar results. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including recall bias. Ibuprofen: Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these post-marketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Acetaminophen: Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.85 times the maximum human daily dose (MHDD= 4 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations. Reference ID: 5482804 When pregnant rats received oral acetaminophen throughout gestation at doses of 1.2 times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral acetaminophen at doses 0.3 times the MHDD (based on a body surface area comparison). In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.43, 0.87, and 1.7 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. Ibuprofen: In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.12, 0.32, or 0.97-times the maximum human daily dose of 1,200 mg of ibuprofen based on a body surface area comparison) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.06, 0.16, 0.48, 1.5-times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above. In a published study, rats were orally dosed with 300 mg/kg ibuprofen (2.4-times the maximum human daily dose of 1,200 mg based on a body surface area comparison) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity. One incidence each of a membranous ventricular septal defect and gastroschisis was noted fetuses from rabbits treated with 500 mg/kg (8.1-times the maximum human daily dose) from Gestation Day 9 to 11. 8.2 Lactation Risk Summary The components of COMBOGESIC IV, ibuprofen and acetaminophen, are present in human milk. Limited published literature reports that, orally administered ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose. There are no reports of adverse effects of ibuprofen on the breastfed infant and no effects on milk production. Limited published studies report that orally administered acetaminophen passes rapidly into human milk with similar levels in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral administration of 1 gram acetaminophen. There is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COMBOGESIC IV and any potential adverse effects on the breastfed infant from COMBOGESIC IV or from the underlying maternal condition. Reference ID: 5482804 8.3 Females and Males of Reproductive Potential Infertility Acetaminophen Based on animal data, use of acetaminophen may cause reduced fertility in males and females of reproductive potential. It is not known whether these effects on fertility are reversible. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are approximately 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, and reduced fertility. In female animals given the same doses, reduced implantation sites were reported. Additional published animal studies indicate that acetaminophen exposure in utero adversely impacts reproductive capacity of both male and female offspring at clinically relevant exposures [see Nonclinical Toxicology (13.1)]. Ibuprofen Based on the mechanism of action, the use of prostaglandin-mediated NSAID-containing products, including COMBOGESIC IV, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAID-containing products, including COMBOGESIC IV, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of COMBOGESIC IV in pediatric patients has not been studied in the pediatric population. COMBOGESIC IV is not approved for patients under 18 years of age. 8.5 Geriatric Use Of the total number of subjects in clinical studies of COMBOGESIC IV, 20.2% (N = 62/307) were aged 65 years or over, including 5.2% (N = 16/307) aged 75 years or over [see Adverse Reactions (6.1)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.2, 5.3, 5.4, 5.7,)]. The ibuprofen and acetaminophen in COMBOGESIC IV are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Reference ID: 5482804 8.6 Hepatic Impairment COMBOGESIC IV has not been studied in patients with impaired hepatic function. Because acetaminophen is extensively metabolized by the liver, COMBOGESIC IV is contraindicated in patients with severe hepatic impairment or severe active liver disease. Use of COMBOGESIC IV in patients with hepatic impairment is not recommended [see Warnings and Precautions (5.2)]. 8.7 Renal Impairment COMBOGESIC IV has not been studied in patients with impaired renal function. The use of COMBOGESIC IV in these patients is not recommended [see Warnings and Precautions (5.7)]. 10 OVERDOSAGE COMBOGESIC IV is a combination product. The clinical presentation of overdose may include the signs and symptoms of acetaminophen toxicity, ibuprofen toxicity, or both. Acetaminophen The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis. In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia also occur. Plasma acetaminophen levels > 300 mcg/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are < 150 mcg/mL or < 37.5 mcg/mL at 12 hours after ingestion [see Warnings and Precautions (5.2)]. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack-Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the acetaminophen level is below the lower line. Ibuprofen Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.4, 5.5, 5.7)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). Reference ID: 5482804 >=o HO NH 11 DESCRIPTION COMBOGESIC IV (acetaminophen and ibuprofen) injection contains acetaminophen and ibuprofen, a nonsteroidal anti-inflammatory drug. Acetaminophen chemical name is N-acetyl-p-aminophenol. Acetaminophen is a white, odorless, crystalline powder, possessing a slightly bitter taste. Acetaminophen is soluble in boiling water and 1N sodium hydroxide and is freely soluble in alcohol. Acetaminophen has a molecular weight of 151.16. The molecular formula is C8H9NO2 and the structural formula is: Ibuprofen sodium dihydrate chemical name is 2-(4-isobutyl phenyl) propionic acid sodium salt dihydrate. Ibuprofen sodium dihydrate is a white powder. It has a molecular weight of 264.29. It is freely soluble in water. The molecular formula is C13H21NaO4 and the structural formula of ibuprofen sodium dihydrate is represented below: COMBOGESIC IV injection is a sterile, clear, colorless, non-pyrogenic, isotonic solution, intended for intravenous infusion with a pH stability range of 6.3-7.3. Each single-dose 100 mL vial contains 1,000 mg of acetaminophen and 300 mg of ibuprofen base (equivalent to 385 mg of ibuprofen sodium dihydrate), 25 mg of Cysteine hydrochloride monohydrate, 13 mg of Disodium phosphate dihydrate, 3,285 mg of Mannitol, Hydrochloric acid (for pH adjustment), Sodium hydroxide (for pH adjustment), Water for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action COMBOGESIC IV contains acetaminophen and ibuprofen as active drug substances. Acetaminophen is a non-opiate, non-salicylate analgesic. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to primarily involve central actions. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). Its mechanism of action for analgesia, like that of other NSAIDs, is not completely understood, but involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482804 12.2 Pharmacodynamics Hematological Effects NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. 12.3 Pharmacokinetics The pharmacokinetic profile of the intravenous formulation is dose proportional following the administration of a half dose and a full dose of COMBOGESIC IV. The maximum concentration (Cmax) occurs at the end of the 15-min intravenous infusion of COMBOGESIC IV. While overall exposures (area under the concentration time curve [AUC]) were similar following a single dose of COMBOGESIC IV compared to the same dose given orally, the Cmax of the intravenous formulation was twice that of the oral formulation. As expected, the Tmax following intravenous administration was achieved much faster (in 15 minutes) than with the oral formulation. The mean Cmax and AUC0-inf of COMBOGESIC IV following administration of a single intravenous dose of 1,000 mg acetaminophen and 300 mg ibuprofen in adults were 34.30 mcg/mL and 56.48 mcg.h/mL for acetaminophen and 48.12 mcg/mL and 102.82 mcg.h/mL for ibuprofen, respectively. A single-dose pharmacokinetic study of COMBOGESIC IV in healthy volunteers showed no drug interactions between acetaminophen and ibuprofen. Distribution Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein. Elimination The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Ibuprofen is rapidly metabolized and eliminated in the urine. The serum half-life is 1.8 to 2.0 hours. Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: a) conjugation with glucuronide; b) conjugation with sulfate; and c) oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates. Excretion Less than 9% of acetaminophen is excreted unchanged in the urine. Reference ID: 5482804 The excretion of ibuprofen is virtually complete 24 hours after the last dose. Studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the urine within 24 hours as metabolite A (25%), (+)-2-[p-(2hydroxymethyl-propyl) phenyl] propionic acid and metabolite B (37%), (+)-2-[p-(2carboxypropyl)phenyl]propionic acid; the percentages of free and conjugated ibuprofen were approximately 1% and 14%, respectively. Specific Populations Pediatric Patients The pharmacokinetics of COMBOGESIC IV has not been studied in pediatric patients below 18 years of age. Hepatic Impairment The pharmacokinetics of COMBOGESIC IV in patients with impaired hepatic function has not been studied [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]. Renal Impairment The pharmacokinetics of COMBOGESIC IV in patients with renal impairment has not been studied. [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Acetaminophen Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the MHDD (based on a body surface area comparison). In contrast, there was no evidence of carcinogenic activity in male rats (0.7 times) or mice (1.2 - 1.4 times the MHDD, based on a body surface area comparison). Ibuprofen Adequate long-term animal studies have not been conducted to evaluate the carcinogenic potential of ibuprofen. Mutagenesis Acetaminophen Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast, acetaminophen tested positive in the in vitro mouse lymphoma assay and the in vitro chromosomal aberration assay using human lymphocytes. Reference ID: 5482804 In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1,500 mg/kg/day to the rat model (at 3.6 times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8 times the MHDD, based on a body surface area comparison), suggesting a threshold effect. Ibuprofen In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Impairment of Fertility Acetaminophen In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to approximately 1.1 times the MHDD of acetaminophen, (based on a body surface area comparison). Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming approximately 1.1 times the MHDD (based on a body surface area comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are approximately 0.8 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, and reduced fertility. Females given the same doses also showed reduced implantation sites. These effects appear to increase with the duration of treatment. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. In a published mouse study, oral administration of 50 mg/kg acetaminophen to pregnant mice from Gestation Day 7 to delivery (0.06 times the MHDD) reduced the number of primordial follicles in female offspring and reduced the percentage of full-term pregnancies and number of pups born to these females exposed to acetaminophen in utero. In a published study, pregnant rats oral administration of 350 mg/kg acetaminophen (0.85 times the MHDD) from Gestation Day 13 to 21 (dams), reduced the number of germ cells in the fetal ovary and decreased ovary weight and reduced number of pups per litter in F1 females as well as reduced ovary weights in F2 females. Ibuprofen In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.16-times the MRHD based on body surface area comparison) did not impact male or female fertility or litter size. In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.023-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males but decreased ovulation was reported in females. Reference ID: 5482804 Mean Estimates& 9S%ConfidenGe Intervals 40 30 e .§. 0 ;;: V> " !! 20 !l f ~ ;:: 10 0 Combogesie• IV Ibuprofen Acetaminophen Placebo 14 CLINICAL STUDIES 14.1 Phase 3 Clinical Efficacy Study COMBOGESIC IV was studied in a Phase 3, placebo-controlled, prospective, randomized, double-blind, parallel- design trial comparing the analgesic efficacy and safety of COMBOGESIC IV (n=76/276) with acetaminophen alone (n=75/276), ibuprofen alone (n=76/276) and placebo (n=50/276), after bunionectomy surgery. The demographic and baseline characteristics of the 276 eligible patients were balanced between the treatment groups with the majority of patients being female (82%) and white (62%) with a mean (SD) age of 42.4 (12.2) years. The primary efficacy endpoint was the time-adjusted Sum of Pain Intensity Differences over 48 hours (SPID48) and analyzed with each pre-rescue Visual Analogue Scale (VAS) carried forward up to 2 hours. An analysis of covariance was used for the primary efficacy analysis with treatment as the fixed effect and baseline pain intensity score as the covariate on the intent to treat population. The analysis of time-adjusted SPID48 demonstrated that COMBOGESIC IV (least square mean (LSM) = 36.7, standard error (SE) = 2.2) provided more effective pain relief than placebo (LSM = 17.5, SE = 2.7), acetaminophen (LSM = 19.3, SE = 2.2) or ibuprofen (LSM = 24.6, SE = 2.2). Figure 1: Time-adjusted SPID48 with Pre-Rescue VAS Score Carried Forward up to 2 Hours Reference ID: 5482804 16 HOW SUPPLIED/STORAGE AND HANDLING COMBOGESIC IV (acetaminophen/ ibuprofen) injection 1,000 mg/300 mg per 100 mL (10 mg/3mg per mL): clear, colorless solution in single-dose vial. Discard unused portion. NDC # 0143-9150-10: pack of 10 vials. COMBOGESIC IV is a clear, colorless solution, free from visible particles. Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze. Store in the original carton in order to protect from light. Protect from heat. 17 PATIENT COUNSELING INFORMATION Patients should be informed of the following information before initiating therapy with COMBOGESIC IV. • Hepatotoxicity: Advise patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms). Advise patients to seek immediate medical assistance if these occur [see Warnings and Precautions (5.2)]. • Alcohol: Advise patients that COMBOGESIC IV should not be taken concomitantly with alcohol- containing beverages or other acetaminophen-containing products [see Warnings and Precautions (5.2)]. • Cardiovascular Thrombotic Events: Inform patients that COMBOGESIC IV, like other NSAID- containing medications, may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Advise patients to be alert for the signs and symptoms of cardiovascular thrombotic events including chest pain, shortness of breath, weakness, slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.3)]. • Gastrointestinal Bleeding, Ulceration, and Perforation: Inform patients that COMBOGESIC IV, like other NSAID-containing medications, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to be alert for the signs and symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.4)]. • Heart Failure and Edema: Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.6)]. • Weight Gain and Edema: Advise patients to promptly report unexplained weight gain or edema to their physicians [see Warnings and Precautions (5.6)]. • Hypersensitivity and Anaphylactic Reactions: Discontinue COMBOGESIC IV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use COMBOGESIC IV in patients with known acetaminophen or ibuprofen allergy [see Warnings and Precautions (5.8 and 5.10)]. • Serious Skin Reactions, including DRESS: Advise patients to be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and to ask for medical advice when observing any indicative sign or symptoms [see Warnings and Precautions (5.8, 5.10, 5.11)]. • Female Fertility: Advise females of reproductive potential who desire pregnancy that NSAID containing products, including COMBOGESIC IV, may be associated with a reversible delay in ovulation [see Use Reference ID: 5482804 in Specific Populations (8.3)]. • Fetal Toxicity: Inform pregnant women to avoid use of COMBOGESIC IV and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with COMBOGESIC IV is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1)]. • Use of NSAIDS and Low-Dose Aspirin: Inform patients not to use low-dose aspirin concomitantly with COMBOGESIC IV until they talk to their healthcare provider [see Warnings and Precautions (5.4), see Drug Interactions (7)]. Manufactured by: S.M. Farmaceutici SRL, Zona Industriale, 85050 Tito (PZ), Italy Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Information and patents: https://combogesiciv.com Revised: November 2024 Reference ID: 5482804	custom-source	2025-02-12T15:47:05.370324	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215320s001lbl.pdf', 'application_number': 215320, 'submission_type': 'SUPPL ', 'submission_number': 1}
80,360	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use COXANTO safely and effectively. See full prescribing information for COXANTO. COXANTO (oxaprozin) capsules, for oral use Initial U.S. Approval: 1992 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • COXANTO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) -----------------------------RECENT MAJOR CHANGES------------------------ Warnings and Precautions (5.9) 11/2024 -----------------------------INDICATIONS AND USAGE-------------------------- COXANTO is a non-steroidal anti-inflammatory drug indicated for: • Relief of signs and symptoms of Osteoarthritis (OA) (1) • Relief of signs and symptoms of Rheumatoid Arthritis (RA) (1) • Relief of signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) (1) ------------------------DOSAGE AND ADMINISTRATION---------------------- • Use the lowest effective dosage for shortest duration consistent with individual patent treatment goals (2.1) • OA: 1,200 mg (four 300 mg capsules) given orally once a day (2.2, 2.5, 14.1) • RA: 1,200 mg (four 300 mg capsules) given orally once a day (2.3, 2.5, 14.2) • JRA: 600 mg (two 300 mg capsules) once daily in patients 22 to 31 kg. 900 mg (three 300 mg capsules) once daily in patients 32 to 54 kg. 1,200 mg (four 300 mg capsules) once daily in patients 55 kg or greater (2.4, 2.5) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Capsules: 300 mg (3) -------------------------------CONTRAINDICATIONS------------------------------ • Known hypersensitivity to oxaprozin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of COXANTO in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of COXANTO in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: COXANTO is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue COXANTO at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including COXANTO, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence > 3%) are: constipation, diarrhea, dyspepsia, nausea, rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Solubiomix, LLC. at 1-844-551-9911 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking COXANTO with drugs that interfere with hemostasis. Concomitant use of COXANTO and analgesic doses of aspirin is not generally recommended (7) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with COXANTO may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with COXANTO in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with COXANTO can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) --------------------------USE IN SPECIFIC POPULATIONS-------------------- • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of COXANTO in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482810 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Osteoarthritis 2.3 Rheumatoid Arthritis 2.4 Juvenile Rheumatoid Arthritis 2.5 Individualization of Dosage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Photosensitivity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Osteoarthritis 14.2 Rheumatoid Arthritis 14.3 Juvenile Rheumatoid Arthritis 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482810 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • COXANTO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE COXANTO is indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis • For relief of the signs and symptoms of juvenile rheumatoid arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of COXANTO and other treatment options before deciding to use COXANTO. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Different dose strengths and formulations (e.g., capsules, tablets) of oral oxaprozin are not interchangeable. This difference should be taken into consideration when changing strengths or formulations [see Dosage and Administration (2.2, 2.3, 2.4), Clinical Pharmacology (12.3)]. The highest daily dose for COXANTO is 1,200 mg a day. 2.2 Osteoarthritis For OA, the dosage is 1,200 mg (four 300 mg capsules) given orally once a day [see Dosage and Administration (2.5)]. 2.3 Rheumatoid Arthritis For RA, the dosage is 1,200 mg (four 300 mg capsules) given orally once a day [see Dosage and Administration (2.5)]. 2.4 Juvenile Rheumatoid Arthritis For JRA, in patients 6 to 16 years of age, the recommended dosage given orally once per day should be based on body weight of the patient as given in Table 1 [see Dosage and Administration (2.5)]. Reference ID: 5482810 Table 1. Recommended Daily Dose of COXANTO by Body Weight in Pediatric Patients Body Weight Range (kg) Dose (mg) Number of Capsules 22 to 31 kg 600 mg Two capsules 32 to 54 kg 900 mg Three capsules 55 kg or greater 1,200 mg Four capsules 2.5 Individualization of Dosage After observing the response to initial therapy with COXANTO, the dose and frequency should be adjusted to suit an individual patient’s needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of COXANTO to minimize adverse effects. The maximum recommended total daily dose of COXANTO in adults and pediatric patients is 1,200 mg. Patients with low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1,200 mg, but only with close monitoring [see Clinical Pharmacology (12.3)]. Physicians should ensure that patients are tolerating lower doses without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to larger doses. Most patients will tolerate once-a-day dosing with COXANTO, although divided doses may be tried in patients unable to tolerate single doses. 3 DOSAGE FORMS AND STRENGTHS COXANTO (oxaprozin) capsules: 300 mg capsules, white opaque capsule imprinted “403” on the cap in black ink. 4 CONTRAINDICATIONS COXANTO is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of CABG surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious Reference ID: 5482810 CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as oxaprozin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of COXANTO in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If COXANTO is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including COXANTO, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-times increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as Reference ID: 5482810 aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue COXANTO until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including oxaprozin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), discontinue COXANTO immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDSs, including COXANTO, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of oxaprozin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Reference ID: 5482810 Interactions (7)]. Avoid the use of COXANTO in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If COXANTO is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of COXANTO in patients with advanced renal disease. The renal effects of COXANTO may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating COXANTO. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of COXANTO [see Drug Interactions (7)]. Avoid the use of COXANTO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If COXANTO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Oxaprozin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to oxaprozin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, COXANTO is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When COXANTO is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 5482810 5.9 Serious Skin Reactions NSAIDs, including oxaprozin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of COXANTO at the first appearance of skin rash or any other sign of hypersensitivity. COXANTO is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as COXANTO. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue COXANTO and evaluate the patient immediately. 5.11Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including COXANTO, in pregnant women at about 30 weeks gestation and later. NSAIDs, including COXANTO, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age [see Use in Specific Populations (8.1)]. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including COXANTO, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit COXANTO use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if COXANTO treatment extends beyond 48 hours. Discontinue COXANTO if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with COXANTO has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including COXANTO, may increase the risk of bleeding events. Co-morbid conditions such Reference ID: 5482810 as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of COXANTO in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Photosensitivity Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reaction data were derived from patients who received oxaprozin, the active component of COXANTO, in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2253 patients who took 1,200 mg to 1,800 mg of the active component of COXANTO per day in clinical trials. Of these, 1721 patients were treated for at least 1 month, 971 patients for at least 3 months, and 366 patients for more than 1 year. Incidence Greater than 1%: In clinical trials of oxaprozin, the active component of COXANTO, or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%. Cardiovascular system: edema. Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting. Reference ID: 5482810 Hematologic system: anemia, increased bleeding time. Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache. Skin and appendages: pruritus, rash. Special senses: tinnitus. Urogenital system: abnormal renal function, dysuria or frequency. Incidence Greater than 1%: The following adverse reactions were reported in clinical trials or in patients taking other NSAIDs. Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis. Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis. Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including liver failure, stomatitis, hemorrhoidal or rectal bleeding. Hematologic system: aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, purpura, thrombocytopenia, leukopenia. Metabolic system: hyperglycemia, weight changes. Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness. Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression. Skin: alopecia, angioedema, urticaria, photosensitivity, sweat. Special senses: blurred vision, conjunctivitis, hearing decrease. Urogenital: cystitis, hematuria, increase in menstrual flow, oliguria/ polyuria, proteinuria, renal insufficiency, decreased menstrual flow. Adverse Reactions in Pediatric Patients with Juvenile Rheumatoid Arthritis In a 3-month open label study in 59 pediatric patients with juvenile rheumatoid arthritis treated with oxaprozin, the active component of COXANTO, adverse events were reported by 58% of patients. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Of 30 patients who continued treatment for more than 3 months (19 to 48 weeks range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and five of those discontinued treatment. Reference ID: 5482810 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxaprozin, the active component of COXANTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: serum sickness. Digestive system: hepatitis, pancreatitis. Hematologic system: agranulocytosis, pancytopenia. Skin: pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, fixed drug eruption (FDE), toxic epidermal necrolysis (Lyell’s syndrome). Urogenital: acute interstitial nephritis, nephrotic syndrome, acute renal failure. 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with oxaprozin [see Clinical Pharmacology (12.3)]. Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis Clinical Impact: • Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of COXANTO with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of COXANTO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. COXANTO is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including Reference ID: 5482810 possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of COXANTO and ACE inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of COXANTO and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COXANTO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of COXANTO and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COXANTO and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate. Intervention: During concomitant use of COXANTO and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of COXANTO and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of COXANTO and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended. Pemetrexed Reference ID: 5482810 Clinical Impact: Concomitant use of COXANTO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of COXANTO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with COXANTO may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of COXANTO with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. Glyburide Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. Intervention: During concomitant use of COXANTO and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy. Laboratory Test Interactions False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking COXANTO. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of COXANTO therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish COXANTO from benzodiazepines. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including COXANTO, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of COXANTO use between about 20 and 30 weeks of gestation and avoid COXANTO use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including COXANTO, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Reference ID: 5482810 Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, oral administration of oxaprozin to pregnant rabbits at doses 0.1 times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses 0.2 times and 1.6 times the maximum recommended human dose, respectively, revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at a dose 1.6 times the maximum recommended human dose (based on body surface area). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as oxaprozin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including COXANTO, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If COXANTO treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue COXANTO and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of COXANTO during labor or delivery. In animal studies, NSAIDS, including oxaprozin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Reference ID: 5482810 Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Teratology studies with oxaprozin were performed in mice, rats, and rabbits in pregnant animals administered oral doses up to 200 mg/kg/day, 200 mg/kg/day, and 30 mg/kg/day, respectively, during the period of organogenesis. In rabbits, malformations were observed at doses greater than or equal to 7.5 mg/kg/day of oxaprozin (0.1 times the maximum recommended human daily dose [MRHD] of 1,200 mg based on body surface area). However, in mice and rats, no drug-related developmental abnormalities or embryo-fetal toxicity were observed at doses up to 50 and 200 mg/kg/day of oxaprozin, respectively (0.2 times and 1.6 times the maximum recommended human daily dose of 1,200 mg based on a body surface area comparison, respectively). In fertility/reproductive studies in rats, 200 mg/kg/day oxaprozin was orally administered to female rats for 14 days prior to mating through lactation day (LD) 2, or from gestation day (GD) 15 through LD 2 and the females were mated with males treated with 200 mg/kg/day oxaprozin for 60 days prior to mating. Oxaprozin administration resulted in failure to deliver and a reduction in live birth index at 200 mg/kg/day (1.6 times the maximum recommended human daily dose of 1,200 mg based on a body surface area comparison). 8.2 Lactation Risk Summary There are no data on the presence of oxaprozin in human milk, the effects on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COXANTO and any potential adverse effects on the breastfed infant from the COXANTO or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including COXANTO, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Reference ID: 5482810 Consider withdrawal of NSAIDs, including COXANTO, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males Testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (1.0 times the maximum recommended human daily dose based on body surface area) of oxaprozin for 42 days or 6 months [see Nonclinical Toxicology (13.1)] 8.4 Pediatric Use Safety and effectiveness of oxaprozin, the active component of the COXANTO, have been established for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6 to 16 years. Use of oxaprozin for this indication is supported by evidence from one open label study in 59 pediatric JRA patients and evidence from adequate and well controlled studies in adult rheumatoid arthritis patients [see Clinical Studies (14.1, 14.2, 14.3)]. Gastrointestinal symptoms occurred in pediatric patients at a higher incidence than those historically seen in controlled studies in adults. Of 30 patients in the pediatric JRA trial who continued treatment more than 3 months (19 to 48 weeks range total treatment duration), nine experienced rash on sun- exposed areas of the skin and five of those discontinued treatment [see Adverse Reactions (6.1)]. Safety and effectiveness of COXANTO in pediatric patients below the age of 6 years of age have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. No adjustment of the dose of COXANTO is necessary in the elderly, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging [see Clinical Pharmacology (12.3)]. Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Although selected elderly patients in controlled clinical trials tolerated oxaprozin as well as younger patients, caution should be exercised in treating the elderly. COXANTO is substantially excreted by the kidney, and the risk of toxic reactions to COXANTO may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.6)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Reference ID: 5482810 Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222 1222). 11 DESCRIPTION COXANTO (oxaprozin) is a nonsteroidal anti-inflammatory drug, available as capsules of 300 mg for oral administration. The chemical name is 4,5-diphenyl-2-oxazole-propionic acid. The molecular weight is 293.32 g/mol. Its molecular formula is C18H15NO3, and it has the following chemical structure. Oxaprozin is a white to off-white powder with a slight odor and a melting point of 162°C to 163°C. It is slightly soluble in alcohol and insoluble in water, with an octanol/water partition coefficient of 4.8 at physiologic pH (7.4). The pKa in water is 4.3. The inactive ingredients in COXANTO include: microcrystalline cellulose, pregelatinized corn starch, hypromellose 2910, sodium starch glycolate, stearic acid, and silicon dioxide, in gelatin capsules. COXANTO 300 mg capsules are white opaque capsules imprinted “403” on the cap in black ink. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxaprozin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of COXANTO, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Oxaprozin is a potent inhibitor of prostaglandin synthesis in vitro. Oxaprozin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because oxaprozin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics In dose proportionality studies utilizing 600 mg, 1,200 mg, and 1,800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease Reference ID: 5482810 in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution of the unbound drug and not an increase in the elimination half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing. The pharmacokinetic parameters of oxaprozin in healthy subjects receiving a single dose of 600 mg (two 300 mg capsules) are presented in Table 3. Table 3. Oxaprozin Pharmacokinetic Parameters [Mean (%CV)] (600 mg) Parameter (Units) Healthy Adults (28 – 60 years) (n=26) Mean CV (%) Cmax (µg/mL) 85.144 15.3 Tmax (hours) 3.00 1.50 – 5.00 AUC0-72 (µg∙h/mL) 2939.697 18.2 Cmax: Maximum observed concentration occurring at the time Tmax Tmax: Time of maximum observed concentration AUC0-72: Area under the concentration curve (AUC) from the time zero to 72 hours Absorption COXANTO is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Distribution The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11 to 17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following multiple once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties; however, the amount of oxaprozin excreted in breast milk has not been evaluated. Elimination Metabolism Several oxaprozin metabolites have been identified in human urine or feces. Oxaprozin is primarily metabolized in the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low. Oxaprozin’s metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited. Excretion Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolites. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Reference ID: 5482810 Upon chronic dosing, the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations. Specific Populations Geriatric: A multiple dose study comparing the pharmacokinetics of oxaprozin (1,200 mg once daily) in 20 young (21 to 44 years) adults and 20 elderly (64 to 83 years) adults did not show any statistically significant differences between age groups. Pediatric: A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships, as shown in Table 4. Table 4. Dose to Body Weight Range to Achieve Similar Steady-State Exposure (AUC0-24hr) to Unbound Oxaprozin in JRA Patients Relative to 70 kg Adult Rheumatoid Arthritis Patients Administered Oxaprozin 1,200 mg Once Daily1 Dose (mg) Body Weight Range (kg) 600 22 –31 900 32 –54 1,200 ≥ 55 1Model-based nomogram derived from unbound oxaprozin steady-state plasma concentrations in JRA patients weighing 22.1 – 42.7 kg or ≥45.0 kg administered oxaprozin 600 mg or 1,200 mg once daily for 14 days, respectively. Race: Pharmacokinetic Differences due to race have not been identified. Hepatic Impairment: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well-compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, monitor patients with severe hepatic dysfunction for adverse reactions. Renal Impairment: Oxaprozin’s renal clearance decreased proportionally with creatinine clearance (CrCL), but since only approximately 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCL. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency [see Warnings and Precautions (5.6)]. Cardiac Failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin. Drug Interaction Studies Reference ID: 5482810 ACE inhibitors (enalapril): Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC0-24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0-24) [see Drug Interactions (7)]. Aspirin: When oxaprozin was administered with aspirin, the protein binding of oxaprozin was reduced, although the clearance of free oxaprozin was not altered. The clinical significance of this interaction is not known. An in vitro study showed that oxaprozin significantly interfered with the anti-platelet activity of aspirin [see Drug Interactions (7)]. Beta-blockers (metoprolol): Subjects receiving 1,200 mg oxaprozin once daily with 100 mg metoprolol twice daily exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days [see Drug Interactions (7)]. Glyburide: Oxaprozin altered the pharmacokinetics of glyburide; however, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control [see Drug Interactions (7)]. H2-receptor antagonists (cimetidine, ranitidine): The total clearance of oxaprozin was reduced by 20% in subjects who concurrently received therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy. Lithium: Oxaprozin has produced an elevation in plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20% [see Drug Interactions (7)]. Methotrexate: Coadministration of oxaprozin with methotrexate resulted in approximately 36% reduction in apparent oral clearance of methotrexate [see Drug Interactions (7)]. Other drugs: The coadministration of oxaprozin and acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in rats and mice, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or male or female rats treated with up to 216 mg/kg via the diet (1.7 times the maximum daily human dose of 1,200 mg based on body surface area). The significance of this species- specific finding to man is unknown. Mutagenesis Oxaprozin was not genotoxic in the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, or cell transformation testing in mouse fibroblast. Impairment of Fertility Reference ID: 5482810 Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1.6 times the maximum recommended human daily dose [MRHD] of 1,200 mg based on a body surface area comparison). However, testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (1.0 times the MRHD based on body surface area) of oxaprozin for 42 days or 6 months, a finding not confirmed in other species. The clinical relevance of this finding is not known. 14 CLINICAL STUDIES 14.1 Osteoarthritis Oxaprozin, the active component of COXANTO, was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. The active component of COXANTO was given both in variable (600 to 1,200 mg/day) and in fixed (1,200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2,600 to 3,200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects [see Dosage and Administration (2.5)]. 14.2 Rheumatoid Arthritis Oxaprozin, the active component of COXANTO, was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. Oxaprozin was given in single or divided daily doses of 600 to 1,800 mg/day and was found to be comparable to 2,600 to 3,900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin. Oxaprozin was given as a once-a-day dose of 1,200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1,800 mg/day) were used in selected patients. In some patients, COXANTO may be better tolerated in divided doses. Due to its long half-life, several days of oxaprozin were needed for the drug to reach its full effect [see Dosage and Administration (2.5)]. 14.3 Juvenile Rheumatoid Arthritis In a 3-month open label study, 10 to 20 mg/kg/day of oxaprozin, the active component of COXANTO, were administered to 59 JRA patients. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg [see Clinical Pharmacology (12.3)]. 16 HOW SUPPLIED/STORAGE AND HANDLING COXANTO (oxaprozin) capsules 300 mg are white opaque capsule imprinted “403” on the cap in black ink, supplied as: NDC Number Size 69499-403-60 bottle of 60 Storage Keep bottles tightly closed. Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Protect the unit dose from light. 17 PATIENT COUNSELING INFORMATION Reference ID: 5482810 Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with COXANTO and periodically during the course of ongoing therapy Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop COXANTO and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking COXANTO immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including COXANTO, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of COXANTO and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with COXANTO is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Reference ID: 5482810 SOLUBIOMIX INNOVATING HEALTH SOLUTIONS Inform patients that the concomitant use of COXANTO with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with COXANTO until they talk to their healthcare provider [see Drug Interactions (7)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.solubiomix.com. Manufactured for and Distributed by: Madisonville, LA 70447 Reference ID: 5482810 Medication Guide CoxANto (KOXANTOE) (oxaprozin) capsules COXANTO is a prescription medicine that contains oxaprozin (a nonsteroidal anti-inflammatory drug [NSAID]). What is the most important information I should know about COXANTO, and medicines called nonsteroidal anti-inflammatory drugs (NSAIDs)? COXANTO may cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take COXANTO right before or after a heart surgery called a “coronary artery bypass graft (CABG)”. Avoid taking COXANTO after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take COXANTO after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death • The risk of getting an ulcer or bleeding increases with: o history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “antiplatelet drugs”, “anticoagulants”, “selective serotonin reuptake inhibitors (SSRIs)”, “serotonin norepinephrine reuptake inhibitors (SNRIs)” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems • COXANTO should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What is COXANTO? COXANTO is a prescription medicine used: • for relief of the signs and symptoms of osteoarthritis • for relief of the signs and symptoms of rheumatoid arthritis • for relief of the signs and symptoms of juvenile rheumatoid arthritis. It is not known if COXANTO is safe and effective in children below 6 years of age. Do not take COXANTO: • if you are allergic to oxaprozin or to any of the ingredients in COXANTO. See the end of this Medication Guide for a complete list of ingredients in COXANTO. • if you have had an asthma attack, hives, or other allergic reaction after taking aspirin or any other NSAIDs. Severe allergic reactions that have sometimes led to death have happened in people with a history of allergic reactions to NSAIDs. • right before or after heart bypass surgery. Before taking COXANTO, tell your healthcare provider about all of your or your child’s medical conditions, including if you: • have heart problems • have bleeding problems • have or have had ulcers • have liver or kidney problems • have high blood pressure • have asthma Reference ID: 5482810 • are pregnant or plan to become pregnant. Taking COXANTO at about 20 weeks of pregnancy or later may harm your unborn baby. o If you need to take COXANTO for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take COXANTO after about 30 weeks of pregnancy. o COXANTO may cause fertility problems in females, which may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you. • are breastfeeding or plan to breastfeed. Talk to your healthcare provider about the best way to feed your baby during treatment with COXANTO. Tell your healthcare provider about all of the medicines you or your child take, including prescription or over the-counter medicines, vitamins or herbal supplements. COXANTO and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. How should I take COXANTO? • Take COXANTO exactly as your healthcare provider tells you to take it. • If you take too much COXANTO, call your healthcare provider or Poison Control Center at 1-800-222-1222, or go to the nearest hospital emergency room right away. What are the possible side effects of COXANTO? COXANTO may cause serious side effects, including: See “What is the most important information I should know about COXANTO, and medicines called nonsteroidal anti-inflammatory drugs (NSAIDs)?” • liver problems including liver failure • new or worse high blood pressure • heart failure • kidney problems including kidney failure • increase in blood potassium level (hyperkalemia) • life-threatening allergic reactions • asthma attacks in people who have asthma • serious skin reactions, including life-threatening skin reactions • low red blood cells (anemia) • skin sensitivity to sunlight Other side effects of COXANTO include: constipation, diarrhea, indigestion, nausea, and rash. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking COXANTO and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet These are not all of the possible side effects of COXANTO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs. How should I store COXANTO? • Store COXANTO at room temperature between 68°F to 77°F (20°C to 25°C). • Keep the COXANTO bottles tightly closed. • Protect the bottle from light. Keep COXANTO and all medicines out of the reach of children. Reference ID: 5482810 SOLUBIOMIX INNOVATIN G HEALTH SOLUTIONS General information about the safe and effective use of COXANTO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use COXANTO for a condition for which it was not prescribed. Do not give COXANTO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about COXANTO that is written for health professionals. k What are the ingredients in COXANTO? Active ingredient: oxaprozin Inactive ingredients: microcrystalline cellulose, pregelatinized corn starch, hypromellose 2910, sodium starch glycolate, stearic acid, and silicon dioxide. Manufactured for and Distributed by: Madisonville, LA 70447 For more information, call 1-844-551-9911. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 10/2023 Reference ID: 5482810	custom-source	2025-02-12T15:47:05.389558	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217927s002lbl.pdf', 'application_number': 217927, 'submission_type': 'SUPPL ', 'submission_number': 2}
80,363	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOCIN® CAPSULES safely and effectively. See full prescribing information for INDOCIN. INDOCIN (indomethacin) Capsules, for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ---------------------------RECENT MAJOR CHANGES--------------------------- Warnings and Precautions (5.9) 11/2024 ---------------------------INDICATIONS AND USAGE---------------------------- INDOCIN is a nonsteroidal anti-inflammatory drug indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis (1) ------------------------DOSAGE AND ADMINISTRATION----------------------- Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is INDOCIN 25 mg two or three times a day (2.2) • The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75-150 mg daily in 3 or 4 divided doses (2.3) • The dosage for acute gouty arthritis is INDOCIN 50 mg three times a day (2.4) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- INDOCIN (indomethacin) Capsules: 25 mg (3) -------------------------------CONTRAINDICATIONS------------------------------- • Known hypersensitivity to indomethacin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of INDOCIN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of INDOCIN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue INDOCIN at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including INDOCIN, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Iroko Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking INDOCIN with drugs that interfere with hemostasis. Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with INDOCIN may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with INDOCIN in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with INDOCIN can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) ------------------------USE IN SPECIFIC POPULATIONS----------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of INDOCIN in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482814 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Central Nervous System Effects 5.16 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482814 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE INDOCIN is indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of INDOCIN and other treatment options before deciding to use INDOCIN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Reference ID: 5482814 Dosage recommendations for active stages of the following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis INDOCIN 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used with greater care in the elderly [see Use in Specific Populations (8.5)]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) INDOCIN 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days. 2.4 Acute Gouty Arthritis INDOCIN 50 mg three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS INDOCIN (indomethacin) Capsules: 25 mg - opaque, blue and white hard shell gelatin capsules, printed INDOCIN and MSD 25. Reference ID: 5482814 4 CONTRAINDICATIONS INDOCIN is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in Reference ID: 5482814 NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of INDOCIN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If INDOCIN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue INDOCIN until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Reference ID: 5482814 Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including INDOCIN, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If INDOCIN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Reference ID: 5482814 No information is available from controlled clinical studies regarding the use of INDOCIN in patients with advanced renal disease. The renal effects of INDOCIN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of INDOCIN [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If INDOCIN is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, INDOCIN is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When INDOCIN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform Reference ID: 5482814 patients about the signs and symptoms of serious skin reactions, and to discontinue the use of INDOCIN at the first appearance of skin rash or any other sign of hypersensitivity. INDOCIN is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as INDOCIN. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue INDOCIN and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDS, including INDOCIN, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including INDOCIN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including INDOCIN, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit INDOCIN use to the lowest effective dose and shortest duration possssible. Consider ultrasound monitoring of amniotic fluid if INDOCIN treatment extends beyond 48 hours. Discontinue INDOCIN if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. Reference ID: 5482814 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with INDOCIN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including INDOCIN, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of INDOCIN in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Central Nervous System Effects INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue INDOCIN if severe CNS adverse reactions develop. INDOCIN may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with INDOCIN. 5.16 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN. Be alert to the possible association between the changes noted and INDOCIN. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. INDOCIN is not indicated for long-term treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] Reference ID: 5482814 • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving INDOCIN Capsules than in the group taking INDOCIN Suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with INDOCIN Capsules or Suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for INDOCIN Capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between INDOCIN and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with INDOCIN Capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules. Table 1 Summary of Adverse Reactions for INDOCIN Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM Reference ID: 5482814 Incidence greater than 1% Incidence less than 1% headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with INDOCIN blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY Reference ID: 5482814 Incidence greater than 1% Incidence less than 1% None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2 Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: • Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Reference ID: 5482814 Intervention: Monitor patients with concomitant use of INDOCIN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. INDOCIN is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of INDOCIN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of INDOCIN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together. Both INDOCIN and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of INDOCIN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of INDOCIN and digoxin, monitor serum digoxin levels. Reference ID: 5482814 Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of INDOCIN and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of INDOCIN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of INDOCIN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of INDOCIN and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of INDOCIN and pemetrexed may increase the risk of pemetrexed- associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of INDOCIN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of INDOCIN and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Reference ID: 5482814 INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of INDOCIN use between about 20 and 30 weeks of gestation, and avoid INDOCIN use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDS, including INDOCIN, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Reference ID: 5482814 Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including INDOCIN, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If INDOCIN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reference ID: 5482814 Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INDOCIN and any potential adverse effects on the breastfed infant from the INDOCIN or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight- adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/ kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including INDOCIN, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including INDOCIN, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 5482814 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with INDOCIN Capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of INDOCIN Capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large Reference ID: 5482814 overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1- 800-222-1222). 11 DESCRIPTION INDOCIN (indomethacin) Capsules are nonsteroidal anti-inflammatory drugs, available as capsules containing 25 mg of indomethacin, administered for oral use. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following chemical structure. Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The inactive ingredients in INDOCIN Capsules 25 mg include: colloidal silicon dioxide, FD&C Blue 1, FD&C Red 3, gelatin, lactose, lecithin, magnesium stearate, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of INDOCIN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482814 12.3 Pharmacokinetics Absorption Following single oral doses of INDOCIN Capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered INDOCIN Capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of INDOCIN Oral Suspension was found to be bioequivalent to a 50 mg INDOCIN Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of INDOCIN has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Reference ID: 5482814 Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long- term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying disease. INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING INDOCIN (indomethacin) Capsules, 25 mg each, are opaque, blue and white capsules. NDC 0006-0025-68: bottles of 100 NDC 0006-0025-82: bottles of 1000 Storage Reference ID: 5482814 Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with INDOCIN and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop INDOCIN and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking INDOCIN immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of INDOCIN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with INDOCIN is needed for a pregnant woman between about 20 to 30 weeks Reference ID: 5482814 gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of INDOCIN with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for and Distributed by: Zyla Life Sciences US, Inc.Wayne, PA 19087 Reference ID: 5482814 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the- counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure Reference ID: 5482814 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: 04/2021 • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • more tired or weaker than usual • diarrhea • itching • your skin or eyes look yellow • indigestion or stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for and Distributed by: Zyla Life Sciences US, Inc. Wayne, PA 19087 For more information, go to www.zyla.com or call 1-877-757-0676 Reference ID: 5482814	custom-source	2025-02-12T15:47:05.809030	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/016059s102lbl.pdf', 'application_number': 16059, 'submission_type': 'SUPPL ', 'submission_number': 102}
80,365	------------------------------------------------------------------------------------------------------------------------------------------------------------------ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NALFON safely and effectively. See full prescribing information for NALFON. NALFON (fenoprofen calcium USP) capsules, for oral use Initial U.S. Approval: 1982 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning • Non-Steroidal Anti-Inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • Fenoprofen is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) --------------------- RECENT MAJOR CHANGES ------------------------- Warnings and Precautions (5.9) 11/2024 --------------------- INDICATIONS AND USAGE -------------------------- NALFON a nonsteroidal anti-inflammatory drug indicated for: • Relief of mild to moderate pain in adults. (1) • Relief of the signs and symptoms of rheumatoid arthritis. (1) • Relief of the signs and symptoms of osteoarthritis. (1) -------------------- DOSAGE AND ADMINISTRATION ------------------ • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • Analgesia: For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed (2.1) • Rheumatoid Arthritis and Osteoarthritis: For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. ------------------- DOSAGE FORMS AND STRENGTHS ---------------- NALFON (fenoprofen calcium) capsules: 200 mg and 400 mg (3) ---------------------------- CONTRAINDICATIONS ------------------------ • Known hypersensitivity to fenoprofen or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) -------------------- WARNINGS AND PRECAUTIONS ------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of NALFON in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NALFON in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: NALFON is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue NALFON at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including NALFON, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ---------------------------- ADVERSE REACTIONS ------------------------- Most common adverse reactions (incidence ≥ 5%) are Dyspepsia, headache, somnolence, nausea, dizziness, constipation, nervousness, asthenia, and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact Xspire Pharma at 1-601-990-9497 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch (6) ---------------------------- DRUG INTERACTIONS ------------------------- • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NALFON with drugs that interfere with hemostasis. Concomitant use of NALFON and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with fenoprofen may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with NALFON in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with NALFON can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) ----------------------- USE IN SPECIFIC POPULATIONS --------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NALFON in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482816 ------------------------------------------------------------------------------------------------------------------------------------------------------------------ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1. INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.2 Analgesia 2.3 Rheumatoid Arthritis and Osteoarthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Ocular Effects 5.16 Central Nervous System Effects 5.17 Impact on Hearing 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Cardiovascular Thrombotic Events Gastrointestinal Bleeding, Ulceration, and Perforation Hepatotoxicity Heart Failure and Edema Anaphylactic Reactions Serious Skin Reactions, including DRESS Fetal Toxicity Avoid Concomitant Use of NSAIDs Use of NSAIDS and Low-Dose Aspirin Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482816 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombic Events ● Non-Steroidal Anti-Inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. ● NALFON® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1. INDICATIONS AND USAGE NALFON is indicated for: ● Relief of mild to moderate pain in adults ● Relief of the signs and symptoms of rheumatoid arthritis ● Relief of the signs and symptoms of osteoarthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of NALFON and other treatment options before deciding to use fenoprofen. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals Use lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. NALFON may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. Patients with rheumatoid arthritis generally seem to require larger doses of NALFON than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy. 2.2 Analgesia For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. 2.3 Rheumatoid Arthritis and Osteoarthritis For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. 3 DOSAGE FORMS AND STRENGTHS NALFON® (fenoprofen calcium, USP) capsules: • The 200 mg capsule is opaque yellow No. 97 cap and opaque white body, imprinted with "RX681" on the cap and body. • The 400 mg capsule is opaque green cap and opaque blue body, imprinted with "NALFON 400 mg" on the cap and "EP 123" on the body. 4 CONTRAINDICATIONS NALFON is contraindicated in the following patients: ● Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to fenoprofen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] Reference ID: 5482816 5 ● History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] ● In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as fenoprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post- MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of NALFON in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NALFON is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including NALFON, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated Patients: ● Use the lowest effective dosage for the shortest possible duration. ● Avoid administration of more than one NSAID at a time. ● Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. ● Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. Reference ID: 5482816 ● If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NALFON until a serious GI adverse event is ruled out. ● In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID- treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including fenoprofen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NALFON immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including NALFON, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID- treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of fenoprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of NALFON in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NALFON is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NALFON in patients with advanced renal disease. The renal effects of NALFON may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NALFON. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NALFON [see Drug Interactions (7)]. Avoid the use of NALFON in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NALFON is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Fenoprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to fenoprofen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. Reference ID: 5482816 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NALFON is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NALFON is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including fenoprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be lifethreatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NALFON at the first appearance of skin rash or any other sign of hypersensitivity. NALFON is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NALFON. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NALFON and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including NALFON, in pregnant women at about 30 weeks gestation and later. NSAIDs, including NALFON, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including NALFON, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NALFON use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NALFON treatment extends beyond 48 hours. Discontinue NALFON if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NALFON has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NALFON, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of NALFON in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Reference ID: 5482816 6 5.15 Ocular Effects Studies to date have not shown changes in the eyes attributable to the administration of NALFON. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking NALFON. 5.16 Central Nervous System Effects Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking NALFON. 5.17 Impact on Hearing Since the safety of NALFON has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with NALFON. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: ● Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] ● GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] ● Hepatotoxicity [see Warnings and Precautions (5.3)] ● Hypertension [see Warnings and Precautions (5.4)] ● Heart Failure and Edema [see Warnings and Precautions (5.5)] ● Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] ● Anaphylactic Reactions [see Warnings and Precautions (5.7)] ● Serious Skin Reactions [see Warnings and Precautions (5.9)] ● Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials Digestive System — During clinical trials with NALFON, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving NALFON as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% NALFON vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies. Nervous System — The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. NALFON was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Skin and Appendages— Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. NALFON was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Special Senses — Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. NALFON was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Cardiovascular — Palpitations (2.5% vs. 0.4%). NALFON was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Miscellaneous — Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none). Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials Reference ID: 5482816 Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis. Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis. Hypersensitivity—Angioedema (angioneurotic edema). Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia. Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia. Special Senses—Burning tongue, diplopia, and optic neuritis. Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia. Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fenoprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with fenoprofen. Table 1: Clinically Significant Drug Interactions with Fenoprofen Drugs That Interfere with Hemostasis Clinical Impact: • Fenoprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of fenoprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NALFON with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of NALFON and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. NALFON is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs Reference ID: 5482816 may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of NALFON and ACE-inhibitors, ARBs, or beta blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NALFON, ACE-inhibitors, or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NALFON with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of fenoprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of NALFON and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NALFON and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of fenoprofen and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NALFON and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NALFON and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of fenoprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of fenoprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NALFON and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of fenoprofen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. Reference ID: 5482816 In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Phenobarbital Clinical Impact: Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. Intervention: When phenobarbital is added to or withdrawn from treatment, dosage adjustment of NALFON may be required. Hydantoins, sulfonamides, or sulfonylureas Clinical Impact: In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Intervention: Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. Drug/Laboratory Test Interactions Amerlex-M kit assay values of total and free triiodothyronine in patients receiving NALFON have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroid-stimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected. Thus, results of the Amerlex-M kit assay should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including NALFON, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NALFON use between about 20 and 30 weeks of gestation, and avoid NALFON use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data) Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NALFON, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal lethality and skeletal abnormalities were noted in offspring of pregnant rabbits following oral administration of fenoprofen during organogenesis at 0.6 times the maximum human daily dose of 3200 mg/day. However, there were no major malformations noted following oral administration of fenoprofen calcium to pregnant rats and rabbits during organogenesis at exposures up to 0.3 and 0.6 times the maximum human daily dose of 3200 mg/day. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as fenoprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Reference ID: 5482816 Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NALFON, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NALFON treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NALFON and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of NALFON during labor or delivery. In animal studies, NSAIDS, including fenoprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There are no adequate and well-controlled studies of NALFON in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Pregnant rats were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.15 times and 0.3 times the maximum human daily dose (MHDD) of 3200 mg/day based on body surface area comparison) during the period of organogenesis. No major malformations were noted and there was no evidence of maternal toxicity at these doses, however, the exposures were below the exposures that will occur in humans. Pregnant rabbits were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.3 times and 0.6 times the MHDD of 3200 mg/day based on body surface area comparison) during the period of organogenesis. Maternal toxicity (mortality) was noted in the high dose animals. Although no major malformations were noted, there was an increased incidence of embryo-fetal lethality and skeletal abnormalities were present at 0.6 times the MHDD. Pregnant rats were treated from Gestation Day 14 through Post-Natal Day 20 with oral doses of fenoprofen of 6.25, 12.5, 25, 50, or 100 mg/kg (0.02, 0.04, 0.08, 0.15, or 0.3 times the MDD of 3200 mg/day based on body surface area comparison). All doses produced significant toxicity, including vaginal bleeding, prolonged parturition, increased stillbirths, and maternal deaths. Pregnant rats were treated from Gestation Day 6 through Gestation Day 19 and Post Partum Day 1 to 20 (excluding parturition) with an oral dose of fenoprofen of 100 mg/kg (0.3 times the MDD of 3200 mg/day based on body surface area comparison) demonstrated only a small increase in the incidence of impaired parturition despite the presence of maternal toxicity (gastrointestinal ulceration and renal toxicity). 8.2 Lactation Risk Summary In a published study, after a dose of 600 mg every 6 hours for 4 days in postpartum mothers, breastmilk NALFON levels were reportedly 1.6% of those in maternal plasma. Because there is little published experience with fenoprofen during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NALFON and any potential adverse effects on the breastfed infant from the fenoprofen or from the underlying maternal condition. Reference ID: 5482816 • thyl-3-phenoxy-' ic acid, a-me Benzeneacet It dihydrate, (±)· ca1c,um sa 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NALFON, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NALFON, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients under the age of 18 have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION NALFON (fenoprofen calcium, USP) capsules is a nonsteroidal, anti-inflammatory drug available in 400 mg capsule form for oral administration. The 200 mg capsule is opaque yellow No. 97 cap and opaque white body, imprinted with “RX681” on the cap and body. The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg" on the cap and “EP 123” on the body. The chemical name is Benzeneacetic acid, α-methyl-3-phenoxy-, calcium salt dihydrate, (±)-. The molecular weight is 558.65. Its molecular formula is C30H26CaO6•2H2O, and it has the following chemical structure. Fenoprofen Calcium is an arylacetic acid derivative. It is a white crystalline powder. At 25°C, it dissolves to a 15 mg/mL solution in alcohol (95%). It is slightly soluble in water and insoluble in benzene. The pKa of fenoprofen calcium is 4.5 at 25°C. NALFON capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen. Inactive ingredients in NALFON capsules are crospovidone, magnesium stearate, sodium lauryl sulfate, and talc. In addition, the 400 mg capsules contain gelatin, D&C Yellow #10, FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, and titanium dioxide. Reference ID: 5482816 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fenoprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of NALFON, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Fenoprofen is a potent inhibitor of prostaglandin synthesis in vitro. Fenoprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because fenoprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Under fasting conditions, fenoprofen is rapidly absorbed, and peak plasma levels of 50 mcg/L are achieved within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed between 200 and 600 mg doses in fasting male volunteers. Distribution Fenoprofen is highly bound (99%) to albumin. Elimination Metabolism The plasma half-life is approximately 3 hours. Excretion About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen. Specific Populations Geriatrics Peak plasma levels of fenoprofen in normal elderly volunteers were similar to those observed in normal young volunteers. Elderly volunteers had a mean plasma clearance of 2.2 L/hour while plasma clearance of fenoprofen in normal young volunteers ranged from 3 to 3.5 L/hour. The overall elimination rate constant, plasma half-life and ratio of renal to nonrenal clearance of fenoprofen was the same in elderly and young volunteers. The 30 to 60% decrease in plasma clearance is due to a decrease in the volume of distribution in the body. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Antacid: The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of fenoprofen. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of fenoprofen have not been conducted. Mutagenesis Studies to evaluate the genotoxic potential of fenoprofen have not been conducted. Impairment of Fertility Female and Male rats were treated with 60 to 70 mg/kg/day or 120 to 150 mg/kg/day fenoprofen calcium via the diet (approximately 0.2 or 0.4 times the maximum human daily dose of 3200 mg/day based on body surface area comparison, respectively). Male rats were treated from 77 days prior to mating and during mating. Female rats were treated from 14 days prior to mating and through gestation. Pregnancy rates were slightly reduced in the low and high dose groups compared to controls. There was no adverse effect on implantations, resorptions, or live fetuses. 14 CLINICAL STUDIES Fenoprofen is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Reference ID: 5482816 Results in humans demonstrate that fenoprofen has both anti-inflammatory and analgesic actions. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of NALFON, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity. In all patients with rheumatoid arthritis, the anti-inflammatory action of NALFON has been evidenced by relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of NALFON has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). The use of NALFON in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding NALFON to maintenance therapy with gold salts or steroids. Whether or not NALFON used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown. In patients with osteoarthritis, the anti-inflammatory and analgesic effects of NALFON have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown NALFON to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with NALFON than in aspirin-treated patients. It is not known whether NALFON causes less peptic ulceration than does aspirin. In patients with pain, the analgesic action of NALFON has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. 16 HOW SUPPLIED/STORAGE AND HANDLING NALFON® (fenoprofen calcium, USP) are available in capsule form for oral administration, and are supplied as following: ● The 200 mg capsule has an opaque yellow No. 97 cap and an opaque white body, imprinted with "RX681" on the cap and body. NDC 42195-0600-10 Bottles of 100. ● The 400 mg capsule has an opaque green cap and an opaque blue body, imprinted with "NALFON 400 mg" on the cap and "EP 123" on the body. NDC 42195-0308-09 Bottles of 90. NDC 42195-0308-50 Bottles of 500. Storage: Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Preserve in well-closed containers. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NALFON and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NALFON and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Reference ID: 5482816 Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking NALFON immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9), (5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NALFON, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)] Fetal Toxicity Inform pregnant women to avoid use of NALFON and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NALFON is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NALFON with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NALFON until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for: Xspire Pharma Ridgeland, MS. 39157 500431-13 Rev. 11/2024 Reference ID: 5482816 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: ● Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack ● Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: ● if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs ● right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: ● have liver or kidney problems ● have high blood pressure ● have asthma ● are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider Reference ID: 5482816 may need to monitor the amount of fluid in your womb around your baby.. You should not take NSAIDs after about 30 weeks of pregnancy. ● are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? ● new or worse high blood pressure ● heart failure ● liver problems including liver failure ● kidney problems including kidney failure ● low red blood cells (anemia) ● life-threatening skin reactions ● life-threatening allergic reactions ● Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness Get emergency help right away if you get any of the following symptoms: ● shortness of breath or trouble breathing ● chest pain ● weakness in one part or side of your body ● slurred speech ● swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: ● nausea ● more tired or weaker than usual ● diarrhea ● itching ● your skin or eyes look yellow ● indigestion or stomach pain ● flu-like symptoms ● vomit blood ● there is blood in your bowel movement or it is black and sticky like tar ● unusual weight gain ● skin rash or blisters with fever ● swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs ● Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Reference ID: 5482816 ● Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Xspire Pharma Ridgeland, MS 39157 For more information, go to www.nalfon.com or call 1-601-990-9497. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 04/2021 500431-13 Reference ID: 5482816	custom-source	2025-02-12T15:47:05.821810	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017604s054lbl.pdf', 'application_number': 17604, 'submission_type': 'SUPPL ', 'submission_number': 54}
80,367	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FELDENE safely and effectively. See full prescribing information for FELDENE. FELDENE (piroxicam) capsules, for oral use Initial U.S. Approval: 1982 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • FELDENE is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warnings and Precautions, Serious Skin Reactions (5.9) 11/2024 INDICATIONS AND USAGE FELDENE is a nonsteroidal anti-inflammatory drug indicated for • Relief of the signs and symptoms of osteoarthritis (OA) (1) • Relief of the signs and symptoms of rheumatoid arthritis (RA) (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2) • OA and RA: 20 mg once daily (2) DOSAGE FORMS AND STRENGTHS FELDENE (piroxicam) capsules: 10 mg and 20 mg (3) CONTRAINDICATIONS • Known hypersensitivity to piroxicam or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of FELDENE in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of FELDENE in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: FELDENE is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue FELDENE at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including FELDENE, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (incidence >2% from clinical trials) are: nausea, constipation, flatulence, abdominal pain, diarrhea, headache, dizziness, edema, rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking FELDENE with drugs that interfere with hemostasis. Concomitant use of FELDENE and analgesic doses of aspirin is not generally recommended (7) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with FELDENE may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with FELDENE in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use of FELDENE can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of FELDENE in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482817 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Ophthalmologic Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482817 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • FELDENE is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE FELDENE is indicated: • For relief of the signs and symptoms of osteoarthritis. • For relief of the signs and symptoms of rheumatoid arthritis. 2 DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of FELDENE and other treatment options before deciding to use FELDENE. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with FELDENE, the dose and frequency should be adjusted to suit an individual patient’s needs. For the relief of rheumatoid arthritis and osteoarthritis, the dosage is 20 mg given orally once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE, steady-state blood levels are not reached for 7 to 12 days. Therefore, although the therapeutic effects of FELDENE are evident early in treatment, there is a progressive increase in response over several weeks and the effect of therapy should not be assessed for two weeks. 3 DOSAGE FORMS AND STRENGTHS FELDENE (piroxicam) capsules: 10 mg maroon and blue #322 20 mg maroon #323 4 CONTRAINDICATIONS FELDENE is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to piroxicam or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] Reference ID: 5482817 • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of CABG surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as piroxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of FELDENE in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If FELDENE is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Reference ID: 5482817 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including FELDENE, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-Treated Patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue FELDENE until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including piroxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), discontinue FELDENE immediately, and perform a clinical evaluation of the patient. Reference ID: 5482817 5.4 Hypertension NSAIDs, including FELDENE, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of piroxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of FELDENE in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If FELDENE is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of FELDENE in patients with advanced renal disease. The renal effects of FELDENE may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating FELDENE. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of FELDENE [see Drug Interactions (7)]. Avoid the use of FELDENE in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If FELDENE is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Reference ID: 5482817 Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Piroxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to piroxicam and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, FELDENE is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When FELDENE is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including piroxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of FELDENE at the first appearance of skin rash or any other sign of hypersensitivity. FELDENE is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as FELDENE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue FELDENE and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including FELDENE, in pregnant women at about 30 weeks gestation and later. NSAIDs, including FELDENE, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including FELDENE, at about 20 weeks gestation or later in pregnancy may cause Reference ID: 5482817 fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit FELDENE use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if FELDENE treatment extends beyond 48 hours. Discontinue FELDENE if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with FELDENE has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including FELDENE, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of FELDENE in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Ophthalmologic Effects Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is recommended that patients who develop visual complaints during treatment with FELDENE have ophthalmic evaluations. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] Reference ID: 5482817 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are: Cardiovascular System: Edema Digestive System: Anorexia, abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting Nervous System: Dizziness, headache, vertigo Skin and Appendages: Pruritus, rash Special Senses: Tinnitus Additional adverse experiences reported occasionally include: Cardiovascular System: Palpitations Digestive System: Stomatitis Nervous System: Drowsiness Special Senses: Blurred vision 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of FELDENE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Fever, infection, sepsis, anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic), serum sickness Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope, arrhythmia, exacerbation of angina, hypotension, myocardial infarction, vasculitis Digestive System: Dyspepsia, elevated liver enzymes, gross bleeding/perforation, heartburn, ulcers (gastric/duodenal), dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice, melena, rectal bleeding, eructation, liver failure, pancreatitis Hemic and Lymphatic System: Anemia, increased bleeding time, ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial rash, thrombocytopenia, agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Hypersensitivity: Positive ANA Reference ID: 5482817 Metabolic and Nutritional: Weight changes, Fluid retention, hyperglycemia, hypoglycemia Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, akathisia, convulsions, coma, hallucinations, meningitis, mood alterations Respiratory System: Asthma, dyspnea, respiratory depression, pneumonia Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat, angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, onycholysis, Stevens Johnson Syndrome, fixed drug eruption (FDE), urticaria, vesiculobullous reaction Special Senses: Conjunctivitis, hearing impairment, swollen eyes Urogenital System: Abnormal renal function, cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, oliguria/polyuria, proteinuria, renal failure, glomerulonephritis Reproductive System and Breast Disorders: Female fertility decreased 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with piroxicam. Table 1: Clinically Significant Drug Interactions with Piroxicam Drugs That Interfere with Hemostasis Clinical Impact: •Piroxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of piroxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. •Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of FELDENE with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of FELDENE and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. FELDENE is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: •NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). Reference ID: 5482817 •In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: •During concomitant use of FELDENE and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. •During concomitant use of FELDENE and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of FELDENE with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of piroxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of FELDENE and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of FELDENE and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of FELDENE and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of FELDENE and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of FELDENE and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of piroxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of piroxicam with other NSAIDs or salicylates is not recommended. Reference ID: 5482817 Pemetrexed Clinical Impact: Concomitant use of FELDENE and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of FELDENE and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Highly Protein Bound Drugs Clinical Impact: FELDENE is highly protein bound and, therefore, might be expected to displace other protein bound drugs. Intervention: Physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on other highly protein bound drugs. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with FELDENE may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of FELDENE with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including FELDENE, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of FELDENE use between about 20 and 30 weeks of gestation, and avoid FELDENE use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including FELDENE, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats and rabbits, there was no evidence of teratogenicity at exposures up to 5 and 10 times the maximum recommended human dose (MRHD), respectively. In rat studies with piroxicam, fetotoxicity (postimplantation loss) was observed at exposures 2 times the MRHD, and delayed parturition and an Reference ID: 5482817 increased incidence of stillbirth were noted at doses equivalent to the MRHD of piroxicam. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as piroxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including FELDENE, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If FELDENE treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue FELDENE and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of FELDENE during labor or delivery. In animal studies, NSAIDS, including piroxicam inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Reference ID: 5482817 Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Pregnant rats administered piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation Days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of piroxicam (equivalent to 2 and 5 times the MRHD, of 20 mg respectively, based on a mg/m2 body surface area [BSA]). There were no drug-related developmental abnormalities noted in offspring. Gastrointestinal tract toxicity was increased in pregnant rats in the last trimester of pregnancy compared to non-pregnant rats or rats in earlier trimesters of pregnancy. Pregnant rabbits administered piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation Days 7 to 18) demonstrated no drug-related developmental abnormalities in offspring (up to 10 times the MRHD based on a mg/m2 BSA). In a pre- and post-natal development study in which pregnant rats were administered piroxicam at 2, 5, or 10 mg/kg/day on Gestation Day 15 through delivery and weaning of offspring, reduced weight gain and death were observed in dams at 10 mg/kg/day (5 times the MRHD based on a mg/m2 BSA) starting on Gestation Day 20. Treated dams revealed peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis and dead fetuses in utero. Parturition was delayed and there was an increased incidence of stillbirth in all piroxicam-treated groups (at doses equivalent to the MRHD). Postnatal development could not be reliably assessed due to the absence of maternal care secondary to severe maternal toxicity. 8.2 Lactation Risk Summary Limited data from 2 published reports that included a total of 6 breastfeeding women and 2 infants showed piroxicam is excreted in human milk at approximately 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in maternal plasma during treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FELDENE and any potential adverse effects on the breastfed infant from the FELDENE or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FELDENE, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including FELDENE, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 5482817 8.4 Pediatric Use FELDENE has not been investigated in pediatric patients. The safety and effectiveness of FELDENE have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. 10 OVERDOSAGE Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an acute NSAID overdose. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. 11 DESCRIPTION FELDENE (piroxicam) capsule is a nonsteroidal anti-inflammatory drug, available as maroon and blue #322 10 mg capsules and maroon #323 20 mg capsules for oral administration. The chemical name is 4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. The molecular weight is 331.35. Its molecular formula is C15H13N3O4S, and it has the following chemical structure. 4′ O C NH OH N CH3 S N 5 6 7 8 1 2 3 4 2′ 6′ 5′ 3′ _() O2 Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The inactive ingredients in FELDENE include: Blue 1, Red 3, lactose, magnesium stearate, sodium lauryl sulfate, starch. Reference ID: 5482817 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Piroxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of FELDENE, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Piroxicam is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Piroxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because piroxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics The pharmacokinetics of piroxicam have been characterized in healthy subjects, special populations and patients. The pharmacokinetics of piroxicam are linear. Proportional increase in exposure is observed with increasing doses. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and significant accumulation upon multiple dosing. Most patients approximate steady state plasma levels within 7 to 12 days. Higher levels, which approximate steady state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred. Absorption Piroxicam is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 mg and 20 mg doses and generally peak within three to five hours after administration. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 mcg/mL to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily administration of 20 mg piroxicam, usually stabilize at 3 mcg/mL to 8 mcg/mL. With food there is a slight delay in the rate but not the extent of absorption following oral administration. The concomitant administration of antacids (aluminum hydroxide or aluminum hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of orally administered piroxicam. Distribution The apparent volume of distribution of piroxicam is approximately 0.14 L/kg. Ninety nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long term conditions (52 days). Piroxicam appeared in breast milk at approximately 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Reference ID: 5482817 Elimination Metabolism Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the 5′-hydroxy piroxicam, the major metabolite [see Clinical Pharmacology (12.5)]. The biotransformation products of piroxicam metabolism are reported to not have any anti-inflammatory activity. Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects [see Clinical Pharmacology (12.5)]. Excretion Piroxicam and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is excreted unchanged. The plasma half-life (t½) for piroxicam is approximately 50 hours. Specific Populations Pediatric Piroxicam has not been investigated in pediatric patients. Race Pharmacokinetic differences due to race have not been identified. Hepatic Impairment The effects of hepatic disease on piroxicam pharmacokinetics have not been established. However, a substantial portion of piroxicam elimination occurs by hepatic metabolism. Consequently, patients with hepatic disease may require reduced doses of piroxicam as compared to patients with normal hepatic function. Renal Impairment Piroxicam pharmacokinetics have been investigated in patients with renal insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing adjustments. However, the pharmacokinetic properties of piroxicam in patients with severe renal insufficiency or those receiving hemodialysis are not known. Drug Interaction Studies Antacids Concomitant administration of antacids had no effect on piroxicam plasma levels. Aspirin When piroxicam was administered with aspirin, its protein binding was reduced, although the clearance of free FELDENE was not altered. Plasma levels of piroxicam were decreased to approximately 80% of their normal values when FELDENE was administered (20 mg/day) in conjunction with aspirin (3900 mg/day). The clinical significance of this interaction is not known [see Drug Interactions (7)]. Reference ID: 5482817 12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C92 and CYP2C93 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C91/2 (n=9), heterozygous CYP2C91/3 (n=9), and homozygous CYP2C93/3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C91/1 (n=17, normal metabolizer genotype) following administration of a single oral dose. The mean elimination half-life values of piroxicam for subjects with CYP2C91/3 (n=9) and CYP2C93/3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C91/1 (n=17). It is estimated that the frequency of the homozygous3/3 genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been reported in certain ethnic groups. Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) consider dose reduction as they may have abnormally high plasma levels due to reduced metabolic clearance. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies have not been conducted to characterize the carcinogenic potential of piroxicam. Mutagenesis Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal mutation assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice. Impairment of Fertility Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up to 5 times the MRHD of 20 mg based on mg/m2 body surface area [BSA]) revealed no impairment of male or female fertility. 14 CLINICAL STUDIES In controlled clinical trials, the effectiveness of FELDENE has been established for both acute exacerbations and long term management of rheumatoid arthritis and osteoarthritis. The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation. Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus. FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a “steroid sparing” effect has not been adequately studied to date. Reference ID: 5482817 16 HOW SUPPLIED/STORAGE AND HANDLING FELDENE® (piroxicam) 10 mg capsules are maroon and blue #322, supplied as: NDC Number Size 0069-3220-66 bottles of 100 FELDENE® (piroxicam) 20 mg capsules are maroon #323, supplied as: NDC Number Size 0069-3230-66 bottles of 100 Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with FELDENE and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop FELDENE and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking FELDENE immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Reference ID: 5482817 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including FELDENE, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of FELDENE and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with FELDENE is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of FELDENE with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with FELDENE until they talk to their healthcare provider [see Drug Interactions (7)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For medical information about FELDENE, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-0206-19.1 Reference ID: 5482817 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death • The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids,” “antiplatelet drugs,” “anticoagulants,” “SSRIs” or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems • NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482817 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is • diarrhea black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0788-4.1 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised November 2022 Reference ID: 5482817	custom-source	2025-02-12T15:47:06.175470	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018147s053lbl.pdf', 'application_number': 18147, 'submission_type': 'SUPPL ', 'submission_number': 53}
80,369	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOCIN® SR safely and effectively. See full prescribing information for INDOCIN SR. INDOCIN SR (indomethacin) extended-release capsules for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • INDOCIN SR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) -----------------------------------RECENT MAJOR---------------------------------- Warnings and Precautions (5.9) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- INDOCIN SR is a nonsteroidal anti-inflammatory drug indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) (1) -----------------------DOSAGE AND ADMINISTRATION----------------------- • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is one INDOCIN SR 75 mg capsule daily (2.2) • The dosage for acute painful shoulder (bursitis and/or tendinitis) is one INDOCIN SR 75 mg capsule once or twice daily (2.3) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- INDOCIN SR (indomethacin) extended-releasde capsules: 75 mg (3) -------------------------------CONTRAINDICATIONS------------------------------ • Known hypersensitivity to indomethacin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of INDOCIN SR in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of INDOCIN SR in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN SR is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue INDOCIN SR at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including INDOCIN SR, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Iroko Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking INDOCIN SR with drugs that interfere with hemostasis. Concomitant use of INDOCIN SR and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with INDOCIN SR may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with INDOCIN SR in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with INDOCIN SR can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of INDOCIN SR in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482818 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Central Nervous System Effects 5.16 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482818 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • INDOCIN SR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE INDOCIN SR is indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of INDOCIN SR and other treatment options before deciding to use INDOCIN SR. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. THIS SECTION PREDOMINANTLY REFERENCES THE INDOMETHACIN IMMEDIATE-RELEASE CAPSULE ORAL DOSAGE AND IS INTENDED TO PROVIDE GUIDANCE IN USING INDOCIN SR EXTENDED-RELEASE CAPSULES, 75 MG Reference ID: 5482818 INDOCIN SR, 75 mg once a day can be substituted for indomethacin immediate-release capsules, 25 mg three times a day. However, there will be significant differences between the two dosage regimens in indomethacin blood levels, especially after 12 hours [see Clinical Pharmacology (12)]. In addition, INDOCIN SR, 75 mg twice a day can be substituted for indomethacin immediate-release capsules, USP 50 mg three times a day. INDOCIN SR may be substituted for all the indications for indomethacin immediate- release capsules, USP except acute gouty arthritis. Dosage Recommendations for Active Stages of the Following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin immediate-release capsules, 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, INDOCIN SR should be used with greater care in the elderly [see Use in Specific Populations (8.5)]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) Indomethacin immediate-release capsules 75-150 mg daily in 3 or 4 divided doses. Discontinue INDOCIN SR treatment after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days. 3 DOSAGE FORMS AND STRENGTHS INDOCIN SR (indomethacin) extended-release capsules 75 mg - opaque blue cap and clear body hard shell gelatin capsules, containing a mixture of blue and white pellets, printed with both 157 and WPPh. Reference ID: 5482818 4 CONTRAINDICATIONS INDOCIN SR is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Reference ID: 5482818 Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of INDOCIN SR in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If INDOCIN SR is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue INDOCIN SR until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. Reference ID: 5482818 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN SR immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including INDOCIN SR, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of INDOCIN SR in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If INDOCIN SR is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of Reference ID: 5482818 an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of INDOCIN SR in patients with advanced renal disease. The renal effects of INDOCIN SR may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN SR. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of INDOCIN SR [see Drug Interactions (7)]. Avoid the use of INDOCIN SR in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If INDOCIN SR is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, INDOCIN SR is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When INDOCIN SR is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 5482818 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drugeruption (FDE). FDE may present as a more severe variant known asgeneralized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of INDOCIN SR at the first appearance of skin rash or any other sign of hypersensitivity. INDOCIN SR is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as INDOCIN SR. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue INDOCIN SR and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including INDOCIN SR, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including INDOCIN SR, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Reference ID: 5482818 Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including INDOCIN SR, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit INDOCIN SR use to the lowest effective dose and shortest duration possssible. Consider ultrasound monitoring of amniotic fluid if INDOCIN SR treatment extends beyond 48 hours. Discontinue INDOCIN SR if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with INDOCIN SR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including INDOCIN SR, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of INDOCIN SR in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Central Nervous System Effects INDOCIN SR may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue INDOCIN SR if severe CNS adverse reactions develop. INDOCIN SR may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with INDOCIN SR. Reference ID: 5482818 5.16 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN SR. Be alert to the possible association between the changes noted and INDOCIN SR. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. INDOCIN SR is not indicated for long-term treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin immediate-release capsules than in the group taking indomethacin suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin immediate- release capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin immediate-release capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between INDOCIN and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with indomethacin immediate-release capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules. Reference ID: 5482818 Table 1 Summary of Adverse Reactions for INDOCIN Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * with or without vomiting dyspepsia * (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness * vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with INDOCIN blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme Reference ID: 5482818 Incidence greater than 1% Incidence less than 1% toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 5482818 Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2 Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: • Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of INDOCIN SR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of INDOCIN SR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. INDOCIN SR is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of INDOCIN SR and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of INDOCIN SR and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Reference ID: 5482818 It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN SR resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN SR and triamterene should not be administered together. Both INDOCIN SR and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of INDOCIN SR and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of INDOCIN SR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of INDOCIN SR and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of INDOCIN SR and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of INDOCIN SR and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of INDOCIN SR and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of INDOCIN SR and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of INDOCIN SR and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of INDOCIN SR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Reference ID: 5482818 NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of INDOCIN SR and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN SR, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of INDOCIN SR use between about 20 and 30 weeks of gestation, and avoid INDOCIN SR use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDS, including INDOCIN SR, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Reference ID: 5482818 Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including INDOCIN SR, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If INDOCIN SR treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN SR and follow up according to clinical practice (see Data). Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These Reference ID: 5482818 adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INDOCIN SR and any potential adverse effects on the breastfed infant from the INDOCIN SR or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight- adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/ kg/day assuming breast milk intake of 150 mL/kg/day. Reference ID: 5482818 This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including INDOCIN SR, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including INDOCIN SR, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. INDOCIN SR should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin immediate-release capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin immediate-release capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use Reference ID: 5482818 caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)] 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). 11 DESCRIPTION INDOCIN SR (indomethacin) extended-release capsules are nonsteroidal anti-inflammatory drugs, available as capsules containing 75 mg of indomethacin, administered for oral use. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following chemical structure. Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The inactive ingredients in INDOCIN SR Capsules, 75 mg include: cellulose, confectioner's sugar, FD&C Blue 1, FD&C Blue 2, FD&C Red 3, gelatin, hydroxypropyl methylcellulose, magnesium stearate, polyvinyl acetate- crotonic acid copolymer, starch, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. Reference ID: 5482818 The mechanism of action of INDOCIN SR, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3Pharmacokinetics Absorption Following single oral doses of indomethacin immediate-release capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin immediate- release capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of INDOCIN oral suspension was found to be bioequivalent to a 50 mg INDOCIN Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. INDOCIN SR 75 mg are designed to release 25 mg of the drug initially and the remaining 50 mg over approximately 12 hours (90% of dose absorbed by 12 hours). When measured over a 24-hour period, the cumulative amount and time-course of indomethacin absorption from a single indomethacin extended-release capsule are comparable to those of 3 doses of 25 mg indomethacin immediate-release capsules given at 4-6 hour intervals Plasma concentrations of indomethacin fluctuate less and are more sustained following administration of indomethacin extended-release capsules than following administration of 25 mg indomethacin immediate-release capsules given at 4-6 hour intervals. In multiple-dose comparisons, the mean daily steady-state plasma level of indomethacin attained with daily administration of indomethacin extended-release capsules 75 mg was indistinguishable from that following indomethacin immediate-release capsules 25 mg given at 0, 6 and 12 hours daily. However, there was a significant difference in indomethacin plasma levels between the two dosage regimens especially after 12 hours. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Reference ID: 5482818 Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of INDOCIN SR has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of INDOCIN SR has not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of INDOCIN SR has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively). Reference ID: 5482818 Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. INDOCIN SR affords relief of symptoms; it does not alter the progressive course of the underlying disease. INDOCIN SR suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN SR may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING INDOCIN SR (indomethacin) extended-release capsules, 75 mg each, are opaque blue cap and clear body, containing a mixture of blue and white pellets. NDC 60951-774-60: unit of use bottles of 60 NDC 60951-774-70: bottles of 100 Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with INDOCIN SR and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Reference ID: 5482818 Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop INDOCIN SR and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking INDOCIN SR immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN SR, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of INDOCIN SR and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with INDOCIN SR is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of INDOCIN SR with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with INDOCIN SR until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 5482818 Manufactured for and Distributed by: Zyla Life Sciences US, Inc. Wayne, PA 19087 Reference ID: 5482818 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure Reference ID: 5482818 • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for and Distributed by: Zyla Life Sciences US, Inc. Wayne, PA 19087 For more information, go to www.zyla.com or call 1-877-757-0676 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: 04/2021 Reference ID: 5482818	custom-source	2025-02-12T15:47:06.416425	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018185s059lbl.pdf', 'application_number': 18185, 'submission_type': 'SUPPL ', 'submission_number': 59}
80,371	Indomethacin Capsules, USP 25 mg Rx only WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS). • Indomethacin is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.) DESCRIPTION Indomethacin capsules, USP for oral administration contains 25 mg of indomethacin. Each capsule contains the following inactive ingredients: croscarmellose sodium, D&C Yellow #10, FD&C Green #3, gelatin, lactose monohydrate, pharmaceutical glaze, polyethylene glycol 3350, propylene glycol, silicon dioxide, sodium lauryl sulfate, starch, stearic acid, synthetic black iron oxide, talc and titanium dioxide. Indomethacin is a nonsteroidal anti-inflammatory indole derivative designated chemically as 1 – (4 chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The structural formula is: Indomethacin is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The molecular weight of indomethacin is 357.79 and its molecular formula is C19H16ClNO4 CLINICAL PHARMACOLOGY Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic properties. Its mode of action, like that of other anti-inflammatory drugs, is not known. However, its therapeutic action is not due to pituitary-adrenal stimulation. Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached during therapy which have been demonstrated to have an effect in vivo as well. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Moreover, prostaglandins are known to be among the mediators of inflammation. Since indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482819 1 Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease. Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. Indomethacin has been reported to diminish basal and CO2 stimulated cerebral blood flow in healthy volunteers following acute oral and intravenous administration. In one study after one week of treatment with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. The clinical significance of this effect has not been established. Indomethacin capsules have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis — [see INDICATIONS AND USAGE]. Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered Indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food. Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl desbenzoyl metabolites, all in the unconjugated form. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is recovered in feces (1.5 percent as indomethacin). About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of indomethacin capsules, USP and other treatment options before deciding to use indomethacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see Warnings: Gastrointestinal Bleeding, Ulceration, and Perforation). Indomethacin has been found effective in active stages of the following: 1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease. 2. Moderate to severe ankylosing spondylitis. Reference ID: 5482819 2 3. Moderate to severe osteoarthritis. 4. Acute painful shoulder (bursitis and/or tendinitis). 5. Acute gouty arthritis. CONTRAINDICATIONS Indomethacin is contraindicated in patients with known hypersensitivity to indomethacin or the excipients (see Warnings; Anaphylactic/Anaphylactoid Reactions). Indomethacin should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS; Preexisting Asthma). • Indomethacin is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see Warnings; Cardiovascular Thrombatic Events). WARNINGS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see WARNINGS]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat Reference ID: 5482819 3 after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including indomethacin, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including indomethacin, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see Precautions; Drug Interactions]. Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including indomethacin, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. Rarely, in patients taking indomethacin, intestinal ulceration has been associated with stenosis and obstruction. Gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) has occurred. Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely. NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAIDs therapy, concomitant use of oral corticosteroids, Reference ID: 5482819 4 aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occured in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate over renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients with volume depletion, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Increases in serum potassium concentration, including hyperkalemia, have been reported with use of indomethacin, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state [see PRECAUTIONS, Drug Interactions]. Indomethacin and potassium-sparing diuretics each may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. Therefore, treatment with indomethacin is not recommended in these patients with advanced renal disease. If indomethacin therapy must be initiated, close monitoring of the patient’s renal function is advisable. Anaphylactic/Anaphylactoid Reactions As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to indomethacin. Indomethacin should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma]. Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs. Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized Reference ID: 5482819 5 bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin rash or any other sign of hypersensitivity. Indomethacin is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin capsules. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue indomethacin capsules and evaluate the patient immediately. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including indomethacin capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs including indomethacin capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including indomethacin capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit indomethacin capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin capsules treatment extends beyond 48 hours. Discontinue indomethacin capsules if oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS; Pregnancy]. Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. The prescribing physician should be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged. Central Nervous System Effects: Indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, indomethacin should be discontinued. Indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also Reference ID: 5482819 6 cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin. PRECAUTIONS General Indomethacin cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of indomethacin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including indomethacin. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with indomethacin. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), indomethacin should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including indomethacin. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including indomethacin, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving indomethacin who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin- sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, indomethacin should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see WARNINGS]. Reference ID: 5482819 7 2. Indomethacin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up [see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation]. 3. Serious Skin Reactions, including DRESS Advise patients to stop taking indomethacin capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS]. 4. Heart Failure And Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see WARNINGS]. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see WARNINGS]. 7. Fetal Toxicity Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy]. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, indomethacin should be discontinued. Drug Interactions ACE-Inhibitors and Angiotensin II Antagonists Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. Indomethacin can reduce the antihypertensive effects of captopril and losartan. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE- inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co- administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Aspirin When indomethacin is administered with aspirin, its protein binding is reduced, although the clearance of free indomethacin is not altered. The clinical significance of this interaction is not known. Reference ID: 5482819 8 The use of indomethacin in conjunction with aspirin or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of indomethacin and aspirin does not produce any greater therapeutic effect than the use of indomethacin alone. In a clinical study of the combined use of indomethacin and aspirin, the incidence of gastrointestinal side effects was significantly increased with combined therapy. In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20%. Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. Beta-adrenoceptor blocking agents Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal anti- inflammatory drugs including indomethacin has been reported. Therefore, when using these blocking agents to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained. Cyclosporine Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored. Diflunisal In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, diflunisal and indomethacin should not be used concomitantly. Digoxin Indomethacin given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when indomethacin and digoxin are used concomitantly, serum digoxin levels should be closely monitored. Diuretics In some patients, the administration of indomethacin can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. This response has been attributed to inhibition of renal prostaglandin synthesis. Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Indomethacin and potassium-sparing diuretics each may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently. Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by indomethacin. Reference ID: 5482819 9 During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium Indomethacin capsules 50 mg t.i.d. produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when NSAIDs and lithium are given concomitantly, the patient should be carefully observed for signs of lithium toxicity. (Read circulars for lithium preparations before use of such concomitant therapy.) In addition, the frequency of monitoring serum lithium concentration should be increased at the outset of such combination drug treatment. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. NSAIDs The concomitant use of indomethacin with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. Oral anticoagulants Clinical studies have shown that indomethacin does not influence the hypoprothrombinemia produced by anticoagulants. However, when any additional drug, including indomethacin, is added to the treatment of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time. In post-marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and indomethacin. Caution should be exercised when indomethacin and anticoagulants are administered concomitantly. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Probenecid When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Drug/Laboratory Test Interactions False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the maximum recommended human daily dose (MRHD) of 200 mg/day based on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times and 0.07 times the MRHD on a mg/m2 basis, respectively) . Reference ID: 5482819 10 Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). Pregnancy Risk Summary Use of NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of indomethacin capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin capsules use at about 30 weeks of gestation and later in pregnancy [see WARNINGS; Fetal Toxicity]. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including indomethacin capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Reference ID: 5482819 11 --- Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If indomethacin capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin capsules and follow up according to clinical practice (see WARNINGS; Fetal Toxicity). Labor and Delivery There are no studies on the effects of indomethacin capsules during labor and delivery. In animal studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, caused delayed parturition, and increase the incidence of stillbirths. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses, however, no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the Reference ID: 5482819 12 MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. Use in Nursing Mothers Indomethacin is excreted in the milk of lactating mothers. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition. Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. Indomethacin should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. Geriatric Use As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions [see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND ADMINISTRATION]. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population [see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation]. Indomethacin may cause confusion or, rarely, psychosis [see ADVERSE REACTIONS]; physicians should remain alert to the possibility of such adverse effects in the elderly. This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function [see WARNINGS, Renal Effects]. ADVERSE REACTIONS The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely. Reference ID: 5482819 13 Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of pre existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC Reference ID: 5482819 14 None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY None pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson Syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.) Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 5482819 15 Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency. A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome [see also PRECAUTIONS, General]. OVERDOSAGE The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness, and convulsions. Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent. If vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage have been reported as adverse reactions of indomethacin. Use of antacids may be helpful. The oral LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of indomethacin and other treatment options before deciding to use indomethacin . Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see WARNINGS]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Indomethacin is available as 25 mg capsules Adverse reactions appear to correlate with the size of the dose of indomethacin in most patients but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient. Pediatric Use Indomethacin ordinarily should not be prescribed for pediatric patients 14 years of age and under (see PRECAUTIONS, Pediatric Use). Adult Use Reference ID: 5482819 16 Dosage Recommendations for Active Stages of the Following: 1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis. Suggested Dosage: Indomethacin capsules 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150-200 mg is reached. DOSES ABOVE THIS AMOUNT GENERALLY DO NOT INCREASE THE EFFECTIVENESS OF THE DRUG. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and OBSERVE THE PATIENT CLOSELY. If severe adverse reactions occur, STOP THE DRUG. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly [see PRECAUTIONS, Geriatric Use]. 2. Acute painful shoulder (bursitis and/or tendinitis). Initial Dose: 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days. 3. Acute gouty arthritis. Suggested Dosage: Indomethacin capsules 50 mg t.i.d. until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. HOW SUPPLIED Indomethacin Capsules, USP are available containing 25 mg of indomethacin. 25mg (green/green) capsules are imprinted “Par 067” and are supplied in bottles of 100 (NDC 0603 xxxx-xx), 500 (NDC 0603-xxxx-xx), and 1000 (NDC 0603-xxxx-xx) Capsules. Store at 20˚ to 25˚C (68˚ to 77˚F) [see USP controlled room temperature]. Revised 11/2024 Reference ID: 5482819 17 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. Reference ID: 5482819 1 You should not take NSAIDs after 29 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and sticky like tar • diarrhea • unusual weight gain • itching • skin rash or blisters with fever • your skin or eyes look yellow • swelling of the arms, legs, hands and feet • indigestion or stomach pain • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Reference ID: 5482819 2 Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Chartwell RX, LLC, Congers, NY 10920 For more information, contact Chartwell RX, LLC at 845-232-1683. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2022 L71084 Reference ID: 5482819 3	custom-source	2025-02-12T15:47:07.174448	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018829s025lbl.pdf', 'application_number': 18829, 'submission_type': 'SUPPL ', 'submission_number': 25}
80,373	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SOLARAZE® safely and effectively. See full prescribing information for SOLARAZE. SOLARAZE (diclofenac sodium) topical gel Initial U.S. Approval: 2000 -------------------------- RECENT MAJOR CHANGES -------------------------- Warnings and Precautions (5.3) 11/2024 WARNING: RISK OF SERIOUS CARDIOVASCULAR EVENTS AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. x Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.4) x SOLARAZE is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.4) x NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.5) --------------------------- INDICATIONS AND USAGE -------------------------- SOLARAZE is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the topical treatment of actinic keratoses (AK). (1) ---------------------- DOSAGE AND ADMINISTRATION ---------------------- x Use the lowest effective dosage for shortest duration consistent with the individual patient treatment goals. (2) x Apply to lesion areas twice daily to adequately cover each lesion. (2) x Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. (2) x The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. (2) x Avoid contact in eyes, nose, or mouth. (2) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Topical gel, 3%. ------------------------------ CONTRAINDICATIONS ----------------------------- x Known hypersensitivity to diclofenac or any components of the drug product. (4, 11) x History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. (4) x Use on damaged skin. (4) x In the setting of coronary artery bypass graft (CABG) surgery. (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- x Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.1) x Exacerbation of Asthma Related to Aspirin Sensitivity: SOLARAZE is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with pre-existing asthma (without aspirin sensitivity). (5.2) x Serious Skin Reactions: Discontinue SOLARAZE at first appearance of skin rash or other signs of hypersensitivity. (5.3, 5.15) x Hepatoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.6) x Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.7, 7) x Heart Failure and Edema: Avoid use of SOLARAZE in patients with severe heart failure. (5.8) x Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of SOLARAZE in patients with advanced renal disease. (5.9) x Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue SOLARAZE and evaluate clinically. (5.10) x Fetal Toxicity: Limit use of NSAIDs, including SOLARAZE, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) x Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12, 7). x Photosensitivity: Avoid exposure of treated area(s) to natural or artificial sunlight. (5.15) x Exposure to Eyes and Mucosal Membranes: Avoid contact of SOLARAZE with eyes and mucosal membranes. (5.16) x Oral Nonsteroidal Anti-inflammatory Drugs: Avoid concurrent use with oral NSAIDs. (5.17) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions with SOLARAZE are application site reactions, including dermatitis. (6) To report SUSPECTED ADVERSE REACTIONS, contact Fougera Pharmaceuticals Inc., 1-800-645-9833 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- x Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are using SOLARAZE concomitantly with drugs that interfere with hemostasis. (7) x ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with SOLARAZE may diminish the antihypertensive effect of these drugs. (7) x ACE Inhibitors and ARBs: Concomitant use with SOLARAZE in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. (7) x Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. (7) x Digoxin: Concomitant use with SOLARAZE may increase serum concentration and prolong half-life of digoxin. (7) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of SOLARAZE in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised 11/2024 Reference ID: 5482946 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTRONINESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylactic Reactions 5.2 Exacerbation of Asthma Related to Aspirin Sensitivity 5.3 Serious Skin Reactions 5.4 Cardiovascular Thrombotic Events 5.5 Gastrointestinal Bleeding, Ulceration, and Perforation 5.6 Hepatotoxicity 5.7 Hypertension 5.8 Heart Failure and Edema 5.9 Renal Toxicity and Hyperkalemia 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Photosensitivity 5.16 Exposure to Eyes and Mucosal Membranes 5.17 Oral Nonsteroidal Anti-inflammatory Drugs 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482946 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTRONINESTINAL EVENTS Cardiovascular Thrombotic Events x Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.4)]. x SOLARAZE is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.4)]. Gastrointestinal Bleeding, Ulceration, and Perforation x NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at a greater risk for serious GI events [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE SOLARAZE® is indicated for the topical treatment of actinic keratoses (AK). 2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Apply SOLARAZE gently to lesion areas twice daily. to adequately cover each lesion. Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. Avoid contact of SOLARAZE with eyes and mucous membranes. 3 DOSAGE FORMS AND STRENGTHS Topical gel, 3%. Each gram of SOLARAZE topical gel contains 30 mg of diclofenac sodium in a clear, transparent, colorless to slightly yellow gel base. SOLARAZE is supplied in 100 g tubes. 4 CONTRAINDICATIONS SOLARAZE is contraindicated in the following patients: x With known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.1, 5.3, 5.10) and Description (11)] x With the history of asthma, urticaria, or other allergic type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.1, 5.2)] x Application on damaged skin resulting from any etiology, including exudative dermatitis, eczema, infected lesions, burns or wounds [see Warnings and Precautions (5.3)] x In the setting of coronary bypass graft (CABG) surgery [see Warnings and Precautions (5.4)] Reference ID: 5482946 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.2)]. Seek emergency help if an anaphylactic reaction occurs. 5.2 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, SOLARAZE is contraindicated in patients with this form of aspirin sensitivity. When SOLARAZE is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.3 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of SOLARAZE at the first appearance of skin rash or any other sign of hypersensitivity. SOLARAZE is contraindicated in patients with previous serious skin reactions to NSAIDs. Do not apply SOLARAZE to open skin wounds, infections, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug [see Contraindications (4)]. 5.4 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG. Reference ID: 5482946 Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first-year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of SOLARAZE in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SOLARAZE is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.5 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-Treated Patients: x x Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. x x x Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SOLARAZE until a serious GI adverse event is ruled out. x In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.6 Hepatotoxicity In clinical trials with SOLARAZE, 2-3% of subjects had elevations of liver function tests (LFTs) [see Clinical Trials Experience (6.1)]. To minimize the potential risk for an adverse liver-related event in patients treated with SOLARAZE, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing SOLARAZE with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics). Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum Reference ID: 5482946 times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), SOLARAZE should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SOLARAZE immediately, and perform a clinical evaluation of the patient. 5.7 Hypertension NSAIDs, including SOLARAZE, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.8 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)]. Avoid the use of SOLARAZE in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If SOLARAZE is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.9 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical trials regarding the use of SOLARAZE in patients with advanced renal disease. The renal effects of SOLARAZE may hasten the progression of renal dysfunction in patients with pre existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating SOLARAZE. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of SOLARAZE [see Drug Interactions (7)]. Avoid the use of SOLARAZE in patients with advanced renal disease unless the benefits are Reference ID: 5482946 expected to outweigh the risk of worsening renal function. If SOLARAZE is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as SOLARAZE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue SOLARAZE and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including SOLARAZE, in pregnant women at about 30 weeks gestation and later. NSAIDs, including SOLARAZE, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If, after careful consideration of alternative treatment options for actinic keratoses, NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit SOLARAZE use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac treatment extends beyond 48 hours. Discontinue SOLARAZE if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with SOLARAZE has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including SOLARAZE, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake Reference ID: 5482946 I inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of SOLARAZE in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.5, 5.6, 5.9)]. 5.15 Photosensitivity Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using SOLARAZE. If patients need to be outdoors while using SOLARAZE, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Advise patients to discontinue treatment with SOLARAZE at the first evidence of sunburn. 5.16 Exposure to Eyes and Mucosal Membranes Avoid contact of SOLARAZE with eyes and mucosa. Advise patients that if contact in the eye, or mucosal membranes occurs, immediately wash out the eye or mucosal membranes with water or saline and consult a physician if irritation persists for more than an hour. 5.17 Oral Nonsteroidal Anti-inflammatory Drugs Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use SOLARAZE in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: x Anaphylactic Reactions [see Warnings and Precautions (5.1)] x Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.2)] x Serious Skin Reactions [see Warnings and Precautions (5.3)] x Cardiovascular Thrombotic Events [see Warnings and Precautions (5.4)] x GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.5)] x Hepatotoxicity [see Warnings and Precautions (5.6)] x Hypertension [see Warnings and Precautions (5.7)] x Heart Failure and Edema [see Warnings and Precautions (5.8)] x Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.9)] x DRESS [see Warnings and Precautions (5.10)] x Hematologic Toxicity [see Warnings and Precautions (5.12)] x Photosensitivity [see Warnings and Precautions (5.15)] Reference ID: 5482946 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Of the 423 subjects evaluable for safety in adequate and well-controlled trials, 211 were treated with SOLARAZE drug product and 212 were treated with a vehicle gel. Eighty-seven percent (87%) of the SOLARAZE-treated subjects (183 subjects) and 84% of the vehicle-treated subjects (178 subjects) experienced one or more adverse events (AEs) during the trials. The majority of these reactions were mild to moderate in severity and resolved upon discontinuation of therapy. Of the 211 subjects treated with SOLARAZE, 172 (82%) experienced AEs involving skin and the application site compared to 160 (75%) vehicle-treated subjects. Application site reactions (ASRs) were the most frequent AEs in both SOLARAZE-and vehicle-treated groups. Of note, four reactions, contact dermatitis, rash, dry skin and exfoliation (scaling) were significantly more prevalent in the SOLARAZE group than in the vehicle-treated subjects. Eighteen percent of SOLARAZE-treated subjects and 4% of vehicle-treated subjects discontinued from the clinical trials due to adverse events (whether considered related to treatment or not). These discontinuations were mainly due to skin irritation or related cutaneous adverse reactions. Table 1 below presents the AEs reported at an incidence of >1% for subjects treated with either SOLARAZE or vehicle (60- and 90-day treatment groups) during the phase 3 trials. Table 1. Adverse Events Reported (>1% in Any Treatment Group) During SOLARAZE Phase 3 Clinical Trials Incidences for 60-Day and 90-Day Treatments 60-day Treatment 90-day Treatment SOLARAZE (%) Gel Vehicle (%) SOLARAZE (%) Gel Vehicle (%) N=48 N=49 N=114 N=114 BODY AS A WHOLE 21 20 20 18 Abdominal Pain 2 0 1 0 Accidental Injury 0 0 4 2 Allergic Reaction 0 0 1 3 Asthenia 0 0 2 0 Back Pain 4 0 2 2 Chest Pain 2 0 1 0 Chills 0 2 0 0 Flu Syndrome 10 6 1 4 Headache 0 6 7 6 Infection 4 6 4 5 Neck Pain 0 0 2 0 Pain 2 0 2 2 CARDIOVASCULAR SYSTEM 2 4 3 1 Hypertension 2 0 1 0 Migraine 0 2 1 0 Phlebitis 0 2 0 0 DIGESTIVE SYSTEM 4 0 6 8 Constipation 0 0 0 2 Diarrhea 2 0 2 3 Dyspepsia 2 0 3 4 METABOLIC AND NUTRITIONAL DISORDERS 2 8 7 2 Creatine Phosphokinase Increased 0 0 4 1 Creatinine Increased 2 2 0 1 Reference ID: 5482946 Edema 0 2 0 0 Hypercholesteremia 0 2 1 0 Hyperglycemia 0 2 1 0 SGOT Increased 0 0 3 0 SGPT Increased 0 0 2 0 MUSCULOSKELETAL SYSTEM 4 0 3 4 Arthralgia 2 0 0 2 Arthrosis 2 0 0 0 Myalgia 2 0 3 1 NERVOUS SYSTEM 2 2 2 5 Anxiety 0 2 0 1 Dizziness 0 0 0 4 Hypokinesia 2 0 0 0 RESPIRATORY SYSTEM 8 8 7 6 Asthma 2 0 0 0 Dyspnea 2 0 2 0 Pharyngitis 2 8 2 4 Pneumonia 2 0 0 1 Rhinitis 2 2 2 2 Sinusitis 0 0 2 0 SKIN AND APPENDAGES 75 86 86 71 Acne 0 2 0 1 Application Site Reaction 75 71 84 70 Acne 0 4 1 0 Alopecia 2 0 1 1 Contact Dermatitis 19 4 33 4 Dry Skin 27 12 25 17 Edema 4 0 3 0 Exfoliation 6 4 24 13 Hyperesthesia 0 0 3 1 Pain 15 22 26 30 Paresthesia 8 4 20 20 Photosensitivity Reaction 0 2 3 0 Pruritus 31 59 52 45 Rash 35 20 46 17 Vesiculobullous Rash 0 0 4 1 Contact Dermatitis 2 0 0 0 Dry Skin 0 4 3 0 Herpes Simplex 0 2 0 0 Maculopapular Rash 0 2 0 0 Pain 2 2 1 0 Pruritus 4 6 4 1 Rash 2 10 4 0 Skin Carcinoma 0 6 2 2 Skin Nodule 0 2 0 0 Skin Ulcer 2 0 1 0 SPECIAL SENSES 2 0 4 2 Conjunctivitis 2 0 4 1 Eye Pain 0 2 2 0 UROGENITAL SYSTEM 0 0 4 5 Hematuria 0 0 2 1 OTHER 0 0 0 3 Procedure 0 0 0 3 Reference ID: 5482946 --- Skin and Appendages Adverse Events Reported for SOLARAZE at Less Than 1% Incidence in the Phase 3 Studies: skin hypertrophy, paresthesia, seborrhea, urticaria, application site reactions (skin carcinoma, hypertonia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation). Adverse Reactions Reported for Oral Diclofenac Dosage Form (not topical SOLARAZE): Incidence Greater than 1% marked with asterisk. Body as a Whole: abdominal pain or cramps, headache, fluid retention, abdominal distention, malaise, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions, chest pain. Cardiovascular: hypertension, congestive heart failure, palpitations, flushing, tachycardia, premature ventricular contractions, myocardial infarction, hypotension. Digestive: diarrhea, indigestion, nausea, constipation, flatulence, liver test abnormalities, PUB, i.e., peptic ulcer, with or without bleeding and/or perforation, or bleeding without ulcer, vomiting, jaundice, melena, esophageal lesions, aphthous stomatitis, dry mouth and mucous membranes, bloody diarrhea, hepatitis, hepatic necrosis, cirrhosis, hepatorenal syndrome, appetite change, pancreatitis with or without concomitant hepatitis, colitis, intestinal perforation. Hemic and Lymphatic: hemoglobin decrease, leukopenia, thrombocytopenia, eosinophilia, hemolytic anemia, aplastic anemia, agranulocytosis, purpura, allergic purpura, bruising. Metabolic and Nutritional Disorders: azotemia, hypoglycemia, weight loss. Nervous System: dizziness, insomnia, drowsiness, depression, diplopia, anxiety, irritability, aseptic meningitis, convulsions, paresthesia, memory disturbance, nightmares, tremor, tic, abnormal coordination, disorientation, psychotic reaction. Respiratory: epistaxis, asthma, laryngeal edema, dyspnea, hyperventilation, edema of pharynx. Skin and Appendages: rash, pruritus, alopecia, urticaria, eczema, dermatitis, bullous eruption, erythema multiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis. Special Senses: tinnitus*, blurred vision, taste disorder, reversible and irreversible hearing loss, scotoma, vitreous floaters, night blindness, amblyopia. Urogenital: nephrotic syndrome, proteinuria, oliguria, interstitial nephritis, papillary necrosis, acute renal failure, urinary frequency, nocturia, hematuria, impotence, vaginal bleeding. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SOLARAZE and other topical diclofenac products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions from SOLARAZE: burning sensation, hypersensitivity. Adverse reactions from other topical diclofenac products: hypoesthesia, gait disturbance, musculoskeletal stiffness. Skin and Appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Reference ID: 5482946 Drugs That Interfere with Hemostasis Clinical Impact: x Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. x Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: x Monitor patients with concomitant use of SOLARAZE with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.5)]. Aspirin Clinical Impact: x In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.5)]. Intervention: x Concomitant use of SOLARAZE and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. SOLARAZE is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: x NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). x In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: x During concomitant use of SOLARAZE and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. x During concomitant use of SOLARAZE and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.9)]. Diuretics Clinical Impact: x Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: x During concomitant use of SOLARAZE with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.9)]. Digoxin Reference ID: 5482946 Clinical Impact: x The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: x During concomitant use of SOLARAZE and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: x NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: x During concomitant use of SOLARAZE and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: x Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: x During concomitant use of SOLARAZE and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: x Concomitant use of SOLARAZE and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: x During concomitant use of SOLARAZE and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: x Concomitant use of SOLARAZE with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.5)]. Intervention: x The concomitant use of SOLARAZE with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: x Concomitant use of SOLARAZE and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing Intervention: x During concomitant use of SOLARAZE and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including SOLARAZE, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose Reference ID: 5482946 and duration of SOLARAZE use between about 20 and 30 weeks of gestation and avoid SOLARAZE use at about 30 weeks of gestation and later in pregnancy. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including SOLARAZE, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses at least 15 times, the maximum recommended human dose (MRHD) of SOLARAZE (see Data). Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization, and administration of prostaglandin synthesis inhibitors such as diclofenac sodium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SOLARAZE, can cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment If after careful consideration of alternative treatment options for actinic keratoses, an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If SOLARAZE treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SOLARAZE and follow up according to clinical practice. Labor or Delivery There are no studies on the effects of SOLARAZE during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus Reference ID: 5482946 Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data The multiples provided in this labeling are based on an MRHD that assumes 10% bioavailability following topical application of 2 g SOLARAZE per day (1 mg/kg diclofenac sodium). Reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the MRHD based on body surface area (BSA) comparisons) in mice, 10 mg/kg/day (15 times the MRHD based on BSA comparisons) in rats, and 10 mg/kg/day (30 times the MRHD based on BSA comparisons) in rabbits have revealed no evidence of malformations despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats. 8.2 Lactation Risk Summary Data from published literature cases with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SOLARAZE and any potential adverse effects on the breastfed infant from the SOLARAZE or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). The systemic bioavailability after topical application of SOLARAZE is lower than after oral dosing [see Clinical Pharmacology (12.3)]. 8.3 Females and Males of Reproductive Potential Female Infertility Based on the mechanism of action, the use of prostaglandin mediated NSAIDs, including SOLARAZE, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Reference ID: 5482946 Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including SOLARAZE, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Actinic keratoses is not a condition seen within the pediatric population. SOLARAZE should not be used by children. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.4, 5.5, 5.6, 5.9, 5.14)]. Of the 211 subjects treated with SOLARAZE in controlled clinical trials, 143 subjects were 65 years of age and over. Of those 143 subjects, 55 subjects were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, and coma have been reported. [see Warnings and Precautions (5.4, 5.5, 5.7, 5.9)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. In the event of oral ingestion, resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. For additional information about overdosage treatment, call a poison control center (1-800-222-1222). 11 DESCRIPTION SOLARAZE® (diclofenac sodium) topical gel, 3%, intended for dermatologic use, contains the active ingredient, diclofenac sodium, in a clear, transparent, colorless to slightly yellow gel base. Diclofenac sodium is a white to slightly yellow crystalline powder. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insoluble in ether. The chemical name for diclofenac sodium is: Sodium [o-(2,6-dichloranilino) phenyl] acetate Diclofenac sodium has a molecular weight of 318.13. The CAS number is CAS-15307-79-6. The structural formula is represented below: Reference ID: 5482946 SOLARAZE also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water. 1 g of SOLARAZE® (diclofenac sodium) topical gel contains 30 mg of the active substance, diclofenac sodium. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown. 12.2 Pharmacodynamics The pharmacodynamics of SOLARAZE in the treatment of actinic keratosis has not been assessed. 12.3 Pharmacokinetics Absorption Diclofenac levels were measured at the end of treatment from 60 patients with AK lesions treated with SOLARAZE® in three adequate and well-controlled clinical trials. Each patient was administered 0.5 g of SOLARAZE® Gel twice a day for up to 105 days. There were up to three 5 cm x 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. Serum concentrations of diclofenac were, on average, at or below 20 ng/mL. Distribution Diclofenac binds tightly to serum albumin. Metabolism Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise. Elimination Diclofenac and its metabolites are excreted mainly in the urine after oral dosing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There did not appear to be any increase in drug-related neoplasms following daily topical applications of diclofenac sodium gel for 2 years at concentrations up to 0.035% diclofenac sodium and 2.5% hyaluronate sodium in albino mice. Reference ID: 5482946 When administered orally for 2 years, diclofenac showed no evidence of carcinogenic potential in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the MRHD based on BSA comparison), or in mice given diclofenac sodium at up to 0.3 mg/kg/day in males and 1 mg/kg/day in females (25% and 83%, respectively, of the MRHD based on BSA comparison). Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also negative in the transformation assay utilizing BALB/3T3 mouse embryo cells. Fertility studies have not been conducted with SOLARAZE Diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the MRHD based on BSA comparison) in male or female rats. 14 CLINICAL STUDIES Clinical trials were conducted involving a total of 427 patients (213 treated with SOLARAZE and 214 with a gel vehicle). Each patient had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any patient. All patients were 18 years of age or older (male and female) with no clinically significant medical problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel, 50% glycolic acid peel) and hyaluronan-containing cosmetics. Patients were excluded from participation for reasons of known or suspected hypersensitivity to any SOLARAZE ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Patients were instructed to apply a small amount of SOLARAZE Gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the primary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence. Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (all locations) SOLARAZE Vehicle p-value Study 1 90 days treatment 27/58 (47%) 11/59 (19%) <0.001 Study 2 90 days treatment 18/53 (34%) 10/55 (18%) 0.061 Study 3 60 days treatment 30 days treatment 15/48 (31%) 7/49 (14%) 5/49 (10%) 2/49 (4%) 0.021 0.221 Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (by location) Scalp Forehead Face Arm/Forearm Back of Hand Study 1 90 days treatment SOLARAZE 1/4 (25%) 17/30 (57%) 9/17 (53%) 4/12 (33%) 6/16 (38%) Vehicle 3/9 (33%) 8/24 (33%) 5/17 (29%) 4/12 (33%) 0/14 (0) p-value 0.7646 0.0908 0.1682 1.000 0.0650 Study 2 90 days treatment Reference ID: 5482946 SOLARAZE 2/6 (33%) 9/19 (47%) 4/5 (80%) 5/8 (63%) 1/17 (6%) Vehicle 0/4 (0) 6/22 (27%) 2/8 (25%) 0/5 (0) 3/16 (19%) p-value 0.4235 0.1870 0.0727 0.0888 0.2818 Study 3 60 days treatment SOLARAZE 3/7 (43%) 13/31 (42%) 10/19 (53%) 0/1 (0) 2/8 (25%) Vehicle 0/6 (0) 5/36 (14%) 2/13 (15%) 0/2 (0) 1/9 (11%) p-value 0.2271 0.0153 0.0433 - 0.4637 30 days treatment SOLARAZE 2/5 (40%) 4/29 (14%) 3/14 (21%) 0/0 (0) 0/9 (0) Vehicle 0/5 (0) 2/29 (7%) 2/18 (11%) 0/1 (0) 1/9 (11%) p-value 0.2299 0.3748 0.4322 - 0.6521 All data combined SOLARAZE 8/22 (36%) 43/109 (39%) 26/55 (47%) 9/21 (43%) 9/50 (18%) Vehicle 3/24 (13%) 21/111 (19%) 11/56 (20%) 4/20 (20%) 5/48 (10%) p-value 0.0903 0.0013 0.0016 0.2043 0.3662 16 HOW SUPPLIED/STORAGE AND HANDLING Available in tubes of 100 g (NDC 10337-844-01). Each gram of topical gel contains 30 mg of diclofenac sodium. Storage: Store at controlled room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F). Protect from heat. Avoid freezing. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with SOLARAZE and periodically during the course of ongoing therapy. Special Application Instructions x Instruct patients not to apply SOLARAZE to damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. x Instruct patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using SOLARAZE. If patients need to be outdoors while using SOLARAZE, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Advise patients to discontinue treatment with SOLARAZE at the first evidence of sunburn. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.1)]. Exacerbation of Asthma Related to Aspirin Sensitivity Inform patients with aspirin sensitive asthma not to use SOLARAZE. Advise patients with preexisting asthma to report any changes in the signs and symptoms of asthma to their healthcare provider [see Contraindications (4) and Warnings and Precautions 5.2]. Reference ID: 5482946 Serious Skin Reactions including DRESS Advise patients to stop using SOLARAZE immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.3, 5.10)]. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.4)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.5)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). Inform the patient that SOLARAZE may increase the risk of elevated liver enzymes. Advise the patient that laboratory evaluation is needed prior to and periodically during treatment. Advise the patient that if signs or symptoms of liver injury occur, discontinue SOLARAZE and seek medical advice promptly [see Warnings and Precautions (5.6)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.8)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including SOLARAZE, may be associated with reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of SOLARAZE and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with SOLARAZE is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of SOLARAZE with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity [see Warnings and Precautions (5.5) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with SOLARAZE until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 5482946 Exposure to Eyes and Mucosal Membranes Instruct patients to avoid contact of SOLARAZE with the eyes and mucosal membranes. Advise patients that if eye or mucosal membrane contact occurs, immediately wash out with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions (5.16)]. PharmaDerm® A division of Fougera Pharmaceuticals Inc. Melville, New York 11747 USA Reference ID: 5482946	custom-source	2025-02-12T15:47:07.291098	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021005s025lbl.pdf', 'application_number': 21005, 'submission_type': 'SUPPL ', 'submission_number': 25}
80,374	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DAYPRO safely and effectively. See full prescribing information for DAYPRO. DAYPRO® (oxaprozin) caplets, for oral use Initial U.S. Approval: 1992 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • DAYPRO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warnings and Precautions, Serious Skin Reactions (5.9) 11/2024 INDICATIONS AND USAGE DAYPRO is a non-steroidal anti-inflammatory drug indicated for: • Relief of signs and symptoms of Osteoarthritis (OA) (1) • Relief of signs and symptoms of Rheumatoid Arthritis (RA) (1) • Relief of signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • OA: 1200 mg (two 600 mg caplets) given orally once a day (2.2, 2.5, 14.1) • RA: 1200 mg (two 600 mg caplets) given orally once a day (2.3, 2.5, 14.2) • JRA: 600 mg once daily in patients 22-31 kg. 900 mg once daily in patients 32-54 kg. 1200 mg once daily in patients ≥55 kg (2.4, 2.5) DOSAGE FORMS AND STRENGTHS DAYPRO (oxaprozin) caplets: 600 mg (3) CONTRAINDICATIONS • Known hypersensitivity to oxaprozin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of DAYPRO in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of DAYPRO in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: DAYPRO is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue DAYPRO at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including DAYPRO, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (>3%) are: constipation, diarrhea, dyspepsia, nausea, rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking DAYPRO with drugs that interfere with hemostasis. Concomitant use of DAYPRO and analgesic doses of aspirin is not generally recommended (7) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with DAYPRO may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with DAYPRO in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with DAYPRO can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of DAYPRO in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482822 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Osteoarthritis 2.3 Rheumatoid Arthritis 2.4 Juvenile Rheumatoid Arthritis 2.5 Individualization of Dosage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Photosensitivity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Osteoarthritis 14.2 Rheumatoid Arthritis 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482822 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • DAYPRO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE DAYPRO is indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis • For relief of the signs and symptoms of juvenile rheumatoid arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of DAYPRO and other treatment options before deciding to use DAYPRO. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. 2.2 Osteoarthritis For OA, the dosage is 1200 mg (two 600 mg caplets) given orally once a day [see Dosage and Administration (2.5)]. 2.3 Rheumatoid Arthritis For RA, the dosage is 1200 mg (two 600 mg caplets) given orally once a day [see Dosage and Administration (2.5)]. 2.4 Juvenile Rheumatoid Arthritis For JRA, in patients 6 to 16 years of age, the recommended dosage given orally once per day should be based on body weight of the patient as given in Table 1 [see Dosage and Administration (2.5)]. Reference ID: 5482822 Table 1. Recommended Daily Dose of DAYPRO by Body Weight in Pediatric Patients Body Weight Range (kg) Dose (mg) 22–31 600 32–54 900 ≥55 1200 2.5 Individualization of Dosage After observing the response to initial therapy with DAYPRO, the dose and frequency should be adjusted to suit an individual patient’s needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of DAYPRO to minimize adverse effects. The maximum recommended total daily dose of DAYPRO in adults is 1800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1200 mg have not been studied. Patients with low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1200 mg, but only with close monitoring [see Clinical Pharmacology (12.3)]. In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allows therapy to be started with a one-time loading dose of 1200 mg to 1800 mg (not to exceed 26 mg/kg). Doses larger than 1200 mg/day on a chronic basis should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of peptic ulcer, and whose severity of disease justifies maximal therapy. Physicians should ensure that patients are tolerating doses in the 600 mg to 1200 mg/day range without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to the larger doses. Most patients will tolerate once-a-day dosing with DAYPRO, although divided doses may be tried in patients unable to tolerate single doses. 3 DOSAGE FORMS AND STRENGTHS DAYPRO (oxaprozin) caplets: 600 mg caplets, white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side. 4 CONTRAINDICATIONS DAYPRO is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of CABG surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is Reference ID: 5482822 unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as oxaprozin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of DAYPRO in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If DAYPRO is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including DAYPRO, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Reference ID: 5482822 Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-times increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue DAYPRO until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including oxaprozin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), discontinue DAYPRO immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including DAYPRO, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Reference ID: 5482822 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of oxaprozin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of DAYPRO in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If DAYPRO is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of DAYPRO in patients with advanced renal disease. The renal effects of DAYPRO may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating DAYPRO. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of DAYPRO [see Drug Interactions (7)]. Avoid the use of DAYPRO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If DAYPRO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Oxaprozin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to oxaprozin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Reference ID: 5482822 Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, DAYPRO is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When DAYPRO is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including oxaprozin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of DAYPRO at the first appearance of skin rash or any other sign of hypersensitivity. DAYPRO is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as DAYPRO. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue DAYPRO and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including DAYPRO, in pregnant women at about 30 weeks gestation and later. NSAIDs, including DAYPRO, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including DAYPRO, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit DAYPRO use Reference ID: 5482822 to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if DAYPRO treatment extends beyond 48 hours. Discontinue DAYPRO if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with DAYPRO has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including DAYPRO, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of DAYPRO in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Photosensitivity Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reaction data were derived from patients who received DAYPRO in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2253 patients who took 1200 mg to 1800 mg DAYPRO per day in clinical trials. Of these, 1721 patients were treated Reference ID: 5482822 for at least 1 month, 971 patients for at least 3 months, and 366 patients for more than 1 year. Incidence Greater than 1%: In clinical trials of DAYPRO or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%. Cardiovascular system: edema. Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting. Hematologic system: anemia, increased bleeding time. Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache. Skin and appendages: pruritus, rash. Special senses: tinnitus. Urogenital system: abnormal renal function, dysuria or frequency. Incidence Greater than 1%: The following adverse reactions were reported in clinical trials or in patients taking other NSAIDs. Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis. Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis. Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including liver failure, stomatitis, hemorrhoidal or rectal bleeding. Hematologic system: aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, purpura, thrombocytopenia, leukopenia. Metabolic system: hyperglycemia, weight changes. Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness. Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression. Skin: alopecia, angioedema, urticaria, photosensitivity, sweat. Special senses: blurred vision, conjunctivitis, hearing decrease. Reference ID: 5482822 Urogenital: cystitis, hematuria, increase in menstrual flow, oliguria/ polyuria, proteinuria, renal insufficiency, decreased menstrual flow. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of DAYPRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: serum sickness. Digestive system: hepatitis, pancreatitis. Hematologic system: agranulocytosis, pancytopenia. Skin: pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson Syndrome, fixed drug eruption (FDE), toxic epidermal necrolysis (Lyell’s syndrome). Urogenital: acute interstitial nephritis, nephrotic syndrome, acute renal failure. 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with oxaprozin [see Clinical Pharmacology (12.3)]. Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis Clinical Impact: • Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of DAYPRO with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of DAYPRO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. DAYPRO is not a substitute for low dose aspirin for cardiovascular protection. Reference ID: 5482822 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of DAYPRO and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of DAYPRO and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of DAYPRO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of DAYPRO and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of DAYPRO and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate. Intervention: During concomitant use of DAYPRO and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of DAYPRO and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of DAYPRO and cyclosporine, monitor patients for Reference ID: 5482822 signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of DAYPRO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of DAYPRO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with DAYPRO may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of DAYPRO with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. Glyburide Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. Intervention: During concomitant use of DAYPRO and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy. Laboratory Test Interactions False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking DAYPRO. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of DAYPRO therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish DAYPRO from benzodiazepines. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including DAYPRO, can cause premature closure of the fetal ductus arteriosus and Reference ID: 5482822 fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of DAYPRO use between about 20 and 30 weeks of gestation, and avoid DAYPRO use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including DAYPRO, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, oral administration of oxaprozin to pregnant rabbits at doses 0.1-times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses equivalent to the maximum recommended human dose revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at doses equivalent to the maximum recommended human dose. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as oxaprozin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including DAYPRO, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If DAYPRO treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue DAYPRO and follow up according to clinical practice (see Data). Reference ID: 5482822 --- Labor or Delivery There are no studies on the effects of DAYPRO during labor or delivery. In animal studies, NSAIDS, including oxaprozin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Teratology studies with oxaprozin were performed in mice, rats, and rabbits in pregnant animals administered oral doses up to 200 mg/kg/day, 200 mg/kg/day, and 30 mg/kg/day, respectively, during the period of organogenesis. In rabbits, malformations were observed at doses greater than or equal to 7.5 mg/kg/day of oxaprozin (0.1 times the maximum recommended human daily dose [MRHD] of 1800 mg based on body surface area). However, in mice and rats, no drug-related developmental abnormalities or embryo-fetal toxicity were observed at doses up to 50 and 200 mg/kg/day of oxaprozin, respectively (0.1 times and 1.1 times the maximum recommended human daily dose of 1800 mg based on a body surface area comparison, respectively). In fertility/reproductive studies in rats, 200 mg/kg/day oxaprozin was orally administered to female rats for 14 days prior to mating through lactation day (LD) 2, or from gestation day (GD) 15 through LD 2 and the females were mated with males treated with 200 mg/kg/day oxaprozin for 60 days prior to mating. Oxaprozin administration resulted in failure to deliver and a reduction in live birth index at 200 mg/kg/day (1.1-times the maximum recommended human daily dose of 1800 mg based on a body surface area comparison). Reference ID: 5482822 8.2 Lactation Risk Summary Lactation studies have not been conducted with DAYPRO. It is not known whether DAYPRO is excreted in human milk. DAYPRO should be administered to lactating women only if clearly indicated. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAYPRO and any potential adverse effects on the breastfed infant from the DAYPRO or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DAYPRO, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including DAYPRO, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males Testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (0.7-times the maximum recommended human daily dose based on body surface area) of oxaprozin for 42 days or 6 months [see Nonclinical Toxicology (13.1)] 8.4 Pediatric Use Safety and effectiveness of DAYPRO in pediatric patients below the age of 6 years of age have not been established. The effectiveness of DAYPRO for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6 to 16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of DAYPRO in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug’s mechanism of effect between these two patient populations. Use of DAYPRO in JRA patients 6 to 16 years of age is also supported by the following pediatric studies. The pharmacokinetic profile and tolerability of oxaprozin were assessed in JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight [see Clinical Pharmacology (12.3)]. No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of JRA patients versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most of the adverse events were related to the gastrointestinal tract and were mild to moderate. In a 3 month open label study, 10 to 20 mg/kg/day of oxaprozin were administered to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most of those reported were generally mild to moderate, tolerated by the patients, and did not interfere with continuing treatment. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than Reference ID: 5482822 those historically seen in controlled studies in adults. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients who continued treatment (19 to 48 week range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and 5 of those discontinued treatment. Controlled clinical trials with oxaprozin in pediatric patients have not been conducted. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. No adjustment of the dose of DAYPRO is necessary in the elderly, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging [see Clinical Pharmacology (12.3)]. Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Although selected elderly patients in controlled clinical trials tolerated oxaprozin as well as younger patients, caution should be exercised in treating the elderly. DAYPRO is substantially excreted by the kidney, and the risk of toxic reactions to DAYPRO may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.6)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an acute NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Reference ID: 5482822 11 DESCRIPTION DAYPRO (oxaprozin) caplet is a nonsteroidal anti-inflammatory drug, available as caplets of 600 mg for oral administration. The chemical name is 4,5-diphenyl-2-oxazole-propionic acid. The molecular weight is 293. Its molecular formula is C18H15NO3, and it has the following chemical structure. Oxaprozin is a white to off-white powder with a slight odor and a melting point of 162°C to 163°C. It is slightly soluble in alcohol and insoluble in water, with an octanol/water partition coefficient of 4.8 at physiologic pH (7.4). The pKa in water is 4.3. The inactive ingredients in DAYPRO include: microcrystalline cellulose, hypromellose, methylcellulose, magnesium stearate, polacrilin potassium, starch, polyethylene glycol and titanium dioxide. DAYPRO 600-mg caplets are white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxaprozin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of DAYPRO, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Oxaprozin is a potent inhibitor of prostaglandin synthesis in vitro. Oxaprozin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because oxaprozin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482822 12.3 Pharmacokinetics General Pharmacokinetic Characteristics In dose proportionality studies utilizing 600 mg, 1200 mg, and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution of the unbound drug and not an increase in the elimination half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing. The pharmacokinetic parameters of oxaprozin in healthy subjects receiving a single dose or multiple once-daily doses of 1200 mg are presented in Table 3. Table 3. Oxaprozin Pharmacokinetic Parameters [Mean (%CV)] (1200 mg) Healthy Adults (19-78 years) Total Drug Unbound Drug Single N=35 Multiple N=12 Single N=35 Multiple N=12 Tmax (hr) 3.09 (39) 2.44 (40) 3.03 (48) 2.33 (35) Oral Clearance (L/hr/70 kg) 0.150 (24) 0.301 (29) 136 (24) 102 (45) Apparent Volume of Distribution at Steady State (Vd/F; L/70 kg) 11.7 (13) 16.7 (14) 6230 (28) 2420 (38) Elimination Half-life (hr) 54.9 (49) 41.4 (27) 27.8 (34) 19.5 (15) Tmax = time to reach the maximum plasma concentration of oxaprozin. Absorption DAYPRO is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of DAYPRO absorption. Distribution The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11 to 17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following multiple once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties; however, the amount of oxaprozin excreted in breast milk has not been evaluated. Reference ID: 5482822 Elimination Metabolism Several oxaprozin metabolites have been identified in human urine or feces. Oxaprozin is primarily metabolized in the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low. Oxaprozin’s metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited. Excretion Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolites. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing, the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations. Specific Populations Geriatric: A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg once daily) in 20 young (21 to 44 years) adults and 20 elderly (64 to 83 years) adults did not show any statistically significant differences between age groups. Pediatric: A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships, as shown in Table 4. Table 4. Dose to Body Weight Range to Achieve Similar Steady-State Exposure (AUC0-24hr) to Unbound Oxaprozin in JRA Patients Relative to 70 kg Adult Rheumatoid Arthritis Patients Administered Oxaprozin 1200 mg Once Daily1 Dose (mg) Body Weight Range (kg) 600 22 –31 900 32 –54 1200 ≥ 55 1Model-based nomogram derived from unbound oxaprozin steady-state plasma concentrations in JRA patients weighing 22.1 – 42.7 kg or ≥45.0 kg administered oxaprozin 600 mg or 1200 mg once daily for 14 days, respectively. Race: Pharmacokinetic differences due to race have not been identified. Reference ID: 5482822 Hepatic Impairment: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well-compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, monitor patients with severe hepatic dysfunction for adverse reactions. Renal Impairment: Oxaprozin’s renal clearance decreased proportionally with creatinine clearance (CrCL), but since only approximately 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCL. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency [see Warnings and Precautions (5.6)]. Cardiac Failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin. Drug Interaction Studies ACE inhibitors (enalapril): Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC0-24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0-24) [see Drug Interactions (7)]. Aspirin: When oxaprozin was administered with aspirin, the protein binding of oxaprozin was reduced, although the clearance of free oxaprozin was not altered. The clinical significance of this interaction is not known. An in vitro study showed that oxaprozin significantly interfered with the anti-platelet activity of aspirin [see Drug Interactions (7)]. Beta-blockers (metoprolol): Subjects receiving 1200 mg DAYPRO once daily with 100 mg metoprolol twice daily exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days [see Drug Interactions (7)]. Glyburide: Oxaprozin altered the pharmacokinetics of glyburide; however, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control [see Drug Interactions (7)]. H2-receptor antagonists (cimetidine, ranitidine): The total clearance of oxaprozin was reduced by 20% in subjects who concurrently received therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy. Lithium: Oxaprozin has produced an elevation in plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20% [see Drug Interactions (7)]. Methotrexate: Coadministration of oxaprozin with methotrexate resulted in approximately 36% reduction in apparent oral clearance of methotrexate [see Drug Interactions (7)]. Reference ID: 5482822 Other drugs: The coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in rats and mice, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or male or female rats treated with up to 216 mg/kg via the diet (1.2-times the maximum daily human dose of 1800 mg based on body surface area). The significance of this species-specific finding to man is unknown. Mutagenesis Oxaprozin was not genotoxic in the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, or cell transformation testing in mouse fibroblast. Impairment of Fertility Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1.1-times the maximum recommended human daily dose [MRHD] of 1800 mg based on a body surface area comparison). However, testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (0.7-times the MRHD based on body surface area) of oxaprozin for 42 days or 6 months, a finding not confirmed in other species. The clinical relevance of this finding is not known. 14 CLINICAL STUDIES 14.1 Osteoarthritis DAYPRO was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. DAYPRO was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects [see Dosage and Administration (2.5)]. 14.2 Rheumatoid Arthritis DAYPRO was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. DAYPRO was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin. Reference ID: 5482822 DAYPRO was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, DAYPRO may be better tolerated in divided doses. Due to its long half-life, several days of DAYPRO therapy were needed for the drug to reach its full effect [see Dosage and Administration (2.5)]. 16 HOW SUPPLIED/STORAGE AND HANDLING DAYPRO (oxaprozin) 600 mg caplets are white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side, supplied as: NDC Number 0025-1381-31 0025-1381-51 0025-1381-34 Size bottle of 100 bottle of 500 carton of 100 unit dose Storage Keep bottles tightly closed. Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Protect the unit dose from light. 17 PATIENT COUNSELLING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with DAYPRO and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop DAYPRO and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Reference ID: 5482822 &Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking DAYPRO immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including DAYPRO, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of DAYPRO and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with DAYPRO is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of DAYPRO with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with DAYPRO until they talk to their healthcare provider [see Drug Interactions (7)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For medical information about DAYPRO, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-0189-14.1 Reference ID: 5482822 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)”. Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death • The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “antiplatelet drugs”, “anticoagulants”, “SSRIs”, “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems • NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with Reference ID: 5482822 each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • stroke • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • asthma attacks in people who have asthma • bleeding and ulcers in the stomach and intestine • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. Reference ID: 5482822 &Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, INY 10001 General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0791-5.1 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: November 2022 Reference ID: 5482822	custom-source	2025-02-12T15:47:08.170248	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018841s036lbl.pdf', 'application_number': 18841, 'submission_type': 'SUPPL ', 'submission_number': 36}
80,376	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOMETHACIN CAPSULES safely and effectively. See full prescribing information for INDOMETHACIN CAPSULES. Indomethacin Capsules, USP for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • Indomethacin Capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE Indomethacin Capsules, USP are nonsteroidal anti-inflammatory drug indicated for (1) • Moderate to severe rheumatoid arthritis including acute flares of chronic disease • Moderate to severe ankylosing spondylitis • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is 25 mg two or three times a day (2.2) • The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75-150 mg daily in 3 or 4 divided doses (2.3) • The dosage for acute gouty arthritis is 50 mg three times a day, until pain is tolerable (2.4) DOSAGE FORMS AND STRENGTHS Indomethacin Capsules: 25 mg and 50 mg (3) CONTRAINDICATIONS • Known hypersensitivity to indomethacin or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS •Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of indomethacin capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of indomethacin capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: Indomethacin Capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue indomethacin capsules at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). • Fetal Toxicity: Limit use of NSAIDs, including indomethacin capsules, between about 20 to 30 weeks in pregnancy due to risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse (incidence ≥ 3%) are headache, dizziness, dyspepsia, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking i ndomethacin capsules with drugs that interfere with hemostasis. Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with indomethacin capsules may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with indomethacin capsules in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with indomethacin capsules can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin capsules in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482825 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Central Nervous System Effects 5.16 Ocular Effects 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7. DRUG INTERACTIONS 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10. OVERDOSAGE 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14. CLINICAL STUDIES 16. HOW SUPPLIED/STORAGE AND HANDLING 17. PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Page 2 of 25 Reference ID: 5482825 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • Indomethacin Capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE Indomethacin Capsules are indicated for: • Moderate to severe rheumatoid arthritis including acute flares of chronic disease. • Moderate to severe ankylosing spondylitis. • Moderate to severe osteoarthritis. • Acute painful shoulder (bursitis and/or tendinitis). • Acute gouty arthritis. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Dosage Recommendations for Active Stages of the Following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin Capsules 25 mg twice a day or three times daily. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 - 200 mg is reached. Doses above Reference ID: 5482825 this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly. [see Use in Specific Populations (8.5)] 2.3 Acute painful shoulder (bursitis and/or tendinitis) 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 14 days. 2.4 Acute Gouty Arthritis Indomethacin Capsules 50 mg three times a day, until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS Indomethacin capsules: The 25 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/10” on both the body and cap. Indomethacin capsules: The 50 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/11” on both the body and cap. 4 CONTRAINDICATIONS Indomethacin Capsules are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] Reference ID: 5482825 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV- related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID- treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross Reference ID: 5482825 bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue indomethacin until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including indomethacin capsules, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Reference ID: 5482825 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX 2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of indomethacin capsules in patients with advanced renal disease. The renal effects of indomethacin capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin capsules [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on Reference ID: 5482825 potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin capsules are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of indomethacin capsules at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue indomethacin capsules and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including indomethacin capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs, including indomethacin capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including indomethacin capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Reference ID: 5482825 Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit indomethacin capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin capsules treatment extends beyond 48 hours. Discontinue indomethacin capsules if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with indomethacin capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including indomethacin capsules, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of indomethacin capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Central Nervous System Effects: Indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, indomethacin should be discontinued. Indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin. 5.16 Ocular Effects: Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. The prescribing physician should be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Reference ID: 5482825 • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking indomethacin Suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely. Table 1: Summary of Adverse reactions for Indomethacin Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation Anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) Reference ID: 5482825 associated with stenosis and obstruction CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES Tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None Hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC none Edema weight gain fluid retention flushing or sweating Hyperglycemia glycosuria hyperkalemia INTEGUMENTARY None Pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None Leucopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema Dyspnea asthma purpura angiitis pulmonary edema fever Reference ID: 5482825 GENITOURINARY None Hematuria BUN elevation vaginal bleeding renal insufficiency, including proteinuria renal nephrotic syndrome failure interstitial nephritis MISCELLANEOUS None Epistaxis breast changes, including enlargement and tenderness, or gynecomastia *Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak. Genitourinary: Urinary frequency. A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2: Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Reference ID: 5482825 Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [see Warnings and Precautions (5.6)]. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Reference ID: 5482825 Intervention: Methotrexate Clinical Impact: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: Cyclosporine Clinical Impact: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: NSAIDs and Salic Clinical Impact: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. ylates Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: Pemetrexed Clinical Impact: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Reference ID: 5482825 Risk Summary Use of NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of indomethacin capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin capsules use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including indomethacin capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regrading other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If indomethacin capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin capsules and follow up according to clinical practice (see Data). Reference ID: 5482825 Labor or Delivery There are no studies on the effects of indomethacin capsules during labor or delivery. In animal studies, NSAIDS, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times and 0.2 times the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses, however, no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Reference ID: 5482825 Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. Indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1 - 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 - 200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 - 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Reference ID: 5482825 Indomethacin may cause confusion or, rarely, psychosis [see Adverse Reaction (6)]; physicians should remain alert to the possibility of such adverse effects in the elderly. Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222 1222). 11 DESCRIPTION Indomethacin Capsules, USP is a nonsteroidal anti-inflammatory drug, available as 25 mg and 50 mg capsules for oral administration. The chemical name is1-(4-chlorobenzoyl)-5-methoxy-2 methyl-1H-indole-3-acetic acid. The molecular weight is 357.79. Its molecular formula is C19H16ClNO4, and it has the following chemical structure. Indomethacin is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The inactive ingredients in indomethacin capsules include: D & C Red #28, FD&C Blue #1, FD&C Red #3, gelatin, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, silicon dioxide, sodium lauryl sulfate, starch and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations Reference ID: 5482825 reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482825 12.3 Pharmacokinetics Absorption Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism: Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl desbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion: Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dosage is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of indomethacin capsules have not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% (see Drug Interactions (7). When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal Reference ID: 5482825 clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the maximum recommended human daily dose [MRHD] on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times and 0.07 times the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethal in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease. Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin m ay enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING Indomethacin Capsules are supplied containing 25 mg or 50 mg of indomethacin. The 25 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/10” on both the body and cap. They are supplied in bottles of 100 and 1000 as follows: NDC 23155-010-01 bottles of 100 NDC 23155-010-10 bottles of 1000 The 50 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/11” on both the body and cap. They are supplied in bottles of 100 and 500 as follows: Reference ID: 5482825 NDC 23155-011-01 bottles of 100 NDC 23155-011-05 bottles of 500 Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advice patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advice patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking indomethacin capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks Reference ID: 5482825 •I• h ® ~,':' Avet P arma gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [see Drug Interactions (7)]. Distributed by: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Revised: 11/2024 Reference ID: 5482825 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482825 What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Avet Pharmaceuticals Inc. at 1.866.901.DRUG (3784). Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) For more information, go to www.avetpharma.com or call 1.866.901.DRUG (3784). This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 07/2021 Reference ID: 5482825	custom-source	2025-02-12T15:47:08.399449	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018851s029lbl.pdf', 'application_number': 18851, 'submission_type': 'SUPPL ', 'submission_number': 29}
80,380	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MOBIC safely and effectively. See full prescribing information for MOBIC. MOBIC® (meloxicam tablets), for oral use Initial U.S. Approval: 2000 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • MOBIC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ---------------------------RECENT MAJOR CHANGES-------------------------- Warnings and Precautions (5.9) 11/2024 ----------------------------INDICATIONS AND USAGE-------------------------- MOBIC is a non-steroidal anti-inflammatory drug indicated for: • Osteoarthritis (OA) (1.1) • Rheumatoid Arthritis (RA) (1.2) • Juvenile Rheumatoid Arthritis (JRA) in patients who weigh ≥60 kg (1.3) ----------------------DOSAGE AND ADMINISTRATION---------------------- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1) • OA (2.2) and RA (2.3): • Starting dose: 7.5 mg once daily • Dose may be increased to 15 mg once daily • JRA (2.4): • 7.5 mg once daily in children ≥60 kg • MOBIC Tablets are not interchangeable with approved formulations of oral meloxicam even if the total milligram strength is the same (2.6) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- • MOBIC (meloxicam) Tablets: 7.5 mg and 15 mg (3) -------------------------------CONTRAINDICATIONS----------------------------- • Known hypersensitivity to meloxicam or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of MOBIC in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of MOBIC in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: MOBIC is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue MOBIC at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue MOBIC and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including MOBIC, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ------------------------------ADVERSE REACTIONS------------------------------ • Most common (≥5% and greater than placebo) adverse events in adults are diarrhea, upper respiratory tract infections, dyspepsia, and influenza- like symptoms (6.1) • Adverse events observed in pediatric studies were similar in nature to the adult clinical trial experience (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or FDA at 1-800-FDA 1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking MOBIC with drugs that interfere with hemostasis. Concomitant use of MOBIC and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARBs) or Beta- Blockers: Concomitant use with MOBIC may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with MOBIC in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------- • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of MOBIC in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482828 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 1.1 Osteoarthritis (OA) 1.2 Rheumatoid Arthritis (RA) 1.3 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Osteoarthritis 2.3 Rheumatoid Arthritis 2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course 2.5 Renal Impairment 2.6 Non-Interchangeability with Other Formulations of Meloxicam 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Osteoarthritis and Rheumatoid Arthritis 14.2 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482828 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • MOBIC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 Osteoarthritis (OA) MOBIC is indicated for relief of the signs and symptoms of osteoarthritis [see Clinical Studies (14.1)]. 1.2 Rheumatoid Arthritis (RA) MOBIC is indicated for relief of the signs and symptoms of rheumatoid arthritis [see Clinical Studies (14.1)]. 1.3 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course MOBIC is indicated for relief of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients who weigh ≥60 kg [see Dosage and Administration (2.4) and Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of MOBIC and other treatment options before deciding to use MOBIC. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with MOBIC, adjust the dose to suit an individual patient's needs. In adults, the maximum recommended daily oral dose of MOBIC is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. MOBIC may be taken without regard to timing of meals. 2.2 Osteoarthritis For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of MOBIC is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.3 Rheumatoid Arthritis For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of MOBIC is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course For the treatment of juvenile rheumatoid arthritis, the recommended oral dose of MOBIC is 7.5 mg once daily in children who weigh ≥60 kg. There was no additional benefit demonstrated by increasing the dose above 7.5 mg in clinical trials. MOBIC tablets should not be used in children who weigh <60 kg. 2.5 Renal Impairment The use of MOBIC in subjects with severe renal impairment is not recommended. In patients on hemodialysis, the maximum dosage of MOBIC is 7.5 mg per day [see Clinical Pharmacology (12.3)]. 2.6 Non-Interchangeability with Other Formulations of Meloxicam MOBIC Tablets have not shown equivalent systemic exposure to other approved formulations of oral meloxicam. Therefore, MOBIC Tablets are not interchangeable with other formulations of oral meloxicam product even if the total milligram strength is the same. Do not substitute similar dose strengths of MOBIC Tablets with other formulations of oral meloxicam product. 3 DOSAGE FORMS AND STRENGTHS MOBIC (meloxicam) Tablets: • 7.5 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg. Impressed with the Boehringer Ingelheim logo on one side and the letter “M” on the other. • 15 mg: pastel yellow, oblong, biconvex, uncoated tablet containing meloxicam 15 mg. Impressed with the tablet code “15” on one side and the letter “M” on the other. 4 CONTRAINDICATIONS MOBIC is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] Reference ID: 5482828 5 • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of MOBIC in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If MOBIC is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue MOBIC until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue MOBIC immediately, and perform a clinical evaluation of the patient [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.4 Hypertension NSAIDs, including MOBIC, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Reference ID: 5482828 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of MOBIC in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If MOBIC is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs, including MOBIC, has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of MOBIC may hasten the progression of renal dysfunction in patients with preexisting renal disease. Because some MOBIC metabolites are excreted by the kidney, monitor patients for signs of worsening renal function. Correct volume status in dehydrated or hypovolemic patients prior to initiating MOBIC. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of MOBIC [see Drug Interactions (7)]. No information is available from controlled clinical studies regarding the use of MOBIC in patients with advanced renal disease. Avoid the use of MOBIC in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If MOBIC is used in patients with advanced renal disease, monitor patients for signs of worsening renal function [see Clinical Pharmacology (12.3)]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin- sensitive patients, MOBIC is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When MOBIC is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of MOBIC at the first appearance of skin rash or any other sign of hypersensitivity. MOBIC is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as MOBIC. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue MOBIC and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including MOBIC, in pregnant women at about 30 weeks gestation and later. NSAIDs, including MOBIC, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including MOBIC, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit MOBIC use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if MOBIC treatment extends beyond 48 hours. Discontinue MOBIC if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. Reference ID: 5482828 6 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with MOBIC has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including MOBIC, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of MOBIC in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Boxed Warning and Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Boxed Warning and Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10)] • Fetal Toxicity [see Warnings and Precautions (5.11)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Osteoarthritis and Rheumatoid Arthritis The MOBIC Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with MOBIC 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with MOBIC 15 mg/day. MOBIC at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across MOBIC trials. A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of MOBIC with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of MOBIC with placebo. Table 1a depicts adverse events that occurred in ≥2% of the MOBIC treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial. Table 1b depicts adverse events that occurred in ≥2% of the MOBIC treatment groups in two 12-week placebo-controlled rheumatoid arthritis trials. Table 1a Adverse Events (%) Occurring in ≥2% of MOBIC Patients in a 12-Week Osteoarthritis Placebo- and Active-Controlled Trial Placebo MOBIC MOBIC Diclofenac 7.5 mg daily 15 mg daily 100 mg daily No. of Patients 157 154 156 153 Gastrointestinal 17.2 20.1 17.3 28.1 Abdominal pain 2.5 1.9 2.6 1.3 Diarrhea 3.8 7.8 3.2 9.2 Dyspepsia 4.5 4.5 4.5 6.5 Flatulence 4.5 3.2 3.2 3.9 Nausea 3.2 3.9 3.8 7.2 Body as a Whole Accident household 1.9 4.5 3.2 2.6 Edema1 2.5 1.9 4.5 3.3 Fall 0.6 2.6 0.0 1.3 Influenza-like symptoms 5.1 4.5 5.8 2.6 Central and Peripheral Nervous System Dizziness 3.2 2.6 3.8 2.0 Headache 10.2 7.8 8.3 5.9 Respiratory Pharyngitis 1.3 0.6 3.2 1.3 Upper respiratory tract infection 1.9 3.2 1.9 3.3 Reference ID: 5482828 Skin Rash2 2.5 2.6 0.6 2.0 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined Table 1b Adverse Events (%) Occurring in ≥2% of MOBIC Patients in two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials Placebo MOBIC MOBIC 7.5 mg daily 15 mg daily No. of Patients 469 481 477 Gastrointestinal Disorders 14.1 18.9 16.8 Abdominal pain NOS2 0.6 2.9 2.3 Dyspeptic signs and symptoms1 3.8 5.8 4.0 Nausea2 2.6 3.3 3.8 General Disorders and Administration Site Conditions Influenza-like illness2 2.1 2.9 2.3 Infection and Infestations Upper respiratory tract infections-pathogen class unspecified1 4.1 7.0 6.5 Musculoskeletal and Connective Tissue Disorders Joint related signs and symptoms1 1.9 1.5 2.3 Nervous System Disorders Headaches NOS2 6.4 6.4 5.5 Skin and Subcutaneous Tissue Disorders Rash NOS2 1.7 1.0 2.1 1 MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-pathogen unspecified (laryngitis NOS, pharyngitis NOS, sinusitis NOS), joint related signs and symptoms (arthralgia, arthralgia aggravated, joint crepitation, joint effusion, joint swelling) 2 MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS The adverse events that occurred with MOBIC in ≥2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2. Table 2 Adverse Events (%) Occurring in ≥2% of MOBIC Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials 4 to 6 Weeks Controlled Trials 6 Month Controlled Trials MOBIC MOBIC MOBIC MOBIC 7.5 mg daily 15 mg daily 7.5 mg daily 15 mg daily No. of Patients 8955 256 169 306 Gastrointestinal 11.8 18.0 26.6 24.2 Abdominal pain 2.7 2.3 4.7 2.9 Constipation 0.8 1.2 1.8 2.6 Diarrhea 1.9 2.7 5.9 2.6 Dyspepsia 3.8 7.4 8.9 9.5 Flatulence 0.5 0.4 3.0 2.6 Nausea 2.4 4.7 4.7 7.2 Vomiting 0.6 0.8 1.8 2.6 Body as a Whole Accident household 0.0 0.0 0.6 2.9 Edema1 0.6 2.0 2.4 1.6 Pain 0.9 2.0 3.6 5.2 Central and Peripheral Nervous System Dizziness 1.1 1.6 2.4 2.6 Headache 2.4 2.7 3.6 2.6 Hematologic Anemia 0.1 0.0 4.1 2.9 Musculoskeletal Arthralgia 0.5 0.0 5.3 1.3 Back pain 0.5 0.4 3.0 0.7 Psychiatric Insomnia 0.4 0.0 3.6 1.6 Reference ID: 5482828 Respiratory Coughing 0.2 0.8 2.4 1.0 Upper respiratory tract 0.2 0.0 8.3 7.5 infection Skin Pruritus 0.4 1.2 2.4 0.0 Rash2 0.3 1.2 3.0 1.3 Urinary Micturition frequency 0.1 0.4 2.4 1.3 Urinary tract infection 0.3 0.4 4.7 6.9 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined Higher doses of MOBIC (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of MOBIC should not exceed 15 mg. Pediatrics Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis (JRA) Three hundred and eighty-seven patients with pauciarticular and polyarticular course JRA were exposed to MOBIC with doses ranging from 0.125 to 0.375 mg/kg per day in three clinical trials. These studies consisted of two 12-week multicenter, double-blind, randomized trials (one with a 12-week open-label extension and one with a 40-week extension) and one 1-year open-label PK study. The adverse events observed in these pediatric studies with MOBIC were similar in nature to the adult clinical trial experience, although there were differences in frequency. In particular, the following most common adverse events, abdominal pain, vomiting, diarrhea, headache, and pyrexia, were more common in the pediatric than in the adult trials. Rash was reported in seven (<2%) patients receiving MOBIC. No unexpected adverse events were identified during the course of the trials. The adverse events did not demonstrate an age or gender-specific subgroup effect. The following is a list of adverse drug reactions occurring in <2% of patients receiving MOBIC in clinical trials involving approximately 16,200 patients. Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis Central and Peripheral Nervous System convulsions, paresthesia, tremor, vertigo Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative Heart Rate and Rhythm arrhythmia, palpitation, tachycardia Hematologic leukopenia, purpura, thrombocytopenia Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis Metabolic and Nutritional dehydration Psychiatric abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence Respiratory asthma, bronchospasm, dyspnea Skin and Appendages alopecia, angioedema, bullous eruption, photosensitivity reaction, pruritus, sweating increased, urticaria Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus Urinary System albuminuria, BUN increased, creatinine increased, hematuria, renal failure 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of MOBIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide postmarketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome; fixed drug eruption (FDE); toxic epidermal necrolysis, and infertility female. Reference ID: 5482828 7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. See also Warnings and Precautions (5.2, 5.6, 5.12) and Clinical Pharmacology (12.3). Table 3 Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: • Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. MOBIC is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co- administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention: During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)]. Intervention: During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Reference ID: 5482828 8 Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including MOBIC, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of MOBIC use between about 20 and 30 weeks of gestation, and avoid MOBIC use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including MOBIC, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65- and 6.5-times the maximum recommended human dose (MRHD) of MOBIC. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times MRHD of meloxicam. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the MRHD [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including MOBIC, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If MOBIC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue MOBIC and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of MOBIC during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full- term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the MRHD of 15 mg of MOBIC based on BSA comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65 and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis. Reference ID: 5482828 Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MOBIC and any potential adverse effects on the breastfed infant from the MOBIC or from the underlying maternal condition. Data Animal Data Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including MOBIC, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including MOBIC, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [see Dosage and Administration (2.3), Adverse Reactions (6.1) and Clinical Studies (14.2)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since meloxicam is significantly metabolized in the liver and hepatotoxicity may occur, use meloxicam with caution in patients with hepatic impairment [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of MOBIC in subjects with severe renal impairment is not recommended. In patients on hemodialysis, meloxicam should not exceed 7.5 mg per day. Meloxicam is not dialyzable [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. There is limited experience with meloxicam overdosage. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage. For additional information about overdosage treatment, call a poison control center (1-800-222-1222). 11 DESCRIPTION MOBIC (meloxicam) is a nonsteroidal anti-inflammatory drug (NSAID). Each pastel yellow MOBIC tablet contains 7.5 mg or 15 mg meloxicam for oral administration. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula: CH3 OH O S N N N H S CH3 O O Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. Reference ID: 5482828 12 MOBIC is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam. The inactive ingredients in MOBIC tablets include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium citrate dihydrate. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of MOBIC, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling. Meloxicam oral suspension doses of 7.5 mg/5 mL and 15 mg/10 mL have been found to be bioequivalent to meloxicam 7.5 mg and 15 mg capsules, respectively. Meloxicam capsules have been shown to be bioequivalent to MOBIC tablets. Table 4 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1 Steady State Single Dose Pharmacokinetic Healthy male adults Elderly males Elderly females Renal failure Hepatic insufficiency Parameters (Fed)2 (Fed)2 (Fed)2 (Fasted) (Fasted) (% CV) 7.5 mg3 tablets 15 mg capsules 15 mg capsules 15 mg capsules 15 mg capsules N 18 5 8 12 12 Cmax [µg/mL] 1.05 (20) 2.3 (59) 3.2 (24) 0.59 (36) 0.84 (29) tmax [h] 4.9 (8) 5 (12) 6 (27) 4 (65) 10 (87) t1/2 [h] 20.1 (29) 21 (34) 24 (34) 18 (46) 16 (29) CL/f [mL/min] 8.8 (29) 9.9 (76) 5.1 (22) 19 (43) 11 (44) V /f4 [L] z 14.7 (32) 15 (42) 10 (30) 26 (44) 14 (29) 1 The parameter values in the table are from various studies 2 not under high fat conditions 3 MOBIC tablets 4 Vz/f =Dose/(AUC•Kel) Food and Antacid Effects Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the Cmax values for meloxicam suspension were affected following a similar high fat meal, while mean Tmax values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, MOBIC can be administered without regard to timing of meals or concomitant administration of antacids. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity. Reference ID: 5482828 Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min. Specific Populations Pediatric After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg [see Dosage and Administration (2.4)]. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively. In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of MOBIC in pediatric patients under 2 years of age have not been investigated. Geriatric Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (≥65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger females (≤55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients. Sex Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg MOBIC, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders. Hepatic Impairment Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child- Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Renal Impairment Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of MOBIC in subjects with severe renal impairment is not recommended [see Dosage and Administration (2.5), Warnings and Precautions (5.6) and Use in Specific Populations (8.7)]. Hemodialysis Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. When MOBIC is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every day as compared to subjects receiving lithium alone [see Drug Interactions (7)]. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [see Drug Interactions (7)]. Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC Reference ID: 5482828 with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-times, respectively, the maximum recommended human dose [MRHD] of 15 mg/day MOBIC based on body surface area [BSA] comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and 3.2-times greater, respectively, than the MRHD based on BSA comparison). 14 CLINICAL STUDIES 14.1 Osteoarthritis and Rheumatoid Arthritis The use of MOBIC for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial. MOBIC (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo. The four primary endpoints were investigator’s global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness). Patients on MOBIC 7.5 mg daily and MOBIC 15 mg daily showed significant improvement in each of these endpoints compared with placebo. The use of MOBIC for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks’ to 6 months’ duration. In these trials, the efficacy of MOBIC, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial. The use of MOBIC for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial. MOBIC (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response. Patients receiving MOBIC 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. 14.2 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course The use of MOBIC for the treatment of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older was evaluated in two 12-week, double-blind, parallel-arm, active-controlled trials. Both studies included three arms: naproxen and two doses of meloxicam. In both studies, meloxicam dosing began at 0.125 mg/kg/day (7.5 mg maximum) or 0.25 mg/kg/day (15 mg maximum), and naproxen dosing began at 10 mg/kg/day. One study used these doses throughout the 12-week dosing period, while the other incorporated a titration after 4 weeks to doses of 0.25 mg/kg/day and 0.375 mg/kg/day (22.5 mg maximum) of meloxicam and 15 mg/kg/day of naproxen. The efficacy analysis used the ACR Pediatric 30 responder definition, a composite of parent and investigator assessments, counts of active joints and joints with limited range of motion, and erythrocyte sedimentation rate. The proportion of responders were similar in all three groups in both studies, and no difference was observed between the meloxicam dose groups. 16 HOW SUPPLIED/STORAGE AND HANDLING MOBIC is available as a pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg or as a pastel yellow, oblong, biconvex, uncoated tablet containing meloxicam 15 mg. The 7.5 mg tablet is impressed with the Boehringer Ingelheim logo on one side, and on the other side, the letter “M”. The 15 mg tablet is impressed with the tablet code “15” on one side and the letter “M” on the other. MOBIC (meloxicam) tablets 7.5 mg: NDC 0597-0029-01; Bottles of 100 MOBIC (meloxicam) tablets 15 mg: NDC 0597-0030-01; Bottles of 100 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep MOBIC tablets in a dry place. Dispense tablets in a tight container. Keep this and all medications out of the reach of children. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families or their caregivers of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately [see Warnings and Precautions (5.1)]. Reference ID: 5482828 Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop MOBIC and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking MOBIC immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including MOBIC, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of MOBIC and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with MOBIC is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of MOBIC with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with MOBIC until they talk to their healthcare provider [see Drug Interactions (7)]. For current prescribing information, scan the code or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA MOBIC is a registered trademark of and used under license from Boehringer Ingelheim International GmbH Copyright 2024 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED COL9214BH202024 Reference ID: 5482828 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: Reference ID: 5482828 See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is • diarrhea black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs: • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA MOBIC is a registered trademark of and used under license from Boehringer Ingelheim International GmbH Copyright 2024 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED COL9214BH202024 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 Reference ID: 5482828	custom-source	2025-02-12T15:47:08.815880	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020938s030lbl.pdf', 'application_number': 20938, 'submission_type': 'SUPPL ', 'submission_number': 30}
80,378	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DAYPRO ALTA safely and effectively. See full prescribing information for DAYPRO ALTA. DAYPRO ALTA™ (oxaprozin potassium) tablets, for oral use Initial U.S. Approval: 1992 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • DAYPRO ALTA is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE DAYPRO ALTA is a nonsteroidal anti-inflammatory drug indicated for • Relief of the signs and symptoms of osteoarthritis (1) • Relief of the signs and symptoms of rheumatoid arthritis (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • OA: 1200 mg (two 600 mg tablets) given orally once a day (2.2, 14) • RA: 1200 mg (two 600 mg tablets) given orally once a day (2.3, 14) DOSAGE FORMS AND STRENGTHS DAYPRO ALTA (oxaprozin potassium) tablets: 600 mg (3) CONTRAINDICATIONS • Known hypersensitivity to oxaprozin potassium or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of DAYPRO ALTA in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of DAYPRO ALTA in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: DAYPRO ALTA is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue DAYPRO ALTA at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including DAYPRO ALTA, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (incidence >3%) are: Constipation, diarrhea, dyspepsia, nausea, rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking DAYPRO ALTA with drugs that interfere with hemostasis. Concomitant use of DAYPRO ALTA and analgesic doses of aspirin is not generally recommended (7) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with DAYPRO ALTA may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with DAYPRO ALTA in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with DAYPRO ALTA can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of DAYPRO ALTA in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482827 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Osteoarthritis 2.3 Rheumatoid Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Photosensitivity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482827 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • DAYPRO ALTA is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE DAYPRO ALTA is indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of DAYPRO ALTA and other treatment options before deciding to use DAYPRO ALTA. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with DAYPRO ALTA, the dose and frequency should be adjusted to suit an individual patient’s needs. Divided doses may be tried in patients unable to tolerate single doses. For osteoarthritis patients of low body weight or with milder disease, an initial dose of one 600 mg tablet once a day may be appropriate. The maximum total daily dose is 1200 mg. 2.2 Osteoarthritis For OA, the dosage is 1200 mg (two 600 mg tablets) given orally once a day. Reference ID: 5482827 2.3 Rheumatoid Arthritis For RA, the dosage is 1200 mg (two 600 mg tablets) given orally once a day. 3 DOSAGE FORMS AND STRENGTHS DAYPRO ALTA (oxaprozin potassium) tablets: 600 mg tablets, blue, capsule-shaped, film-coated, with Searle 1391 printed on one side. 4 CONTRAINDICATIONS DAYPRO ALTA is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin potassium or any components of the drug product [see Warnings and Precautions (5.7,5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7,5.8)] • In the setting of CABG surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as oxaprozin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, Reference ID: 5482827 and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of DAYPRO ALTA in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If DAYPRO ALTA is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including DAYPRO ALTA, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-Treated Patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue DAYPRO ALTA until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated Reference ID: 5482827 patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure, have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including oxaprozin potassium. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), discontinue DAYPRO ALTA immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including DAYPRO ALTA, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of oxaprozin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of DAYPRO ALTA in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If DAYPRO ALTA is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of DAYPRO ALTA in patients with advanced renal disease. The renal effects of DAYPRO ALTA may hasten the progression of renal dysfunction in patients with preexisting renal disease. Reference ID: 5482827 Correct volume status in dehydrated or hypovolemic patients prior to initiating DAYPRO ALTA. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of DAYPRO ALTA [see Drug Interactions (7)]. Avoid the use of DAYPRO ALTA in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If DAYPRO ALTA is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Oxaprozin potassium has been associated with anaphylactic reactions in patients with and without known hypersensitivity to oxaprozin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, DAYPRO ALTA is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When DAYPRO ALTA is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including oxaprozin potassium, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of DAYPRO ALTA at the first appearance of skin rash or any other sign of hypersensitivity. DAYPRO ALTA is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as DAYPRO ALTA. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue DAYPRO ALTA and evaluate the patient immediately. Reference ID: 5482827 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including DAYPRO ALTA, in pregnant women at about 30 weeks gestation and later. NSAIDs, including DAYPRO ALTA, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including DAYPRO ALTA, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit DAYPRO ALTA use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if DAYPRO ALTA treatment extends beyond 48 hours. Discontinue DAYPRO ALTA if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with DAYPRO ALTA has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including DAYPRO ALTA, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of DAYPRO ALTA in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Photosensitivity Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] Reference ID: 5482827 • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In patients taking DAYPRO ALTA (oxaprozin potassium tablets), oxaprozin, or other NSAIDs, the following are the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients [see Clinical Studies (14)]: Gastrointestinal experiences including: abdominal pain, anorexia, constipation, diarrhea, dyspepsia, flatulence, gross gastrointestinal bleeding/perforation, GI ulcers (gastric/duodenal), heartburn, nausea, vomiting. Non-gastrointestinal experiences including: abnormal renal function, anemia, confusion, depression, disturbance of sleep, dizziness, dysuria or frequency, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, sedation, somnolence, tinnitus. Additional adverse experiences reported in less than 1% of patients: Body as a whole: anaphylactic reactions, appetite changes, death, fever, infection, sepsis, serum sickness. Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, syncope, tachycardia, vasculitis. Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, hemorrhoidal or rectal bleeding, hepatitis, jaundice, liver failure, pancreatitis, stomatitis. Hemic and lymphatic system: agranulocytosis, aplastic anemia, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia. Metabolic and nutritional: hyperglycemia, weight changes. Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness. Respiratory system: asthma, dyspnea, pneumonia, pulmonary infections, respiratory depression, sinusitis, symptoms of upper respiratory tract infection. Skin and appendages: alopecia, angioedema, increased sweating, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis (Lyell’s syndrome), urticaria. Reference ID: 5482827 Special senses: blurred vision, conjunctivitis, hearing impairment. Urogenital system: acute interstitial nephritis, acute renal failure, cystitis, decreased menstrual flow, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/polyuria, proteinuria, renal insufficiency. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oxaprozin potassium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with oxaprozin potassium [see Clinical Pharmacology (12.3)]. Table 1: Clinically Significant Drug Interactions with Oxaprozin Potassium Drugs That Interfere with Hemostasis Clinical Impact: • Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of DAYPRO ALTA with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of DAYPRO ALTA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. DAYPRO ALTA is not a substitute for low-dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of ACE inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of DAYPRO ALTA and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. Reference ID: 5482827 • During concomitant use of DAYPRO ALTA and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of DAYPRO ALTA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of oxaprozin potassium with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of DAYPRO ALTA and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of DAYPRO ALTA and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate. Intervention: During concomitant use of DAYPRO ALTA and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of DAYPRO ALTA and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of DAYPRO ALTA and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of oxaprozin potassium with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of oxaprozin potassium with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of DAYPRO ALTA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of DAYPRO ALTA and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Reference ID: 5482827 NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with DAYPRO ALTA may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of DAYPRO ALTA with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. Glyburide Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. Intervention During concomitant use of DAYPRO ALTA and glyburide, monitor patients’ blood glucose in the beginning phase of cotherapy. Laboratory Test Interactions False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking oxaprozin. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of oxaprozin therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish oxaprozin from benzodiazepines. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including DAYPRO ALTA, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of DAYPRO ALTA use between about 20 and 30 weeks of gestation, and avoid DAYPRO ALTA use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including DAYPRO ALTA, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, oral administration of oxaprozin to pregnant rabbits at doses 0.1-times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses equivalent to the maximum recommended human dose (MRHD) revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at doses equivalent to the MRHD. Based on animal data, Reference ID: 5482827 prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as oxaprozin potassium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including DAYPRO ALTA, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If DAYPRO ALTA treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue DAYPRO ALTA and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of DAYPRO ALTA during labor or delivery. In animal studies, NSAIDs, including oxaprozin potassium, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of Reference ID: 5482827 other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Teratology studies with oxaprozin potassium were performed in mice, rats, and rabbits in pregnant animals administered oral doses up to 200 mg/kg/day, 200 mg/kg/day, and 30 mg/kg/day, respectively, during the period of organogenesis. In rabbits, malformations were observed at doses greater than or equal to 7.5 mg/kg/day of oxaprozin (0.1-times the MRHD of 1800 mg based on body surface area). However, in mice and rats, no drug-related developmental abnormalities or embryo-fetal toxicity were observed at doses up to 50 and 200 mg/kg/day of oxaprozin, respectively (0.1-times and 1.1-times the MRHD based on body surface area, respectively). In fertility/reproductive studies in rats, 200 mg/kg/day oxaprozin was orally administered to female rats for 14 days prior to mating through lactation day (LD) 2, or from gestation day (GD) 15 through LD 2 and the females were mated with males treated with 200 mg/kg/day oxaprozin for 60 days prior to mating. Oxaprozin administration resulted in failure to deliver and a reduction in live birth index at 200 mg/kg/day (1.1-times the MRHD based on body surface area comparison). 8.2 Lactation Risk Summary Lactation studies have not been conducted with DAYPRO ALTA. It is not known whether DAYPRO ALTA is excreted in human milk. DAYPRO ALTA should be administered to lactating women only if clearly indicated. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAYPRO ALTA and any potential adverse effects on the breastfed infant from the DAYPRO ALTA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DAYPRO ALTA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including DAYPRO ALTA, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males Testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (0.7-times the MRHD based on body surface area) of oxaprozin for 42 days or 6 months [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use DAYPRO ALTA has not been investigated in patients <16 years of age. Safety and effectiveness of DAYPRO ALTA in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly Reference ID: 5482827 patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Age was not shown to have an effect on the pharmacokinetics of DAYPRO ALTA following 600 mg, 1200 mg and 1800 mg doses or on the incidence of adverse reactions reported [see Clinical Pharmacology (12.3)]. In a controlled 6-month clinical trial of 803 patients (322 of whom received DAYPRO ALTA), about 40% of whom were elderly, there was basically no difference detected in terms of the total number of subjects reporting adverse events with respect to age. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients. Caution should be exercised in treating the elderly (65 years and older), and extra care should be taken when choosing a dose. Oxaprozin is substantially excreted by the kidney, and the risk of toxic reactions to DAYPRO ALTA may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.6)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an acute NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. 11 DESCRIPTION DAYPRO ALTA (oxaprozin potassium) tablet is a member of the propionic acid group of NSAIDs, available as tablets of 600 mg (678 mg of oxaprozin potassium equivalent to 600 mg of oxaprozin) for oral administration. The chemical name for oxaprozin potassium is 4,5-diphenyl-2-oxazolepropionic acid, potassium salt. The molecular weight is 331. Its molecular formula is C18H14NO3K, and it has the following chemical structure. It has the following structural formula: Reference ID: 5482827 Oxaprozin potassium is a white to off white powder with a melting point of 215°C. It is slightly soluble in alcohol and very soluble in water. The PK in water is 9.7. The inactive ingredients in DAYPRO ALTA include: microcrystalline cellulose, hydroxypropyl methylcellulose, pregelatinized corn starch, stearic acid, colloidal silicon dioxide, polyethylene glycol, titanium dioxide, FD&C Blue #1 Aluminum Lake, and pharmaceutical glaze. DAYPRO ALTA 600 mg tablets are blue, capsule-shaped, film-coated, with Searle 1391 printed on one side. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action DAYPRO ALTA, the potassium salt of oxaprozin, is a NSAID, which dissociates into the active moiety oxaprozin in vivo. Oxaprozin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of DAYPRO ALTA, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Oxaprozin is a potent inhibitor of prostaglandin synthesis in vitro. Oxaprozin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because oxaprozin potassium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics In dose proportionality studies utilizing 600 mg, 1200 mg and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Concentration dependent changes in the protein binding also resulted in changes in the oxaprozin volume of distribution, which increased for the total drug but decreased for the unbound drug. The pharmacokinetic parameters of oxaprozin in healthy subjects receiving a single dose or multiple once-daily doses of 1200 mg are presented in Table 2. Table 2. Oxaprozin Pharmacokinetic Parameters with DAYPRO ALTA Dosing (1200 mg) [Mean (%CV)] Healthy Adults (18-42 years; N=12-24) Total Drug Unbound Drug Single Multiple Single Multiple Tmax (hr) 1.67 (65) 2.13 (64) 1.71 (63) 1.59 (38) Oral Clearance (L/hr/70 kg) 0.125 (15) 0.289 (17) 123 (20) 86.7 (33) Apparent Volume of Distribution at Steady State (Vd/F; L/70 kg) 10.14 (11) 16.24 (38) 7741 (18) 2067 (38) Elimination Half-life (hr) 57.0 (15) 38.0 (29) 44.8 (23) 16.4 (11) Tmax = time to reach the maximum plasma concentration of oxaprozin. Absorption After oral administration, DAYPRO ALTA dissociates into free oxaprozin which is 95% absorbed. Peak plasma concentration occurs at about 1 hour and 45 minutes after single dose administration (see Table 2). When DAYPRO ALTA is administered with food, the peak concentration of oxaprozin is delayed by about 45 minutes, but the extent of absorption is unchanged. Antacids do not significantly Reference ID: 5482827 affect the extent and rate of oxaprozin absorption. Distribution The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 10 to 16 L/70 kg. Oxaprozin potassium is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated. Elimination Metabolism Several oxaprozin metabolites excreted in human urine or feces are considered not to have significant pharmacologic activity. Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronides are the major conjugated metabolites of oxaprozin. A small amount (<5%) of active phenolic metabolites is produced, but the contribution to overall activity is limited. Excretion Sixty-five percent (65%) of the dose is excreted into the urine and 35% in the feces as metabolites. Renal elimination of oxaprozin metabolites is a major pathway of elimination. Biliary excretion of unchanged oxaprozin is a minor pathway. After multiple doses of DAYPRO ALTA (1200 mg QD), post-steady state mean elimination half-lives of total oxaprozin and protein unbound oxaprozin were 38.0 and 16.4 hours, respectively (see Table 2). Specific Populations Pediatric: DAYPRO ALTA has not been investigated in patients <16 years of age. Geriatric: As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetic reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging. Gender: No differences in pharmacokinetic parameters have been observed between male and female subjects in studies of DAYPRO ALTA. Race: Pharmacokinetic differences due to race have not been identified in studies of DAYPRO ALTA. Hepatic Impairment: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well-compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, monitor patients with severe hepatic dysfunction closely for adverse reactions. Renal Impairment: Oxaprozin’s renal clearance decreased proportionally with creatinine clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal impairment [see Warnings and Precautions (5.6)]. Reference ID: 5482827 Cardiac Failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin. Drug Interaction Studies ACE inhibitors (enalapril): Oxaprozin potassium has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC0-24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0-24) [see Drug Interactions (7)]. Aspirin: When oxaprozin was administered with aspirin, the protein binding of oxaprozin was reduced, although the clearance of free oxaprozin was not altered. The clinical significance of this interaction is not known. An in vitro study showed that oxaprozin significantly interfered with the antiplatelet activity of aspirin [see Drug Interactions (7)]. Beta-blockers (metoprolol): Subjects receiving 1200 mg DAYPRO once daily with 100 mg metoprolol twice daily exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days [see Drug Interactions (7)]. Glyburide: Oxaprozin altered the pharmacokinetics of glyburide; however, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control [see Drug Interactions (7)]. H2-receptor antagonists (cimetidine, ranitidine): The total clearance of oxaprozin was reduced by 20% in subjects who concurrently received therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy. Lithium: Oxaprozin has produced an elevation in plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20% [see Drug Interactions (7)]. Methotrexate: Coadministration of oxaprozin with methotrexate resulted in approximately 36% reduction in apparent oral clearance of methotrexate [see Drug Interactions (7)]. Other drugs: The coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in rats and mice, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or rats treated with up to 216 mg/kg via the diet (1.2-times the MRHD of 1800 mg based on body surface). The significance of this species-specific finding to man is unknown. Mutagenesis Oxaprozin did not genotoxic in the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, Reference ID: 5482827 chromosomal aberration testing in human lymphocytes, or cell transformation testing in mouse fibroblast. Impairment of Fertility Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1.1-times the MRHD of 1800 mg based on body surface area comparison). However, testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (0.7-times the MRHD based on body surface area) of oxaprozin for 42 days or 6 months, a finding not confirmed in other species. The clinical relevance of this finding is not known. 14 CLINICAL STUDIES Osteoarthritis: DAYPRO ALTA 1200 mg once daily was evaluated for the relief of the signs and symptoms of osteoarthritis in a 6-month placebo-controlled study versus oxaprozin acid in over 300 patients. In this trial, treatment with DAYPRO ALTA resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. DAYPRO ALTA demonstrated significant reduction in joint pain compared to placebo and was found to be comparable to 1200 mg once daily of oxaprozin acid. With respect to GI events, DAYPRO ALTA appeared to be less well tolerated than oxaprozin acid in this study. The rates for symptomatic ulcers (2.2%) and nausea (13%) for DAYPRO ALTA treated patients were higher than the rates observed with oxaprozin acid (0% and 6%, respectively) [see Adverse Reactions (6)]. Rheumatoid arthritis: Oxaprozin, the active component of DAYPRO ALTA (oxaprozin potassium tablets), was evaluated for the relief of the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. Oxaprozin was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. 16 HOW SUPPLIED/STORAGE AND HANDLING DAYPRO ALTA 600 mg tablets are blue, capsule-shaped, film-coated, with Searle 1391 printed on one side. NDC Number Size 0025-5500-01 bottle of 100 0025-5500-03 bottle of 500 0025-5500-02 carton of 100-unit dose Store at room temperature 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC to 30ºC (59ºF to 86ºF) (see USP Controlled Room Temperature). Dispense in a tightly-closed container. Protect from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with DAYPRO ALTA and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Reference ID: 5482827 Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop DAYPRO ALTA and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking DAYPRO ALTA immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including DAYPRO ALTA, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of DAYPRO ALTA and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with DAYPRO ALTA is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of DAYPRO ALTA with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with DAYPRO ALTA until they talk to their healthcare provider [see Drug Interactions (7)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. Reference ID: 5482827 &Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 For medical information about DAYPRO ALTA, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-0279-12.2 Reference ID: 5482827 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death • The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “antiplatelet drugs”, “anticoagulants”, “SSRIs” or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems • NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482827 What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • stroke • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • asthma attacks in people who have asthma • bleeding and ulcers in the stomach and intestine • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. Reference ID: 5482827 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 LAB-0790-5.2 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: November 2022 Reference ID: 5482827	custom-source	2025-02-12T15:47:08.848536	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020776s013lbl.pdf', 'application_number': 20776, 'submission_type': 'SUPPL ', 'submission_number': 13}
80,384	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLECTOR® safely and effectively. See full prescribing information for FLECTOR. FLECTOR® (diclofenac epolamine) topical system Initial U.S. Approval: 1988 WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • FLECTOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warning and Precautions (5.9) 11/2024 INDICATIONS AND USAGE • FLECTOR is a nonsteroidal anti-inflammatory drug (NSAID) and is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions in adults and pediatric patients 6 years and older (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consist with the individual patient treatment goals (2.1) • The recommended dose of FLECTOR for adults and pediatric patients 6 years and older is one (1) topical system to the most painful area twice a day (2) • FLECTOR should not be applied to damaged or non-intact skin (2) DOSAGE FORMS AND STRENGTHS FLECTOR® (diclofenac epolamine) topical system 1.3%, for topical use. Each individual FLECTOR is debossed. (3) CONTRAINDICATIONS • Known hypersensitivity to diclofenac or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) • For use on non-intact or damaged skin (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of FLECTOR in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of FLECTOR in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: FLECTOR is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue FLECTOR at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). • Fetal Toxicity: Limit use of NSAIDs, including FLECTOR, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS The most common adverse reactions in FLECTOR and placebo-treated adult patients were pruritus (5% and 8%, respectively) and nausea (3% and 2%, respectively) (6.1). The most common adverse reactions in FLECTOR treated pediatric patients were headache (9%) and application site pruritus (7%) (6.1) To report SUSPECTED ADVERSE REACTIONS, contact IBSA Pharma Inc. at 1-800-587-3513 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly using FLECTOR with drugs that interfere with hemostasis. Concomitant use of FLECTOR and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with FLECTOR may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with FLECTOR in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with FLECTOR may increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of FLECTOR in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482831 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Special Precautions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Accidental Exposure in Children 5.16 Eye Exposure 5.17 Oral Nonsteroidal Anti-inflammatory Drugs 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Strains, Sprains, and Contusions 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482831 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • FLECTOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE FLECTOR® is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions in adults and pediatric patients 6 years and older. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. The recommended dose of FLECTOR is one (1) topical system to the most painful area twice a day both in adults and pediatric patients 6 years of age and older. 2.2 Special Precautions • Inform patients that, if FLECTOR begins to peel-off, the edges of the topical system may be taped down. If problems with adhesion persist, patients may overlay the topical system with a mesh netting sleeve, where appropriate (e.g., to secure topical systems applied to ankles, knees, or elbows). The mesh netting sleeve (e.g., Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non breathable). • Do not apply FLECTOR to non-intact or damaged skin resulting from any etiology e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. • Do not wear a FLECTOR when bathing or showering. • Wash your hands after applying, handling or removing the topical system. • Avoid eye contact. • Do not use combination therapy with FLECTOR and an oral NSAID unless the benefit Reference ID: 5482831 outweighs the risk and conduct periodic laboratory evaluations. 3 DOSAGE FORMS AND STRENGTHS FLECTOR is a 10 cm x 14 cm topical system that contains 1.3% diclofenac epolamine, and is debossed with “FLECTOR® (DICLOFENAC EPOLAMINE) TOPICAL SYSTEM 1.3%.” 4 CONTRAINDICATIONS FLECTOR is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] • FLECTOR is contraindicated for use on non-intact or damaged skin resulting from any etiology, including exudative dermatitis, eczema, infection lesions, burns or wounds. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in Reference ID: 5482831 the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100-person years in NSAID-treated patients compared to 12 per 100-person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of FLECTOR in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If FLECTOR is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-Treated Patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue FLECTOR until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor Reference ID: 5482831 patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), FLECTOR should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue FLECTOR immediately, and perform a clinical evaluation of the patient. Reference ID: 5482831 To minimize the potential risk for an adverse liver related event in patients treated with FLECTOR, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing FLECTOR with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics). 5.4 Hypertension NSAIDs, including FLECTOR, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of FLECTOR in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If FLECTOR is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of FLECTOR in patients with advanced renal disease. The renal effects of FLECTOR may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating FLECTOR. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of FLECTOR [see Drug Interactions (7)]. Avoid the use of FLECTOR in patients with advanced renal disease unless the benefits are expected to Reference ID: 5482831 outweigh the risk of worsening renal function. If FLECTOR is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, FLECTOR is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When FLECTOR is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of FLECTOR at the first appearance of skin rash or any other sign of hypersensitivity. FLECTOR is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as FLECTOR. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue FLECTOR and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including FLECTOR, in pregnant women at about 30 weeks gestation Reference ID: 5482831 and later. NSAIDs, including FLECTOR, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including FLECTOR, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit FLECTOR use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if FLECTOR treatment extends beyond 48 hours. Discontinue FLECTOR if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with FLECTOR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including FLECTOR, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of FLECTOR in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Accidental Exposure in Children Even a used FLECTOR contains a large amount of diclofenac epolamine (as much as 170 mg). The potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used FLECTOR. It is important for patients to store and dispose of FLECTOR out of the reach of children and pets. 5.16 Eye Exposure Avoid contact of FLECTOR with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. Reference ID: 5482831 5.17 Oral Nonsteroidal Anti-inflammatory Drugs Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use combination therapy with FLECTOR and an oral NSAID unless the benefit outweighs the risk. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Clinical Trials Experience In controlled trials during the premarketing development of FLECTOR, approximately 600 patients with minor strains, sprains, and contusions were treated with FLECTOR for up to two weeks. Adverse Events Leading to Discontinuation of Treatment In the controlled trials, 3% of patients in both the FLECTOR and placebo groups discontinued treatment due to an adverse event. The most common adverse events leading to discontinuation were application site reactions, occurring in 2% of both the FLECTOR and placebo groups. Application site reactions leading to dropout included pruritus, dermatitis, and burning. Common Adverse Events Overall, the most common adverse events associated with FLECTOR treatment were skin reactions at the site of treatment. Table 1 lists all adverse events, regardless of causality, occurring in ≥ 1% of patients in controlled trials of FLECTOR. A majority of patients treated with FLECTOR had adverse events with a maximum intensity of “mild” or “moderate.” Reference ID: 5482831 Table 1. Common Adverse Events (by body system and preferred term) in ≥ 1% of Patients treated with FLECTOR or Placebo 1 Diclofenac Placebo Category N=572 N=564 N Percent N Percent Application Site Conditions 64 11 70 12 Pruritus 31 5 44 8 Dermatitis 9 2 3 <1 Burning 2 <1 8 1 Other2 22 4 15 3 Gastrointestinal Disorders 49 9 33 6 Nausea 17 3 11 2 Dysgeusia 10 2 3 <1 Dyspepsia 7 1 8 1 Other3 15 3 11 2 Nervous System Disorders 13 2 18 3 Headache 7 1 10 2 Paresthesia 6 1 8 1 Somnolence 4 1 6 1 Other 4 4 1 3 <1 1 The table lists adverse events occurring in placebo-treated patients because the placebo was comprised of the same ingredients as FLECTOR except for diclofenac. Adverse events in the placebo group may therefore reflect effects of the non-active ingredients. 2 Includes: application site dryness, irritation, erythema, atrophy, discoloration, hyperhidriosis, and vesicles. 3 Includes: gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth. 4 Includes: hypoesthesia, dizziness, and hyperkinesias. Foreign labeling describes that dermal allergic reactions may occur with FLECTOR treatment. Additionally, the treated area may become irritated or develop itching, erythema, edema, vesicles, or abnormal sensation. Pediatric Clinical Trials Experience In one open-label trial, 104 male and female pediatric patients 6 years and older presenting with minor strains, sprains, and contusions received FLECTOR twice a day for as many as 16 days. The most commonly reported adverse events (incidence ≥ 2%) were headache (9%), application site pruritus (7%), nausea (3%), and dyspepsia (3%). No adverse events led to discontinuation of treatment. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of diclofenac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Reference ID: 5482831 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of FLECTOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of FLECTOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. FLECTOR is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of FLECTOR and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of FLECTOR and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Reference ID: 5482831 Drugs That Interfere with Hemostasis Intervention: During concomitant use of FLECTOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of FLECTOR and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of FLECTOR and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of FLECTOR and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of FLECTOR and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of FLECTOR and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of FLECTOR and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of FLECTOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Reference ID: 5482831 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including FLECTOR, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of FLECTOR use between about 20 and 30 weeks of gestation, and avoid FLECTOR use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including FLECTOR, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, diclofenac epolamine administered orally to pregnant rats and rabbits during the period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from the maximum recommended human dose (MRHD) of FLECTOR. In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose. Diclofenac epolamine administered orally to both male and female rats prior to mating and throughout the mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including FLECTOR, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment Reference ID: 5482831 --- If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If FLECTOR treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue FLECTOR and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 15. Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 18. No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 7 times the maximum recommended daily exposure in humans based on a body surface area comparison. Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3 times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight. Reference ID: 5482831 8.2 Lactation Risk Summary Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk (see Data). There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLECTOR and any potential adverse effects on the breastfed infant from the FLECTOR or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). The relative bioavailability for FLECTOR is <1% of a single 50 mg diclofenac tablet. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FLECTOR may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including FLECTOR, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of FLECTOR have been established in pediatric patients 6 years and older based on evidence from adequate and well-controlled studies with FLECTOR in adults, as well as an open-label study in pediatric patients 6 years and older. The pediatric study enrolled 104 patients, 6 years of age and older with minor soft tissue injuries. One FLECTOR was applied to the injury site twice daily for a maximum of 14 days or until treatment was no longer required for pain management, whichever occurred first. Based on the available data from the pediatric study, the safety profile of FLECTOR topical system in pediatric patients is similar to that in adults. The safety and effectiveness of FLECTOR has not been investigated in pediatric patients less than 6 years old. [see Clinical Trials Experience (6.1), Clinical Pharmacology (12.3)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Clinical studies of FLECTOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Reference ID: 5482831 EPOLAMINE Cv 2-(pyrrolidin-1-yl)r.:thanol N+ I CH2-CH2-OH 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION FLECTOR (diclofenac epolamine) topical system 1.3% is a nonsteroidal anti-inflammatory drug for topical application. FLECTOR is a 10 cm x 14 cm topical system comprised of an adhesive material containing 1.3% diclofenac epolamine which is applied to a non-woven polyester felt backing and covered with a polypropylene film release liner. The release liner is removed prior to topical application to the skin. The chemical name of diclofenac epolamine is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, (2-(pyrrolidin-1-yl) ethanol salt, with a molecular formula of C20H24Cl2N2O3, and molecular weight 411.3, an n-octanol/water partition coefficient of 8 at pH 8.5, and the following chemical structure: Each adhesive FLECTOR topical system contains 180 mg of diclofenac epolamine (13 mg per gram adhesive) in an aqueous base. It also contains the following inactive ingredients: butylene glycol, carboxymethylcellulose sodium, dihydroxyaluminum aminoacetate, edetate disodium, fragrance (Dalin PH), gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium polyacrylate, sorbitol solution, tartaric acid, titanium dioxide, and purified water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionDiclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Reference ID: 5482831 12.2 Pharmacodynamics FLECTOR applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin. 12.3 Pharmacokinetics Absorption - Adults Following a single application of the FLECTOR on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application. Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day FLECTOR application. Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with FLECTOR, were lower (<1%) than after a single oral 50-mg diclofenac sodium tablet. The pharmacokinetics of FLECTOR has been tested in healthy volunteers at rest or undergoing moderate exercise (cycling 20 min/h for 12 h at a mean HR of 100.3 bpm). No clinically relevant differences in systemic absorption were observed, with peak plasma concentrations in the range of 2.2 – 8.1 ng/mL while resting, and 2.7 – 7.2 ng/mL during exercise. Absorption – Pediatrics Diclofenac plasma concentration was assessed in pediatric patients 6 years and older at a fixed time point 24-hours after the initial application and at the final visit (Day 3 – 15). The resulting average concentrations were 1.65 ng/mL and 1.80 ng/mL, respectively, both of which are similar to the values observed in adults. Distribution Diclofenac has a very high affinity (>99%) for human serum albumin. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses, and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Elimination Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac. Excretion The plasma elimination half-life of diclofenac after application of FLECTOR is approximately 12 hours. Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in Reference ID: 5482831 the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Specific Populations The pharmacokinetics of FLECTOR has not been investigated in children less than 6 years old, patients with hepatic or renal impairment, or specific racial groups. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or FLECTOR. Mutagenesis Diclofenac epolamine is not mutagenic in Salmonella typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats. Impairment of Fertility Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation). Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and post- implantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. 14 CLINICAL STUDIES 14.1 Strains, Sprains, and Contusions Efficacy of FLECTOR was demonstrated in two of four studies of patients with minor strains, sprains, and contusions. Patients were randomly assigned to treatment with the FLECTOR, or a placebo identical to the FLECTOR minus the active ingredient. In the first of these two studies, patients with ankle sprains were treated once daily for a week. In the second study, patients with strains, sprains, and contusions were treated twice daily for up to two weeks. Pain was assessed over the period of treatment. Patients treated with the FLECTOR experienced a greater reduction in pain as compared to patients randomized to placebo as evidenced by the responder curves presented below (Figures 1-4). Reference ID: 5482831 1 !; I o.; '15 c ~ 8!. .,, !!! e C. _§ ~ iii -~ ll. 0 c .. ~ ll. 100 90 .,, 80 Q) i; 0. 70 j; ., 60 c .S! 50 ;;; ll. 'o 40 i " 30 cf 20 10 0 10 100 90 1=Clclmerw£~1 BO 70 ~ 00 50 40 3) 20 10 0 10 20 3) 40 50 00 70 BO Peroent Improvement from Baselire 100 90 80 70 60 so 40 30 20 10 • • • Dicio'enac Patch E-------B----B Placebo 0 10 20 30 40 50 60 70 80 Percent Improvement from Baseline ........ Diclofenac Patch -8-H---B Placebo 20 30 40 50 70 80 Percent Improvement from Baseline 90 90 90 100 100 100 Figure 1: Patients Achieving Various Levels of Pain Relief at Day 3; 14-Day Study Figure 2: Patients Achieving Various Levels of Pain Relief at End of Study; 14-Day Study Figure 3: Patients Achieving Various Levels of Pain Relief at Day 3; 7-Day Study Reference ID: 5482831 100 90 .,, ., > 80 2 C. .E 70 .l!l 60 C ., .,, 50 il:: 0 40 'E ., " 30 16 a. 20 10 ------ Diclofenac Patch fr---B--E- Placebo 0 10 20 30 40 50 60 70 BO 90 100 Percent Improvement from Baseline Figure 4: Patients Achieving Various Levels of Pain Relief at End of Study; 7-Day Study 16 HOW SUPPLIED/STORAGE AND HANDLING FLECTOR (diclofenac epolamine) topical system is supplied in resealable envelopes, each containing 5 topical systems (10 cm x 14 cm), with 6 envelopes per box (NDC 71858-0405-5). Each FLECTOR is debossed with “FLECTOR® (DICLOFENAC EPOLAMINE) TOPICAL SYSTEM 1.3%”. • The product is intended for topical use only. • Keep out of reach of children and pets. • Envelopes should be sealed at all times when not in use. • Curad® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc. Storage Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with FLECTOR and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” Reference ID: 5482831 symptoms). If these occur, instruct patients to stop FLECTOR and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions including DRESS Advise patients to stop using FLECTOR immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.10, 5.9)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including FLECTOR, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3)] Fetal Toxicity Inform pregnant women to avoid use of FLECTOR and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with FLECTOR is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of FLECTOR with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with FLECTOR until they talk to their healthcare provider [see Drug Interactions (7)]. Eye Exposure Instruct patients to avoid contact of FLECTOR with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions (5.16)]. Special Application Instructions • Instruct patients that, if FLECTOR begins to peel-off, the edges of the topical system may be taped down. If problems with adhesion persist, patients may overlay the topical system with a mesh netting sleeve, where appropriate (e.g., to secure topical system applied to ankles, knees, or elbows). The mesh netting sleeve (e.g., Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non- Reference ID: 5482831 breathable). • Instruct patients not to apply FLECTOR to non-intact or damaged skin resulting from any etiology e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. • Instruct patients not to wear a FLECTOR when bathing or showering. • Instruct patients to wash hands after applying, handling or removing FLECTOR. Manufacturer: Altergon Italia Srl, Zona Industriale ASI, Morra de Sanctis, Avellino 83040, Italy (ITA) Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland Distributed by: IBSA Pharma Inc., Parsippany, NJ 07054 USA FLECTOR is a registered trademark of IBSA Institut Biochimique SA. Reference ID: 5482831 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) Reference ID: 5482831 • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: •shortness of breath or trouble breathing •slurred speech •chest pain •swelling of the face or throat •weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: •nausea • vomit blood •more tired or weaker than usual • there is blood in your bowel movement or •diarrhea it is black and sticky like tar •itching • unusual weight gain •your skin or eyes look yellow • skin rash or blisters with fever •indigestion or stomach pain • swelling of the arms, legs, hands and •flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID, but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufacturer: Altergon Italia Srl, Avellino 83040, Italy (ITA) Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland Distributed by: IBSA Pharma Inc., Parsippany, NJ 07054 USA For more information, go to www.Flector.com or call 1-800-587-3513 FLECTOR is a registered trademark of IBSA Institut Biochimique SA. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 07/2023 Reference ID: 5482831	custom-source	2025-02-12T15:47:10.287757	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021234s024lbl.pdf', 'application_number': 21234, 'submission_type': 'SUPPL ', 'submission_number': 24}
80,382	HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ---------------------- These highlights do not include all the information needed to use CELEBREX safely and effectively. See full prescribing information for CELEBREX. CELEBREX® (celecoxib) capsules, for oral use Initial U.S. Approval: 1998 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. (5.1) • CELEBREX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) -------------------------- RECENT MAJOR CHANGES -------------------------- Warnings and Precautions (5.9) 11/2024 --------------------------- INDICATIONS AND USAGE -------------------------- CELEBREX is a nonsteroidal anti-inflammatory drug indicated for: • Osteoarthritis (OA) (1.1) • Rheumatoid Arthritis (RA) (1.2) • Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older (1.3) • Ankylosing Spondylitis (AS) (1.4) • Acute Pain (AP) (1.5) • Primary Dysmenorrhea (PD) (1.6) ----------------------- DOSAGE AND ADMINISTRATION --------------------- • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2.1) • OA: 200 mg once daily or 100 mg twice daily. (2.2, 14.1) • RA: 100 mg to 200 mg twice daily. (2.3, 14.2) • JRA: 50 mg twice daily in patients 10 kg to 25 kg. 100 mg twice daily in patients more than 25 kg. (2.4, 14.3) • AS: 200 mg once daily single dose or 100 mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg (single or divided doses) may be of benefit. (2.5, 14.4) • AP and PD: 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily as needed. (2.6, 14.5) Hepatic Impairment: Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B). (2.7, 8.6, 12.3) Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers. (2.7, 8.8, 12.3) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- CELEBREX (celecoxib) capsules: 50 mg, 100 mg, 200 mg, and 400 mg (3) ----------------------------- CONTRAINDICATIONS ----------------------------- • Known hypersensitivity to celecoxib, or any components of the drug product or sulfonamides. (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. (4) • In the setting of CABG surgery. (4) • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4, 7) • Heart Failure and Edema: Avoid use of CELEBREX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of CELEBREX in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: CELEBREX is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) • Serious Skin Reactions: Discontinue CELEBREX at first appearance of skin rash or other signs of hypersensitivity. (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.10) • Fetal Toxicity: Limit use of NSAIDs, including CELEBREX, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12, 7) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions in arthritis trials (>2% and >placebo) are: abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1 877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking CELEBREX with drugs that interfere with hemostasis. Concomitant use of CELEBREX and analgesic doses of aspirin is not generally recommended. (7) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with CELEBREX may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) • ACE Inhibitors and ARBs: Concomitant use with CELEBREX in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) • Digoxin: Concomitant use with CELEBREX can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of CELEBREX in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482829 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 1.1 Osteoarthritis (OA) 1.2 Rheumatoid Arthritis (RA) 1.3 Juvenile Rheumatoid Arthritis (JRA) 1.4 Ankylosing Spondylitis (AS) 1.5 Acute Pain 1.6 Primary Dysmenorrhea 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Osteoarthritis 2.3 Rheumatoid Arthritis 2.4 Juvenile Rheumatoid Arthritis 2.5 Ankylosing Spondylitis 2.6 Management of Acute Pain and Treatment of Primary Dysmenorrhea 2.7 Special Populations 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Disseminated Intravascular Coagulation (DIC) 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Poor Metabolizers of CYP2C9 Substrates 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology 14 CLINICAL STUDIES 14.1 Osteoarthritis 14.2 Rheumatoid Arthritis 14.3 Juvenile Rheumatoid Arthritis (NCT00652925) 14.4 Ankylosing Spondylitis 14.5 Analgesia, Including Primary Dysmenorrhea 14.6 Cardiovascular Outcomes Trial: Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION; NCT00346216) 14.7 Special Studies 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482829 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • CELEBREX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE CELEBREX is indicated 1.1 Osteoarthritis (OA) For the management of the signs and symptoms of OA [see Clinical Studies (14.1)]. 1.2 Rheumatoid Arthritis (RA) For the management of the signs and symptoms of RA [see Clinical Studies (14.2)]. 1.3 Juvenile Rheumatoid Arthritis (JRA) For the management of the signs and symptoms of JRA in patients 2 years and older [see Clinical Studies (14.3)]. 1.4 Ankylosing Spondylitis (AS) For the management of the signs and symptoms of AS [see Clinical Studies (14.4)]. 1.5 Acute Pain For the management of acute pain in adults [see Clinical Studies (14.5)]. Reference ID: 5482829 1.6 Primary Dysmenorrhea For the management of primary dysmenorrhea [see Clinical Studies (14.5)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of CELEBREX and other treatment options before deciding to use CELEBREX. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. These doses can be given without regard to timing of meals. 2.2 Osteoarthritis For OA, the dosage is 200 mg per day administered as a single dose or as 100 mg twice daily. 2.3 Rheumatoid Arthritis For RA, the dosage is 100 mg to 200 mg twice daily. 2.4 Juvenile Rheumatoid Arthritis For JRA, the dosage for pediatric patients (age 2 years and older) is based on weight. For patients ≥10 kg to ≤25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is 100 mg twice daily. For patients who have difficulty swallowing capsules, the contents of a CELEBREX capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2°C to 8°C/35°F to 45°F). 2.5 Ankylosing Spondylitis For AS, the dosage of CELEBREX is 200 mg daily in single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options. 2.6 Management of Acute Pain and Treatment of Primary Dysmenorrhea For management of Acute Pain and Treatment of Primary Dysmenorrhea, the dosage is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed. Reference ID: 5482829 2.7 Special Populations Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh Class B), reduce the dose by 50%. The use of CELEBREX in patients with severe hepatic impairment is not recommended [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Poor Metabolizers of CYP2C9 Substrates In adult patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin), initiate treatment with half of the lowest recommended dose. In patients with JRA who are known or suspected to be poor CYP2C9 metabolizers, consider using alternative treatments [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.5)]. 3 DOSAGE FORMS AND STRENGTHS CELEBREX (celecoxib) capsules: • 50 mg white, with reverse printed white on red band of body and cap with markings of 7767 on the cap and 50 on the body. • 100 mg white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body. • 200 mg white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body. • 400 mg white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the body. 4 CONTRAINDICATIONS CELEBREX is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product [see Warnings and Precautions (5.7, 5.9)]. • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]. • In the setting of CABG surgery [see Warnings and Precautions (5.1)]. • In patients who have demonstrated allergic-type reactions to sulfonamides [see Warnings and Precautions (5.7)]. Reference ID: 5482829 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the CELEBREX 400 mg twice daily and CELEBREX 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies (14.7)]. A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists’ Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke [see Clinical Studies (14.6)]. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial Reference ID: 5482829 infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of CELEBREX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If CELEBREX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including celecoxib cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with CELEBREX. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [see Clinical Studies (14.7)]. Strategies to Minimize the GI Risks in NSAID-treated Patients: Reference ID: 5482829 • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue CELEBREX until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including celecoxib. In controlled clinical trials of CELEBREX, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for CELEBREX and 5% for placebo, and approximately 0.2% of patients taking CELEBREX and 0.3% of patients taking placebo had notable elevations of ALT and AST. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), discontinue CELEBREX immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including CELEBREX, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. See Clinical Studies (14.6, 14.7) for additional blood pressure data for CELEBREX. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Reference ID: 5482829 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of celecoxib may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. In the CLASS study [see Clinical Studies (14.7)], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. Avoid the use of CELEBREX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If CELEBREX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of CELEBREX in patients with advanced renal disease. The renal effects of CELEBREX may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating CELEBREX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of CELEBREX [see Drug Interactions (7)]. Avoid the use of CELEBREX in patients with advanced renal disease unless the benefits are expected to outweigh Reference ID: 5482829 the risk of worsening renal function. If CELEBREX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. CELEBREX is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if any anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, CELEBREX is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When CELEBREX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions Serious skin reactions have occurred following treatment with CELEBREX, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE) which may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE). These serious events may occur without warning and can be fatal. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of CELEBREX at the first appearance of skin rash or any other sign of hypersensitivity. CELEBREX is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. Reference ID: 5482829 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CELEBREX. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue CELEBREX and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including CELEBREX, in pregnant women at about 30 weeks gestation and later. NSAIDs, including CELEBREX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including CELEBREX, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit CELEBREX use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if CELEBREX treatment extends beyond 48 hours. Discontinue CELEBREX if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with CELEBREX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Reference ID: 5482829 In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long-term treatment with CELEBREX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. NSAIDs, including CELEBREX, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of CELEBREX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBREX compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. 5.15 Disseminated Intravascular Coagulation (DIC) Because of the risk of disseminated intravascular coagulation with use of CELEBREX in pediatric patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, and inform patients and their caregivers to report symptoms as soon as possible. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] Reference ID: 5482829 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Of the CELEBREX-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of CELEBREX of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received CELEBREX at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more. Pre-marketing Controlled Arthritis Trials Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving CELEBREX from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Events Occurring in ≥2% of CELEBREX Patients from Pre-marketing Controlled Arthritis Trials CBX Placebo NAP DCF IBU N=4146 N=1864 N=1366 N=387 N=345 Gastrointestinal Abdominal Pain 4.1% 2.8% 7.7% 9.0% 9.0% Diarrhea 5.6% 3.8% 5.3% 9.3% 5.8% Dyspepsia 8.8% 6.2% 12.2% 10.9% 12.8% Flatulence 2.2% 1.0% 3.6% 4.1% 3.5% Nausea 3.5% 4.2% 6.0% 3.4% 6.7% Body as a whole Back Pain Peripheral Edema Injury-Accidental 2.8% 2.1% 2.9% 3.6% 1.1% 2.3% 2.2% 2.1% 3.0% 2.6% 1.0% 2.6% 0.9% 3.5% 3.2% Central, Peripheral Nervous system Dizziness Headache 2.0% 15.8% 1.7% 20.2% 2.6% 14.5% 1.3% 15.5% 2.3% 15.4% Psychiatric Insomnia 2.3% 2.3% 2.9% 1.3% 1.4% Respiratory Pharyngitis 2.3% 1.1% 1.7% 1.6% 2.6% Reference ID: 5482829 Rhinitis Sinusitis Upper Respiratory Infection 2.0% 5.0% 8.1% 1.3% 4.3% 6.7% 2.4% 4.0% 9.9% 2.3% 5.4% 9.8% 0.6% 5.8% 9.9% Skin Rash 2.2% 2.1% 2.1% 1.3% 1.2% CBX = CELEBREX 100 mg to 200 mg twice daily or 200 mg once daily; NAP = Naproxen 500 mg twice daily; DCF = Diclofenac 75 mg twice daily; IBU = Ibuprofen 800 mg three times daily. In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving CELEBREX and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain. The following adverse reactions occurred in 0.1% to 1.9% of patients treated with CELEBREX (100 mg to 200 mg twice daily or 200 mg once daily): Gastrointestinal: Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction General: Hypersensitivity, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain Central, peripheral nervous system: Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo Hearing and vestibular: Deafness, tinnitus Heart rate and rhythm: Palpitation, tachycardia Liver and biliary: Hepatic enzyme increased (including SGOT increased, SGPT increased) Metabolic and nutritional: blood urea nitrogen (BUN) increased, creatine phosphokinase (CPK) increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased Musculoskeletal: Arthralgia, arthrosis, myalgia, synovitis, tendinitis Platelets (bleeding or clotting): Ecchymosis, epistaxis, thrombocythemia Psychiatric: Anorexia, anxiety, appetite increased, depression, nervousness, somnolence Hemic: Anemia Respiratory: Bronchitis, bronchospasm, bronchospasm aggravated, cough, dyspnea, laryngitis, pneumonia Skin and appendages: Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria Application site disorders: Cellulitis, dermatitis contact Urinary: Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus The following serious adverse events (causality not evaluated) occurred in <0.1% of patients: Reference ID: 5482829 Cardiovascular: Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis Gastrointestinal: Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus General: Sepsis, sudden death Liver and biliary: Cholelithiasis Hemic and lymphatic: Thrombocytopenia Nervous: Ataxia, suicide [see Drug Interactions (7)] Renal: Acute renal failure The Celecoxib Long-Term Arthritis Safety Study [see Clinical Studies (14.7)] Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on CELEBREX 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with CELEBREX was maintained with or without aspirin use [see Clinical Pharmacology (12.2)]. Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for CELEBREX, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively). Juvenile Rheumatoid Arthritis Study In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea, and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups. In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg twice daily. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged. Reference ID: 5482829 Table 2: Adverse Events Occurring in ≥5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with events) All Doses Twice Daily Celecoxib Celecoxib Naproxen System Organ Class 3 mg/kg 6 mg/kg 7.5 mg/kg Preferred Term N=77 N=82 N=83 Any Event 64 70 72 Eye Disorders 5 5 5 Gastrointestinal 26 24 36 Abdominal pain NOS 4 7 7 Abdominal pain upper 8 6 10 Vomiting NOS 3 6 11 Diarrhea NOS 5 4 8 Nausea 7 4 11 General 13 11 18 Pyrexia 8 9 11 Infections 25 20 27 Nasopharyngitis 5 6 5 Injury and Poisoning 4 6 5 Investigations* 3 11 7 Musculoskeletal 8 10 17 Arthralgia 3 7 4 Nervous System 17 11 21 Headache NOS 13 10 16 Dizziness (excl vertigo) 1 1 7 Respiratory 8 15 15 Cough 7 7 8 Skin & Subcutaneous 10 7 18 * Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis abnormal NOS Other Pre-Approval Studies Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with CELEBREX in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RA studies. Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with CELEBREX in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of CELEBREX were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in Reference ID: 5482829 arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. The APC and PreSAP Trials Adverse Reactions from Long-term, Placebo-controlled Polyp Prevention Studies: Exposure to CELEBREX in the APC and PreSAP trials was 400 mg to 800 mg daily for up to 3 years [see Clinical Studies (14.7)]. Some adverse reactions occurred in higher percentages of patients than in the arthritis pre marketing trials (treatment durations up to 12 weeks; see Adverse events from CELEBREX pre marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with CELEBREX were greater as compared to the arthritis pre-marketing trials were as follows: CELEBREX (400 to 800 mg daily) Placebo N = 2285 N=1303 Diarrhea 10.5% 7.0% Gastroesophageal reflux disease 4.7% 3.1% Nausea 6.8% 5.3% Vomiting 3.2% 2.1% Dyspnea 2.8% 1.6% Hypertension 12.5% 9.8% Nephrolithiasis 2.1% 0.8% The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking CELEBREX, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies: Nervous system disorders: Cerebral infarction Eye disorders: Vitreous floaters, conjunctival hemorrhage Ear and labyrinth: Labyrinthitis Cardiac disorders: Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy Vascular disorders: Deep vein thrombosis Reproductive system and breast disorders: Ovarian cyst Investigations: Blood potassium increased, blood sodium increased, blood testosterone decreased Injury, poisoning, and procedural complications: Epicondylitis, tendon rupture 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of CELEBREX. Because these reactions are reported voluntarily from a population of uncertain size, it is not Reference ID: 5482829 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Cardiovascular: Vasculitis, deep venous thrombosis General: Anaphylactoid reaction, angioedema Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure Hemic and lymphatic: Agranulocytosis, aplastic anemia, pancytopenia, leucopenia Metabolic: Hypoglycemia, hyponatremia Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage Renal: Interstitial nephritis Skin and Appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE) 7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with celecoxib. Table 3: Clinically Significant Drug Interactions with Celecoxib Drugs that Interfere with Hemostasis Clinical Impact: • Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of CELEBREX with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 mg to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 mg to 325 mg). Reference ID: 5482829 Intervention: Concomitant use of CELEBREX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. CELEBREX is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of CELEBREX and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of CELEBREX and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of CELEBREX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of CELEBREX and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of CELEBREX and lithium, monitor patients for signs of lithium toxicity. Reference ID: 5482829 Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). CELEBREX has no effect on methotrexate pharmacokinetics. Intervention: During concomitant use of CELEBREX and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of CELEBREX and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of CELEBREX and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of CELEBREX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of CELEBREX and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or Inducers Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of celecoxib. Intervention: Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when Reference ID: 5482829 celecoxib is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3)]. CYP2D6 substrates Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. Intervention: Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [see Clinical Pharmacology (12.3)]. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with CELEBREX may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of CELEBREX with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including CELEBREX, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of CELEBREX use between about 20 and 30 weeks of gestation and avoid CELEBREX use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including CELEBREX, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 Reference ID: 5482829 times the maximum recommended human dose (MRHD) of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including CELEBREX, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If CELEBREX treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue CELEBREX and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of CELEBREX during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data The available data do not establish the presence or absence of developmental toxicity related to the use of CELEBREX. Reference ID: 5482829 Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human exposure based on the AUC0-24 at 200 mg twice daily for RA) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the AUC0-24 at 200 mg twice daily for RA). Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC0-24 at 200 mg twice daily). The effects of CELEBREX on labor and delivery in pregnant women are unknown. 8.2 Lactation Risk Summary Reference ID: 5482829 Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of CELEBREX in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when CELEBREX is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CELEBREX and any potential adverse effects on the breastfed infant from the CELEBREX or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including CELEBREX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including CELEBREX, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use CELEBREX is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to CELEBREX has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to CELEBREX or other COX-2 selective and non-selective NSAIDs [see Boxed Warning, Warnings and Precautions (5.5), and Clinical Studies (14.3)]. The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). When NSAIDs including celecoxib are used in patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [see Dosage and Administration (2.4), Warnings and Precautions (5.15), Adverse Reactions (6.1), Animal Toxicology (13.2), Clinical Studies (14.3)]. Reference ID: 5482829 Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [see Poor Metabolizers of CYP2C9 Substrates (8.8)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Of the total number of patients who received CELEBREX in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post- marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see Warnings and Precautions (5.2, 5.6)]. 8.6 Hepatic Impairment The daily recommended dose of CELEBREX capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of CELEBREX in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment CELEBREX is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. 8.8 Poor Metabolizers of CYP2C9 Substrates In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C93/3), based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) administer CELEBREX starting with half the lowest recommended dose. Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers [see Dosage and Administration (2.7) and Clinical Pharmacology (12.5)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, Reference ID: 5482829 respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.2, 5.4, 5.6)]. No overdoses of CELEBREX were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800 222-1222). 11 DESCRIPTION CELEBREX (celecoxib) capsule is a nonsteroidal anti-inflammatory drug, available as capsules containing 50 mg, 100 mg, 200 mg and 400 mg celecoxib for oral administration. The chemical name is 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The molecular weight is 381.38. Its molecular formula is C17H14F3N3O2S, and it has the following chemical structure: CH3 N N CF3 S NH2 O O Celecoxib is a white to off-white powder with a pKa of 11.1 (sulfonamide moiety). Celecoxib is hydrophobic (log P is 3.5) and is practically insoluble in aqueous media at physiological pH range. The inactive ingredients in CELEBREX include: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Reference ID: 5482829 Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of COX-2. Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Celecoxib concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics Platelets In clinical trials using normal volunteers, CELEBREX at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of CELEBREX on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of CELEBREX. Fluid Retention Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone. 12.3 Pharmacokinetics Celecoxib exhibits dose-proportional increase in exposure after oral administration up to 200 mg twice daily and less than proportional increase at higher doses. It has extensive distribution and high protein binding. It is primarily metabolized by CYP2C9 with a half-life of approximately 11 hours. Absorption Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose- proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in Cmax and AUC (see Food Effects). Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before Day 5. The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 4. Reference ID: 5482829 Table 4. Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects1 Mean (%CV) PK Parameter Values Cmax, ng/mL Tmax, hr Effective t1/2, hr Vss/F, L CL/F, L/hr 705 (38) 2.8 (37) 11.2 (31) 429 (34) 27.7 (28) 1Subjects under fasting conditions (n=36, 19-52 yrs.) Food Effects When CELEBREX capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. Coadministration of CELEBREX with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. CELEBREX, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption. In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t1/2 after administration of capsule contents on applesauce [see Dosage and Administration (2)]. Distribution In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells. Elimination Metabolism Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Excretion Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. Reference ID: 5482829 The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min. Specific Populations Geriatric At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose [see Use in Specific Populations (8.5)]. Pediatric The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 JRA patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient. Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non-inferiority of celecoxib to naproxen 7.5 mg/kg twice daily [see Dosage and Administration (2.4)]. Celecoxib has not been studied in JRA patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks. Race Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown. Hepatic Impairment A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the daily recommended dose of CELEBREX capsules should be reduced by approximately 50% in Reference ID: 5482829 patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBREX in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.7) and Use in Specific Populations (8.6)]. Renal Impairment In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, CELEBREX is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.6)]. Drug Interaction Studies In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. In vivo studies have shown the following: Aspirin When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Lithium In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with CELEBREX 200 mg twice daily as compared to subjects receiving lithium alone [see Drug Interactions (7)]. Fluconazole Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole [see Drug Interactions (7)]. Other Drugs The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, [see Drug Interactions (7)], phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found. 12.5 Pharmacogenomics Reference ID: 5482829 CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C92 and CYP2C93 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C93/3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C91/1 or I/3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 2, 5, 6, 9 and 11. It is estimated that the frequency of the homozygous 3/3 genotype is 0.3% to 1.0% in various ethnic groups [see Dosage and Administration (2.7), Use in Specific Populations (8.8)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Celecoxib was not carcinogenic in Sprague-Dawley rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 2- to 4-times the human exposure as measured by the AUC0-24 at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to human exposure as measured by the AUC0-24 at 200 mg twice daily) for two years. Mutagenesis Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow. Impairment of Fertility Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day (approximately 11-times human exposure at 200 mg twice daily based on the AUC0-24). At ≥50 mg/kg/day (approximately 6-times human exposure based on the AUC0-24 at 200 mg twice daily) there was increased preimplantation loss. 13.2 Animal Toxicology An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown. Reference ID: 5482829 14 CLINICAL STUDIES 14.1 Osteoarthritis CELEBREX has demonstrated significant reduction in joint pain compared to placebo. CELEBREX was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with CELEBREX 100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, CELEBREX doses of 100 mg twice daily and 200 mg twice daily provided significant reduction of pain within 24 to 48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the effectiveness of CELEBREX was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily. 14.2 Rheumatoid Arthritis CELEBREX has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. CELEBREX was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. CELEBREX was shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. CELEBREX doses of 100 mg twice daily and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg twice daily. Although CELEBREX 100 mg twice daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100 mg to 200 mg twice daily. 14.3 Juvenile Rheumatoid Arthritis (NCT00652925) In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non- inferiority study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or systemic onset JRA (with currently inactive systemic features), received one of the following treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib 6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80% and 67% in the celecoxib 3 mg/kg twice daily, celecoxib 6 mg/kg twice daily, and naproxen 7.5 mg/kg twice daily treatment groups, respectively. Reference ID: 5482829 The efficacy and safety of CELEBREX for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to CELEBREX has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to CELEBREX or other COX-2 selective and non-selective NSAIDs [see Boxed Warning, Warnings and Precautions (5.1, 5.15)]. 14.4 Ankylosing Spondylitis CELEBREX was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. CELEBREX at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg CELEBREX doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to CELEBREX 400 mg, 53%, than to CELEBREX 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 mm to 100 mm scale, in at least three of the four following domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks. 14.5 Analgesia, Including Primary Dysmenorrhea In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, CELEBREX relieved pain that was rated by patients as moderate to severe. Single doses [see Dosage and Administration (2.6)] of CELEBREX provided pain relief within 60 minutes. 14.6 Cardiovascular Outcomes Trial: Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION; NCT00346216) Design The PRECISION trial was a double-blind randomized controlled trial of cardiovascular safety in OA and RA patients with or at high risk for cardiovascular disease comparing celecoxib with naproxen and ibuprofen. Patients were randomized to a starting dose of 100 mg twice daily of celecoxib, 600 mg three times daily of ibuprofen, or 375 mg twice daily of naproxen, with the option of escalating the dose as needed for pain management. Based on labeled doses, OA patients randomized to celecoxib could not dose escalate. The primary endpoint, the Antiplatelet Trialists’ Collaboration (APTC) composite, was an independently adjudicated composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke with 80% power to evaluate non-inferiority. Reference ID: 5482829 All patients were prescribed open-label esomeprazole (20-40 mg) for gastroprotection. Treatment randomization was stratified by baseline low-dose aspirin use. Additionally, there was a 4-month substudy assessing the effects of the three drugs on blood pressure as measured by ambulatory monitoring. Results Among subjects with OA, only 0.2% (17/7259) escalated celecoxib to the 200 mg twice daily dose, whereas 54.7% (3946/7208) escalated ibuprofen to 800 mg three times daily, and 54.8% (3937/7178) escalated naproxen to the 500 mg twice daily dose. Among subjects with RA, 55.7% (453/813) escalated celecoxib to the 200 mg twice daily dose, 56.5% (470/832) escalated ibuprofen to 800 mg three times daily, and 54.6% (432/791) escalated naproxen to the 500 mg twice daily dose; however, the RA population accounted for only 10% of the trial population. Because relatively few celecoxib patients overall (5.8% [470/8072]) dose-escalated to 200 mg twice daily, the results of the PRECISION trial are not suitable for determining the relative CV safety of celecoxib at 200 mg twice daily compared to ibuprofen and naproxen at the doses taken. Primary Endpoint The trial had two prespecified analysis populations: • Intent-to-treat population (ITT): Comprised of all randomized subjects followed for a maximum of 30 months • Modified Intent-to-treat population (mITT): Comprised of all randomized subjects who received at least one dose of study medication and had at least one post-baseline visit followed until the earlier of treatment discontinuation plus 30 days, or 43 months Celecoxib, at the 100 mg twice daily dose, as compared with either naproxen or ibuprofen at the doses taken, met all four prespecified non-inferiority criteria (p<0.001 for non-inferiority in both comparisons) for the APTC endpoint, a composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke [see Table 5]. Non- inferiority was prespecified as a hazard ratio (HR) of ≤1.12 in both ITT and mITT analyses, and upper 95% CI of ≤1.33 for ITT analysis and ≤1.40 for mITT analysis. The primary analysis results for ITT and mITT are described in Table 5. Table 5. Primary Analysis of the Adjudicated APTC Composite Endpoint Intent-To-Treat Analysis (ITT, through month 30) Celecoxib Ibuprofen Naproxen N 8,072 8,040 7,969 Subjects with Events 188 (2.3%) 218 (2.7%) 201 (2.5%) Pairwise Comparison Celecoxib vs. Naproxen Celecoxib vs. Ibuprofen Ibuprofen vs. Naproxen HR (95% CI) 0.93 (0.76, 1.13) 0.86 (0.70, 1.04) 1.08 (0.89, 1.31) Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43) Reference ID: 5482829 Celecoxib Ibuprofen Naproxen N 8,030 7,990 7,933 Subjects with Events 134 (1.7%) 155 (1.9%) 144 (1.8%) Pairwise Comparison Celecoxib vs. Naproxen Celecoxib vs. Ibuprofen Ibuprofen vs. Naproxen HR (95% CI) 0.90 (0.72, 1.14) 0.81 (0.64, 1.02) 1.12 (0.89, 1.40) Table 6. Summary of the Adjudicated APTC Components Intent-To-Treat Analysis (ITT, through month 30) Celecoxib Ibuprofen Naproxen N 8,072 8,040 7,969 CV Death 68 (0.8%) 80 (1.0%) 86 (1.1%) Non-Fatal MI 76 (0.9%) 92 (1.1%) 66 (0.8%) Non-Fatal Stroke 51 (0.6%) 53 (0.7%) 57 (0.7%) Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43) N 8,030 7,990 7,933 CV Death 35 (0.4%) 51 (0.6%) 49 (0.6%) Non-fatal MI 58 (0.7%) 76 (1.0%) 53 (0.7%) Non-fatal Stroke 43 (0.5%) 32 (0.4%) 45 (0.6%) *A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome In the ITT analysis population through 30 months, all-cause mortality was 1.6% in the celecoxib group, 1.8% in the ibuprofen group, and 2.0% in the naproxen group. Ambulatory Blood Pressure Monitoring (ABPM) Substudy In the PRECISION-ABPM substudy, among the total of 444 analyzable patients at Month 4, celecoxib dosed at 100 mg twice daily decreased mean 24-hour systolic blood pressure (SBP) by 0.3 mmHg, whereas ibuprofen and naproxen at the doses taken increased mean 24-hour SBP by 3.7 and 1.6 mmHg, respectively. These changes resulted in a statistically significant and clinically meaningful difference of 3.9 mmHg (p=0.0009) between celecoxib and ibuprofen and a non-statistically significant difference of 1.8 (p=0.119) mmHg between celecoxib and naproxen. 14.7 Special Studies Adenomatous Polyp Prevention Studies (NCT00005094 and NCT00141193) Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three- year studies involving patients with Sporadic Adenomatous Polyps treated with CELEBREX: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint (adjudicated): • In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 Reference ID: 5482829 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. • In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 - 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk. Celecoxib Long-Term Arthritis Safety Study (CLASS) This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for CELEBREX (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation, or obstruction). Patients were allowed to take concomitant low-dose (≤ 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA subgroups: CELEBREX, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between CELEBREX and the combined group of ibuprofen and diclofenac were not statistically significant. Patients on CELEBREX and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not on ASA, respectively [see Warnings and Precautions (5.4)]. The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with CELEBREX 400 mg twice daily are described in Table 7. Table 7 also displays results for patients less than or greater than 65 years of age. The difference in rates between CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users. Table 7: Complicated and Symptomatic Ulcer Rates in Patients Taking CELEBREX 400 mg Twice Daily (Kaplan-Meier Rates at 9 months [%]) Based on Risk Factors All Patients CELEBREX alone (n=3105) 0.78 CELEBREX with ASA (n=882) 2.19 Reference ID: 5482829 Patients <65 Years CELEBREX alone (n=2025) 0.47 CELEBREX with ASA (n=403) 1.26 Patients ≥65 Years CELEBREX alone (n=1080) 1.40 CELEBREX with ASA (n=479) 3.06 In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking CELEBREX alone or CELEBREX with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the CELEBREX, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree. In the CLASS study, the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. The rates of hypertension from the CLASS trial in the CELEBREX, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively. Endoscopic Studies The correlation between findings of short-term endoscopic studies with CELEBREX and the relative incidence of clinically significant serious upper GI events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving CELEBREX in controlled and open-labeled trials [see Warnings and Precautions (5.2) and Clinical Studies (14.7)]. A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking CELEBREX 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However, CELEBREX was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial [see Clinical Studies (14.7)]. The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose Reference ID: 5482829 relationship for the incidence of gastroduodenal ulcers and the dose of CELEBREX (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2% and 17.6% in the two studies, for placebo was 2.0% and 2.3%, and for all doses of CELEBREX the incidence ranged between 2.7%-5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with CELEBREX and naproxen. In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin. 16 HOW SUPPLIED/STORAGE AND HANDLING CELEBREX (celecoxib) 50 mg capsules are white, with reverse printed white on red band of body and cap with markings of 7767 on the cap and 50 on the body, supplied as: NDC Number Size 58151-082-91 bottle of 60 CELEBREX (celecoxib) 100 mg capsules are white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body, supplied as: NDC Number Size 58151-083-01 bottle of 100 58151-083-05 bottle of 500 58151-083-88 carton of 100 unit dose CELEBREX (celecoxib) 200 mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body, supplied as: NDC Number Size 58151-084-01 bottle of 100 58151-084-05 bottle of 500 58151-084-88 carton of 100 unit dose CELEBREX (celecoxib) 400 mg capsules are white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the body, supplied as: NDC Number Size 58151-085-91 bottle of 60 58151-085-88 carton of 100 unit dose Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Reference ID: 5482829 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with CELEBREX and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop CELEBREX and seek immediate medical therapy [see Warnings and Precautions (5.3), Use in Specific Populations (8.6)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, Including DRESS Advise patients to stop taking CELEBREX immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Reference ID: 5482829 • VIATR1s·· Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including CELEBREX, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of CELEBREX and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with CELEBREX is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of CELEBREX with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with CELEBREX until they talk to their healthcare provider [see Drug Interactions (7)]. Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. © 2024 Viatris Inc. CELEBREX is a registered trademark of G.D. Searle LLC, a Viatris Company. UPJ:CLBRXC:RX Revised: 11/2024 Reference ID: 5482829 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death • The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “antiplatelet drugs”, “anticoagulants”, “SSRIs” or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems • NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma Reference ID: 5482829 • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is • diarrhea black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088. Reference ID: 5482829 • VIATR1s·· Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. © 2024 Viatris Inc. CELEBREX is a registered trademark of G.D. Searle LLC, a Viatris Company. For more information, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX). This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 UPJ:MG:CLBRXC:RX Reference ID: 5482829	custom-source	2025-02-12T15:47:10.588875	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020998s058lbl.pdf', 'application_number': 20998, 'submission_type': 'SUPPL ', 'submission_number': 58}
80,386	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use meloxicam oral suspension safely and effectively. See full prescribing information for meloxicam oral suspension. Meloxicam oral suspension Initial U.S. Approval: 2004 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • Meloxicam oral suspension is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ----------------------------RECENT MAJOR CHANGES------------------------- Warnings and Precautions (5.9) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- Meloxicam oral suspension is a non-steroidal anti-inflammatory drug indicated for: • Osteoarthritis (OA) (1.1) • Rheumatoid Arthritis (RA) (1.2) • Juvenile Rheumatoid Arthritis (JRA) in patients 2 years of age or older (1.3) ----------------------DOSAGE AND ADMINISTRATION---------------------- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1) • OA (2.2) and RA (2.3): • Starting dose: 7.5 mg once daily • Dose may be increased to 15 mg once daily • JRA (2.4): • 0.125 mg/kg once daily up to a maximum of 7.5 mg. JRA dosing using the oral suspension should be individualized based on the weight of the child (2.4) • Meloxicam oral suspension is not interchangeable with approved formulations of oral meloxicam even if the total milligram strength is the same (2.6) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- • Meloxicam) oral suspension: 7.5 mg/5 mL (3) -------------------------------CONTRAINDICATIONS----------------------------- • Known hypersensitivity to meloxicam or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of meloxicam oral suspension in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of meloxicam oral suspension in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: Meloxicam oral suspension is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue meloxicam oral suspension at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including meloxicam oral suspension, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ------------------------------ADVERSE REACTIONS------------------------------ • Most common (≥5% and greater than placebo) adverse events in adults are diarrhea, upper respiratory tract infections, dyspepsia, and influenza- like symptoms (6.1) • Adverse events observed in pediatric studies were similar in nature to the adult clinical trial experience (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Avondale Pharmaceuticals, LLC at 800-528-3058 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking meloxicam oral suspension with drugs that interfere with hemostasis. Concomitant use of meloxicam oral suspension and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARBs) or Beta- Blockers: Concomitant use with meloxicam oral suspension may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with meloxicam oral suspension in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------- • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of meloxicam oral suspension in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482832 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 1.1 Osteoarthritis (OA) 1.2 Rheumatoid Arthritis (RA) 1.3 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Osteoarthritis 2.3 Rheumatoid Arthritis 2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course 2.5 Renal Impairment 2.6 Non-Interchangeability with Other Formulations of Meloxicam 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Osteoarthritis and Rheumatoid Arthritis 14.2 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482832 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • Meloxicam oral suspension is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 Osteoarthritis (OA) Meloxicam oral suspension is indicated for relief of the signs and symptoms of osteoarthritis [see Clinical Studies (14.1)]. 1.2 Rheumatoid Arthritis (RA) Meloxicam oral suspension is indicated for relief of the signs and symptoms of rheumatoid arthritis [see Clinical Studies (14.1)]. 1.3 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course Meloxicam oral suspension is indicated for relief of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of meloxicam oral suspension and other treatment options before deciding to use meloxicam oral suspension. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with meloxicam oral suspension, adjust the dose to suit an individual patient's needs. In adults, the maximum recommended daily oral dose of meloxicam oral suspension is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Meloxicam oral suspension 7.5 mg/5 mL or 15 mg/10 mL may be substituted for meloxicam tablets 7.5 mg or 15 mg, respectively. Shake the oral suspension gently before using. Meloxicam oral suspension may be taken without regard to timing of meals. 2.2 Osteoarthritis For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam oral suspension is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.3 Rheumatoid Arthritis For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam oral suspension is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course To improve dosing accuracy in smaller weight children, the use of the meloxicam oral suspension is recommended. Meloxicam oral suspension is available in the strength of 7.5 mg/5 mL. For the treatment of juvenile rheumatoid arthritis, the recommended oral dose of meloxicam oral suspension is 0.125 mg/kg once daily up to a maximum of 7.5 mg. There was no additional benefit demonstrated by increasing the dose above 0.125 mg/kg once daily in these clinical trials. Juvenile Rheumatoid Arthritis dosing using the oral suspension should be individualized based on the weight of the child: 0.125 mg/kg Dose Weight (1.5 mg/mL) Delivered dose 12 kg (26 lb) 1.0 mL 1.5 mg 24 kg (54 lb) 2.0 mL 3.0 mg 36 kg (80 lb) 3.0 mL 4.5 mg 48 kg (106 lb) 4.0 mL 6.0 mg ≥60 kg (132 lb) 5.0 mL 7.5 mg 2.5 Renal Impairment The use of meloxicam oral suspension in subjects with severe renal impairment is not recommended. In patients on hemodialysis, the maximum dosage of meloxicam oral suspension is 7.5 mg per day [see Clinical Pharmacology (12.3)]. Reference ID: 5482832 2.6 Non-Interchangeability with Other Formulations of Meloxicam Meloxicam oral suspension has not shown equivalent systemic exposure to other approved formulations of oral meloxicam. Therefore, meloxicam oral suspension is not interchangeable with other formulations of oral meloxicam product even if the total milligram strength is the same. Do not substitute similar dose strengths of meloxicam oral suspension with other formulations of oral meloxicam product. 3 DOSAGE FORMS AND STRENGTHS Meloxicam oral suspension: • yellowish green tinged viscous suspension containing 7.5 mg meloxicam per 5 mL. 4 CONTRAINDICATIONS Meloxicam oral suspension is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of meloxicam oral suspension in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meloxicam oral suspension is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue meloxicam oral suspension until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Reference ID: 5482832 Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam oral suspension immediately, and perform a clinical evaluation of the patient [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.4 Hypertension NSAIDs, including meloxicam oral suspension, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of meloxicam oral suspension in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam oral suspension is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs, including meloxicam oral suspension, has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of meloxicam oral suspension may hasten the progression of renal dysfunction in patients with preexisting renal disease. Because some meloxicam oral suspension metabolites are excreted by the kidney, monitor patients for signs of worsening renal function. Correct volume status in dehydrated or hypovolemic patients prior to initiating meloxicam oral suspension. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of meloxicam oral suspension [see Drug Interactions (7)]. No information is available from controlled clinical studies regarding the use of meloxicam oral suspension in patients with advanced renal disease. Avoid the use of meloxicam oral suspension in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If meloxicam oral suspension is used in patients with advanced renal disease, monitor patients for signs of worsening renal function [see Clinical Pharmacology (12.3)]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin- sensitive patients, meloxicam oral suspension is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When meloxicam oral suspension is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam oral suspension at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam oral suspension is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam oral suspension. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meloxicam oral suspension and evaluate the patient immediately. Reference ID: 5482832 6 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including meloxicam oral suspension, in pregnant women at about 30 weeks gestation and later. NSAIDs, including meloxicam oral suspension, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including meloxicam oral suspension, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meloxicam oral suspension use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam oral suspension treatment extends beyond 48 hours. Discontinue meloxicam oral suspension if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with meloxicam oral suspension has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam oral suspension , may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of meloxicam oral suspension in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Boxed Warning and Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Boxed Warning and Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Osteoarthritis and Rheumatoid Arthritis The meloxicam Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with meloxicam 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials. A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of meloxicam with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of meloxicam with placebo. Table 1a depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial. Table 1b depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in two 12-week placebo-controlled rheumatoid arthritis trials. Table 1a Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in a 12-Week Osteoarthritis Placebo- and Active-Controlled Trial Placebo Meloxicam Meloxicam Diclofenac 7.5 mg daily 15 mg daily 100 mg daily No. of Patients 157 154 156 153 Gastrointestinal 17.2 20.1 17.3 28.1 Reference ID: 5482832 Abdominal pain 2.5 1.9 2.6 1.3 Diarrhea 3.8 7.8 3.2 9.2 Dyspepsia 4.5 4.5 4.5 6.5 Flatulence 4.5 3.2 3.2 3.9 Nausea 3.2 3.9 3.8 7.2 Body as a Whole Accident household 1.9 4.5 3.2 2.6 Edema1 2.5 1.9 4.5 3.3 Fall 0.6 2.6 0.0 1.3 Influenza-like symptoms 5.1 4.5 5.8 2.6 Central and Peripheral Nervous System Dizziness 3.2 2.6 3.8 2.0 Headache 10.2 7.8 8.3 5.9 Respiratory Pharyngitis 1.3 0.6 3.2 1.3 Upper respiratory tract infection 1.9 3.2 1.9 3.3 Skin Rash2 2.5 2.6 0.6 2.0 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined Table 1b Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials Placebo Meloxicam Meloxicam 7.5 mg daily 15 mg daily No. of Patients 469 481 477 Gastrointestinal Disorders 14.1 18.9 16.8 Abdominal pain NOS2 0.6 2.9 2.3 Dyspeptic signs and symptoms1 3.8 5.8 4.0 Nausea2 2.6 3.3 3.8 General Disorders and Administration Site Conditions Influenza-like illness2 2.1 2.9 2.3 Infection and Infestations Upper respiratory tract infections-pathogen class unspecified1 4.1 7.0 6.5 Musculoskeletal and Connective Tissue Disorders Joint related signs and symptoms1 1.9 1.5 2.3 Nervous System Disorders Headaches NOS2 6.4 6.4 5.5 Skin and Subcutaneous Tissue Disorders Rash NOS2 1.7 1.0 2.1 1 MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-pathogen unspecified (laryngitis NOS, pharyngitis NOS, sinusitis NOS), joint related signs and symptoms (arthralgia, arthralgia aggravated, joint crepitation, joint effusion, joint swelling) 2 MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS The adverse events that occurred with meloxicam in ≥2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2. Table 2 Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials 4 to 6 Weeks Controlled Trials 6 Month Controlled Trials No. of Patients Meloxicam7.5 mg Meloxicam15 mg daily daily 8955 256 Meloxicam 7.5 mg daily 169 Meloxicam 15 mg daily 306 Gastrointestinal 11.8 18.0 26.6 24.2 Abdominal pain 2.7 2.3 4.7 2.9 Constipation 0.8 1.2 1.8 2.6 Diarrhea 1.9 2.7 5.9 2.6 Dyspepsia 3.8 7.4 8.9 9.5 Flatulence 0.5 0.4 3.0 2.6 Nausea 2.4 4.7 4.7 7.2 Reference ID: 5482832 Vomiting 0.6 0.8 1.8 2.6 Body as a Whole Accident household 0.0 0.0 0.6 2.9 Edema1 0.6 2.0 2.4 1.6 Pain 0.9 2.0 3.6 5.2 Central and Peripheral Nervous System Dizziness 1.1 1.6 2.4 2.6 Headache 2.4 2.7 3.6 2.6 Hematologic Anemia 0.1 0.0 4.1 2.9 Musculoskeletal Arthralgia 0.5 0.0 5.3 1.3 Back pain 0.5 0.4 3.0 0.7 Psychiatric Insomnia 0.4 0.0 3.6 1.6 Respiratory Coughing 0.2 0.8 2.4 1.0 Upper respiratory tract 0.2 0.0 8.3 7.5 infection Skin Pruritus 0.4 1.2 2.4 0.0 Rash2 0.3 1.2 3.0 1.3 Urinary Micturition frequency 0.1 0.4 2.4 1.3 Urinary tract infection 0.3 0.4 4.7 6.9 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined Higher doses of meloxicam(22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of meloxicam oral suspension should not exceed 15 mg. Pediatrics Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis (JRA) Three hundred and eighty-seven patients with pauciarticular and polyarticular course JRA were exposed to meloxicam with doses ranging from 0.125 to 0.375 mg/kg per day in three clinical trials. These studies consisted of two 12-week multicenter, double-blind, randomized trials (one with a 12-week open-label extension and one with a 40-week extension) and one 1-year open-label PK study. The adverse events observed in these pediatric studies with meloxicam were similar in nature to the adult clinical trial experience, although there were differences in frequency. In particular, the following most common adverse events, abdominal pain, vomiting, diarrhea, headache, and pyrexia, were more common in the pediatric than in the adult trials. Rash was reported in seven (<2%) patients receiving meloxicam C. No unexpected adverse events were identified during the course of the trials. The adverse events did not demonstrate an age or gender-specific subgroup effect. The following is a list of adverse drug reactions occurring in <2% of patients receiving meloxicam in clinical trials involving approximately 16,200 patients. Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis Central and Peripheral Nervous System convulsions, paresthesia, tremor, vertigo Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative Heart Rate and Rhythm arrhythmia, palpitation, tachycardia Hematologic leukopenia, purpura, thrombocytopenia Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis Metabolic and Nutritional dehydration Psychiatric abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence Respiratory asthma, bronchospasm, dyspnea Skin and Appendages alopecia, angioedema, bullous eruption, photosensitivity reaction, pruritus, sweating increased, urticaria Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus Reference ID: 5482832 7 Urinary System albuminuria, BUN increased, creatinine increased, hematuria, renal failure 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of meloxicam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide post marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome; fixed drug eruption (FDE); toxic epidermal necrolysis; and infertility female. DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. See also Warnings and Precautions (5.2, 5.6, 5.12) and Clinical Pharmacology (12.3). Table 3 Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: • Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of meloxicam oral suspension with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of meloxicam oral suspension and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. Meloxicam oral suspension is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co- administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of meloxicam oral suspension and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of meloxicam oral suspension and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention: During concomitant use of meloxicam oral suspension with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)]. Intervention: During concomitant use of meloxicam oral suspension and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of meloxicam oral suspension and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. Reference ID: 5482832 8 Intervention: During concomitant use of meloxicam oral suspension and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of meloxicam oral suspension and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. Sodium Polystyrene Sulfonate) Clinical Impact: Cases of intestinal necrosis (possibly fatal) have been described in patients who received concomitant sorbitol and sodium polystyrene sulfonate. Due to the presence of sorbitol in meloxicam o suspension, use with sodium polystyrene sulfonate is not recommended. Intervention: The concomitant use of meloxicam oral suspension with sodium polystyrene sulfonate is not recommended. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam oral suspension, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of meloxicam oral suspension use between about 20 and 30 weeks of gestation, and avoid meloxicam oral suspension use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam oral suspension, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65- and 6.5-times the maximum recommended human dose (MRHD) of meloxicam oral suspension. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times MRHD of meloxicam. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the MRHD [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam oral suspension, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam oral suspension treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam oral suspension and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of meloxicam oral suspension during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Reference ID: 5482832 Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full- term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the MRHD of 15 mg of meloxicam based on BSA comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65 and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meloxicam oral suspension and any potential adverse effects on the breastfed infant from the meloxicam oral suspension or from the underlying maternal condition. Data Animal Data Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam oral suspension, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including meloxicam oral suspension, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [see Dosage and Administration (2.3), Adverse Reactions (6.1) and Clinical Studies (14.2)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since meloxicam is significantly metabolized in the liver and hepatotoxicity may occur, use meloxicam with caution in patients with hepatic impairment [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of meloxicam oral suspension in subjects with severe renal impairment is not recommended. In patients on hemodialysis, meloxicam should not exceed 7.5 mg per day. Meloxicam is not dialyzable [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Reference ID: 5482832 10 S O O N CH3 H N S N O OH There is limited experience with meloxicam overdosage. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage. For additional information about overdosage treatment, call a poison control center (1-800-222-1222). 11 DESCRIPTION Meloxicam oral suspension, USP is a nonsteroidal anti-inflammatory drug (NSAID). Each bottle of meloxicam oral suspension contains 7.5 mg meloxicam per 5 mL. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula: CH3 Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. Meloxicam is available as an oral suspension containing 7.5 mg meloxicam per 5 mL. The inactive ingredients in meloxicam oral suspension include colloidal silicon dioxide, hydroxyethylcellulose, sorbitol, glycerol, xylitol, monobasic sodium phosphate (dihydrate), saccharin sodium, sodium benzoate, citric acid (monohydrate), raspberry flavor, and purified water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam oral suspension, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling. Meloxicam oral suspension doses of 7.5 mg/5 mL and 15 mg/10 mL have been found to be bioequivalent to meloxicam 7.5 mg and 15 mg capsules, respectively. Meloxicam capsules have been shown to be bioequivalent to meloxicam tablets. Table 4 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1 Steady State Single Dose Pharmacokinetic Healthy male adults Elderly males Elderly females Renal failure Hepatic insufficiency Parameters (Fed)2 (Fed)2 (Fed)2 (Fasted) (Fasted) (% CV) 7.5 mg3 tablets 15 mg capsules 15 mg capsules 15 mg capsules 15 mg capsules N 18 5 8 12 12 Cmax [µg/mL] 1.05 (20) 2.3 (59) 3.2 (24) 0.59 (36) 0.84 (29) tmax [h] 4.9 (8) 5 (12) 6 (27) 4 (65) 10 (87) t1/2 [h] 20.1 (29) 21 (34) 24 (34) 18 (46) 16 (29) CL/f [mL/min] 8.8 (29) 9.9 (76) 5.1 (22) 19 (43) 11 (44) V /f4 [L] z 14.7 (32) 15 (42) 10 (30) 26 (44) 14 (29) 1 The parameter values in the table are from various studies 2 not under high fat conditions 3 Meloxicam tablets Reference ID: 5482832 4 Vz/f =Dose/(AUC•Kel) Food and Antacid Effects Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the Cmax values for meloxicam suspension were affected following a similar high fat meal, while mean Tmax values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, meloxicam oral suspension can be administered without regard to timing of meals or concomitant administration of antacids. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity. Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min. Specific Populations Pediatric After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg [see Dosage and Administration (2.4)]. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively. In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of meloxicam oral suspension in pediatric patients under 2 years of age have not been investigated. Geriatric Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (≥65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger females (≤55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients. Sex Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders. Hepatic Impairment Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child- Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Renal Impairment Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam oral suspension in subjects with severe renal impairment is not recommended [see Dosage and Administration (2.5), Warnings and Precautions (5.6) and Use in Specific Populations (8.7)]. Hemodialysis Reference ID: 5482832 Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every day as compared to subjects receiving lithium alone [see Drug Interactions (7)]. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [see Drug Interactions (7)]. Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam oral suspension with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-times, respectively, the maximum recommended human dose [MRHD] of 15 mg/day meloxicam oral suspension based on body surface area [BSA] comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and 3.2-times greater, respectively, than the MRHD based on BSA comparison). 14 CLINICAL STUDIES 14.1 Osteoarthritis and Rheumatoid Arthritis The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial. Meloxicam (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo. The four primary endpoints were investigator’s global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness). Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo. The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks’ to 6 months’ duration. In these trials, the efficacy of meloxicam , in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial. The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial. Meloxicam (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response. Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. 14.2 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course The use of meloxicam for the treatment of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older was evaluated in two 12-week, double-blind, parallel-arm, active-controlled trials. Both studies included three arms: naproxen and two doses of meloxicam. In both studies, meloxicam dosing began at 0.125 mg/kg/day (7.5 mg maximum) or 0.25 mg/kg/day (15 mg maximum), and naproxen dosing began at 10 mg/kg/day. One study used these doses throughout the 12-week dosing period, while the other incorporated a titration after 4 weeks to doses of 0.25 mg/kg/day and 0.375 mg/kg/day (22.5 mg maximum) of meloxicam and 15 mg/kg/day of naproxen. The efficacy analysis used the ACR Pediatric 30 responder definition, a composite of parent and investigator assessments, counts of active joints and joints with limited range of motion, and erythrocyte sedimentation rate. The proportion of responders were similar in all three groups in both studies, and no difference was observed between the meloxicam dose groups. 16 HOW SUPPLIED/STORAGE AND HANDLING Meloxicam oral suspension, USP is available as a yellowish green tinged viscous oral suspension containing 7.5 mg meloxicam in 5 mL. Reference ID: 5482832 17 Meloxicam oral suspension, USP, 7.5 mg/5 mL: NDC 71740-339-11; Bottles of 100 mL Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep oral suspension container tightly closed. Keep this and all medications out of the reach of children. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families or their caregivers of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop meloxicam oral suspension and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking meloxicam oral suspension immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9), (5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including meloxicam oral suspension , may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of meloxicam oral suspension and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meloxicam oral suspension is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of meloxicam oral suspension with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with meloxicam oral suspension until they talk to their healthcare provider [see Drug Interactions (7)]. For current prescribing information call Avondale Pharmaceuticals, LLC at 800-528-3058. Manufactured for Avondale Pharmaceuticals, LLC, Birmingham, AL 35209 USA Made in Canada ©2024 Avondale Pharmaceuticals, LLC C-A236R1 Reference ID: 5482832 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb and around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: Reference ID: 5482832 See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is • diarrhea black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs: • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for Avondale Pharmaceuticals, LLC, Birmingham, AL 35209 USA Made in Canada © 2024 Avondale Pharmaceuticals, LLC This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: April 2022 Reference ID: 5482832	custom-source	2025-02-12T15:47:10.626767	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021530s020lbl.pdf', 'application_number': 21530, 'submission_type': 'SUPPL ', 'submission_number': 20}
80,388	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZIPSOR® safely and effectively. See full prescribing information for ZIPSOR. ZIPSOR® (diclofenac potassium) 25 mg capsule, for oral use Initial U.S. Approval: 1988 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINALEVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • ZIPSOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE ZIPSOR is a non-steroidal anti-inflammatory drug indicated for relief of mild to moderate acute pain in adult and pediatric patients 12 years of age and older. (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • The dosage is 25 mg four times a day DOSAGE FORMS AND STRENGTHS ZIPSOR (diclofenac potassium) capsule: 25 mg (3) CONTRAINDICATIONS • Known hypersensitivity to diclofenac or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) • ZIPSOR contains gelatin and should not be given to patients with known hypersensitivity to bovine protein. (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) Heart Failure and Edema: Avoid use of ZIPSOR in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZIPSOR in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: ZIPSOR is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue ZIPSOR at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10). • Fetal Toxicity: Limit use of NSAIDs, including ZIPSOR, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1). • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 1%) are gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, dizziness, headache, somnolence, pruritus, and increase sweating (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Actelion Therapeutics, Inc. at 1-866-458-6389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ZIPSOR with drugs that interfere with hemostasis. Concomitant use of ZIPSOR and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with ZIPSOR may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with ZIPSOR in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with ZIPSOR can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of ZIPSOR in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482834 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINALEVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Dosage Adjustment in Patients with Hepatic Impairment 2.3 Non-Interchangeability with Other Formulations of Diclofenac 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUGINTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICALPHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICALTOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482834 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • ZIPSOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE ZIPSOR is indicated for relief of mild to moderate acute pain in adult and pediatric patients 12 years of age and older. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of ZIPSOR and other treatment options before deciding to use ZIPSOR. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. For treatment of mild to moderate acute pain in adult and pediatric patients 12 years of age and older, the dosage is 25 mg four times a day. 2.2 Dosage Adjustments in Patients with Hepatic Impairment Patients with hepatic disease may require reduced doses of ZIPSOR compared to patients with normal hepatic function [see Clinical Pharmacology (12)]. As with other diclofenac products, start treatment at the lowest dose. If efficacy is not achieved with the lowest dose, discontinue use. 2.3 Non-Interchangeability with Other Formulations of Diclofenac Different dose strengths and formulations of oral diclofenac are not interchangeable. This difference should be taken into consideration when changing strengths or formulations. The only approved dosing regimen for ZIPSOR is 25 mg four times a day. 3 DOSAGE FORMS AND STRENGTHS ZIPSOR (diclofenac potassium) capsule: 25 mg Reference ID: 5482834 4 CONTRAINDICATIONS ZIPSOR is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] • ZIPSOR contains gelatin and is contraindicated in patients with known hypersensitivity to bovine protein. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Reference ID: 5482834 Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ZIPSOR in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ZIPSOR is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ZIPSOR until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. Reference ID: 5482834 5.3 Hepatotoxicity In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2–6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3–8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female sex, doses of 150 mg or more, and duration of use for more then 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with ZIPSOR, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), ZIPSOR should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ZIPSOR immediately, and perform a clinical evaluation of the patient. Reference ID: 5482834 To minimize the potential risk for an adverse liver-related event in patients treated with ZIPSOR, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing ZIPSOR with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics). 5.4 Hypertension NSAIDs, including ZIPSOR, can lead to new onset of hypertension or worsening of pre existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of ZIPSOR in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ZIPSOR is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of ZIPSOR in patients with advanced renal disease. The renal effects of ZIPSOR may hasten the progression of renal dysfunction in patients with preexisting renal disease. Reference ID: 5482834 Correct volume status in dehydrated or hypovolemic patients prior to initiating ZIPSOR. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ZIPSOR [see Drug Interactions (7)]. Avoid the use of ZIPSOR in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ZIPSOR is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ZIPSOR is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ZIPSOR is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ZIPSOR at the first appearance of skin rash or any other sign of hypersensitivity. ZIPSOR is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ZIPSOR. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ZIPSOR and evaluate the patient immediately. Reference ID: 5482834 5.11 Fetal Toxicity: Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including ZIPSOR, in pregnant women at about 30 weeks gestation and later. NSAIDs, including ZIPSOR, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including ZIPSOR, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ZIPSOR use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ZIPSOR treatment extends beyond 48 hours. Discontinue ZIPSOR if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ZIPSOR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including ZIPSOR, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplateletagents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of ZIPSOR in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] Reference ID: 5482834 • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with the rates in clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZIPSOR was evaluated in 965 adult subjects. In patients treated with ZIPSOR 25 mg (N=345) or a higher dose, three or four times a day, for 4 to 5 days, the most common adverse reactions (i.e., reported in ≥ 1% of ZIPSOR treated patients) were as follows: gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, dizziness, headache, somnolence, pruritus, and increased sweating. (see Table 1). The safety of ZIPSOR was evaluated in 125 pediatric patients, 12 years to 17 years of age. Forty-nine (49) patients with mild to moderate acute pain from a surgical procedure or an acute painful condition were treated with ZIPSOR 25 mg up to four times a day, for 4 days. Seventy-six (76) pediatric patients who underwent insertion of either orthodontic separators or arch wires were treated with a single-dose of either ZIPSOR 25 mg or ZIPSOR 50 mg after completion of the procedure. The most common adverse reactions in the multiple-dose studies were nausea (14.3%), headache (10.2%), constipation (8.2%), abdominal pain (4.1%), vomiting (4.1%), dizziness (4.1%), back pain (4.1%), and musculoskeletal pain (4.1%). Reference ID: 5482834 Table 1 Incidence of Treatment Emergent Adverse Reactions with Incidence ≥ 1% of ZIPSOR Treated Patients in Multiple-Dose Studies MedDRA System ZIPSOR* Placebo* Organ Class and 25 mg Preferred Term n=345 n=327 n (%) n (%) Any Adverse Events 144 (41.7) 181 (55.4) Nausea 57 (16.5) 66 (20.2) Headache 43 (12.5)) 56 (17.1) Abdominal Pain 24 (7.0) 11 (3.4) Vomiting 20 (5.8) 17 (5.2) Dizziness 12 (3.5) 66 (20.2) Constipation 11 (3.2) 9 (2.8) Somnolence 9 (2.6) 6 (1.8) Diarrhea 8 (2.3) 9 (2.8) Pruritus 5 (1.4) 6 (1.8) Dyspepsia 4 (1.2) 8 (2.4) Sweating Increase 4 (1.2) 2 (0.6) *There was greater use of concomitant opioid rescue medication in placebo treated patients than in ZIPSOR treated patients In patients taking other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus. Additional adverse experiences reported in patients taking other NSAIDs occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses: blurred vision Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions in patients taking other NSAIDs, which occur rarely are: Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: colitis, eructation, liver failure, pancreatitis Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, Reference ID: 5482834 lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome, urticaria Special Senses: conjunctivitis, hearing impairment 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of diclofenac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with diclofenac. Table 3: Clinically Significant Drug Interactions with diclofenac Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ZIPSOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of ZIPSOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. ZIPSOR is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Reference ID: 5482834 Intervention: • During concomitant use of ZIPSOR and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of ZIPSOR and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ZIPSOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ZIPSOR and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ZIPSOR and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ZIPSOR and methotrexate, monitor patients for methotrexatetoxicity. Cyclosporine Clinical Impact: Concomitant use of ZIPSOR and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of ZIPSOR and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of ZIPSOR and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of ZIPSOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Reference ID: 5482834 NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or Inducers: Clinical Impact Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co- administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including ZIPSOR, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ZIPSOR use between about 20 and 30 weeks of gestation, and avoid ZIPSOR use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ZIPSOR, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations was observed in mice, rats, and rabbits given diclofenac during the period of organogenesis at doses up to approximately 1, 1, and 2 times, respectively, the maximum recommended human dose (MRHD) of ZIPSOR, despite the presence of maternal and fetal toxicity at these doses. In published studies, administration of clinically relevant doses of diclofenac to pregnant rats produced adverse effects on brain, kidney, and testicular development [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Reference ID: 5482834 The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ZIPSOR, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest dose and shortest duration possible. If ZIPSOR treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ZIPSOR and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of ZIPSOR during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full- term infant exposed to NSAIDs through maternal use is uncertain. Diclofenac has been shown to cross the placental barrier in humans. Reference ID: 5482834 Animal data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD] of ZIPSOR, 100 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 1 and 2 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.2 and 0.4 times the MRHD based on BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats. In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0.1 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3.6 mg/kg, IP; 0.3 times the MRHD based on BSA comparison), and caused adverse effects on the developing testes (6.1 mg/kg, PO; 0.6 times the MRHD based on BSA comparison). 8.2 Lactation Risk Summary Data from published literature reports with oral preparations of diclofenac indicate the presence of diclofenac in small amounts human milk (see Data). There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZIPSOR and any potential adverse effects on the breastfed infant from the ZIPSOR or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ZIPSOR, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including ZIPSOR, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear [See Nonclinical Toxicology (13.1)]. Reference ID: 5482834 8.4 Pediatric Use The safety and effectiveness of ZIPSOR in pediatric patients 12 years to 17 years of age have been established. Use of ZIPSOR in this age group is based on extrapolation of efficacy from adequate and well-controlled studies in adults and supported by pharmacokinetic and safety data from two open-label studies in 49 patients 12 years to 17 years of age with mild to moderate acute pain and one active-controlled study in 76 pediatric patients 12 years to 16 years of age with orthodontic discomfort. Based on the available data, the plasma diclofenac concentration in adolescent patients was comparable to that observed in healthy adults. The safety profile of ZIPSOR in adolescent patients was similar to adults. The safety and effectiveness of ZIPSOR in patients less than 12 years of age have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). 11 DESCRIPTION ZIPSOR (diclofenac potassium) capsule is a nonsteroidal anti-inflammatory drug, available as liquid-filled capsules of 25 mg base, equivalent to 28.3 mg potassium salt for oral administration. Diclofenac potassium is a white to slight yellowish crystalline powder. It is sparingly soluble in water at 25°C. The chemical name is benzeneacetic acid, 2-[(2,6 dichlorophenyl) amino]-, monopotassium salt. The molecular weight is 334.24. Its molecular formula is C14H10Cl2NKO2, and it has the following chemical structure. Reference ID: 5482834 0 The inactive ingredients in ZIPSOR include: ProSorb (a proprietary combination of polyethylene glycol 400, glycerin, sorbitol, povidone, polysorbate 80, and hydrochloric acid), isopropyl alcohol, and mineral oil. The capsule shells contain gelatin, sorbitol, isopropyl alcohol, glycerin, and mineral oil. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of ZIPSOR, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics The pharmacokinetics of ZIPSOR was assessed in 24 healthy, normal adult volunteers who received 25 mg ZIPSOR under fasting conditions. The mean pharmacokinetic parameters for ZIPSOR are shown in Table 4. The pharmacokinetics of ZIPSOR was also assessed in pediatric patients 12 to 17 years of age [see Specific Populations: Pediatric] and was found to be similar to adults. Table 4 Mean Pharmacokinetics of ZIPSOR in Adults PK Parameter Number of Subjects Mean ± Standard Deviation Tmax (hr) 24 0.47 ± 0.17 Terminal Half-life (hr) 24 1.07 ± 0.29 Cmax (ng/mL) 24 1087 ± 419 AUC(0-∞) (ng⋅h/mL) 24 597 ± 151 Reference ID: 5482834 Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of diclofenac in plasma occurred. The extent of diclofenac absorption is not significantly affected when ZIPSOR is taken with food. However, the rate of absorption is reduced by food, as indicated by a two-fold increase of Tmax and a 47% decrease in Cmax. Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses. Diclofenac has been shown to cross the placental barrier in humans. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Elimination Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'- hydroxy 4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy- diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy-and 5 hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 1 hour. Reference ID: 5482834 Specific Populations Pediatric: The pharmacokinetics of ZIPSOR was assessed in 24 pediatric patients 12 years to 17 years of age with mild to moderate acute pain who received 25 mg ZIPSOR every six hours as needed for pain for up to four days. The mean pharmacokinetic parameters of ZIPSOR on Day 1 in pediatric patients 12 years to 17 years of age are shown in Table 5. Peak plasma levels were noted in one hour, with an elimination half-life of less than 2 hours. The pharmacokinetics of ZIPSOR in pediatric patients 12 years to 17 years of age was similar to that in adults. Table 5 Mean Pharmacokinetics of ZIPSOR (Day1) in Pediatric Patients 12 Years to 17 Years of Age PK Parameter Number of Subjects Mean ± Standard Deviation Tmax (hr) 24 0.94 ± 0.42 Terminal Half-life (hr) 24 1.81 ± 0.92 Cmax (ng/mL) 24 699 ± 464 AUC(0-∞) (ng⋅h/mL) 24 659 ± 208 Race: Pharmacokinetic differences due to race have not been studied. Hepatic Impairment: Hepatic metabolism accounts for almost 100% of diclofenac elimination. Therefore, in patients with hepatic impairment, start with the lowest dose and if efficacy is not achieved, consider use of an alternate product [see Warnings and Precautions (5.3)]. Renal Impairment: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.2 times the maximum recommended human dose (MRHD) of ZIPSOR, 100 mg/day, based on body surface area (BSA) comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.014 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.04 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential. Mutagenesis Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was Reference ID: 5482834 , o g B 7 3 2 0 varloble T ime V\J'~>-----------------4_S_ H_o_u_ r_s __________________ _, \ \ \ ' \ \ ' ' ' .... , .., .... ' ' ....... ...... .-' ..... - ' ' \. ' , ..... __ -------___ .-,, Base e d Line of Dose 1 e, d of Dose 3 e l-.d of Dose 4 eJ..d of Dose 5 0 10 Dosing Intervals - 2S mg Zips.or Legend:-- - 25 mg Z ipsor,+ - P lacebo Pain intensity scale: 0 = no pain . 1 0 = worst pain . ehd of Dose 7 .... _ end of Dose a nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.4 times the MRHD based on BSA comparison) did not affect fertility. However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (1 times the MRHD based on BSA comparison) for 14 days and at 0.25 mg/kg (0.025 times the MRHD based on BSA comparison) for 30 days produced adverse effects on male reproductive hormones and testes. 14 CLINICAL STUDIES The efficacy of ZIPSOR in adults was demonstrated in two multicenter, randomized, double-blind, placebo- controlled, parallel arm, multiple-dose clinical trials comparing ZIPSOR 25 mg and placebo in patients with pain following bunionectomy with osteotomy. Once patients met the criteria for randomization (pain intensity ≥4 on a 0-10 numerical pain rating scale) they received their initial dose of study medication followed by a remedication dose when requested by the patient, and were then dosed every six hours over four days. Pain intensity was recorded at 3 and 6 hours postdose during the fixed dosing period. In Study 1, mean baseline pain intensity scores were 6.9 in the ZIPSOR group (range: 4 – 10) and 7.3 in the placebo group (range: 4 – 10). In both studies, patients treated with ZIPSOR had a lower mean pain intensity score over the 48-hour inpatient period following the first remedication dose (see Figure 1). The median time to onset of pain relief was less than one hour for ZIPSOR 25 mg across the clinical trials. The results were similar in Study 2. Figure 1 Mean Pain Intensity Scores at the Midpoint and End of Each Dose Interval in Postbunionectomy Pain Study 1 Reference ID: 5482834 16 HOW SUPPLIED/STORAGE AND HANDLING ZIPSOR (diclofenac potassium) 25 mg, are translucent, pale yellow, liquid-filled capsules printed with “X592” in black ink supplied as: Bottles of 100 Capsules NDC# 13913-008-11. Bottles of 120 Capsules NDC# 13913-008-12. Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture Dispense in tight container (USP). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with ZIPSOR and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop ZIPSOR and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Reference ID: 5482834 Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking ZIPSOR immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including ZIPSOR, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of ZIPSOR and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with ZIPSOR is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of ZIPSOR with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with ZIPSOR until they talk to their healthcare provider [see Drug Interactions (7)]. US Patents: 6,365,180; 7,662,858; 7,884,095; 7,939,518; 8,110,606; 6,287,594; 8,623,920 Distributed by: Assertio Therapeutics, Inc. Lake Forest, IL 60045, USA Issued:11/2024 Reference ID: 5482834 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) Reference ID: 5482834 • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: •shortness of breath or trouble breathing •slurred speech •chest pain •swelling of the face or throat •weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: •nausea • vomit blood •more tired or weaker than usual • there is blood in your bowel movement or •diarrhea it is black and sticky like tar •itching • unusual weight gain •your skin or eyes look yellow • skin rash or blisters with fever •indigestion or stomach pain • swelling of the arms, legs, hands and •flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Assertio Therapeutics, Inc., Lake Forest, IL 60045, For more information, go to www.ZIPSOR.com or call 1-866-458-6389 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: April 2021 ZIP-001-C.7 Reference ID: 5482834	custom-source	2025-02-12T15:47:10.722865	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022202s016lbl.pdf', 'application_number': 22202, 'submission_type': 'SUPPL ', 'submission_number': 16}
80,391	_________________ ______________ _____________ ____________________ ___________________ _______________ _______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SPRIX® safely and effectively. See full prescribing information for SPRIX®. SPRIX® (ketorolac tromethamine) Nasal Spray Initial U.S. Approval: 1989 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDS) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • SPRIX® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDS cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) __________________RECENT MAJOR CHANGES _________________ Warnings and Precautions (5.9) 11/2024 __________________ INDICATIONS AND USAGE SPRIX is a nonsteroidal anti-inflammatory drug indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level. (1) _______________ DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2.1) • SPRIX is not an inhaled product. For adult patients < 65 years of age: 31.5 mg (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg. (2.2, 2.3) • For patients ≥ 65 years of age, renally impaired patients, and patients less than 50 kg (110 lbs): 15.75 mg (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg. (2.4) • SPRIX nasal spray should be discarded within 24 hours of taking the first dose, even if the bottle still contains some medication. (2.5) ______________ DOSAGE FORMS AND STRENGTHS SPRIX (ketorolac tromethamine) Nasal Spray: 15.75 mg of ketorolac tromethamine in each 100 µL spray. Each 1.7 g bottle contains 8 sprays. (3) CONTRAINDICATIONS • Known hypersensitivity to ketorolac or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) • Use in patients with active peptic ulcer disease or with recent GI bleeding or perforation (4) • Use as a prophylactic analgesic before any major surgery (4) • Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion (4) • Use in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis, and those at high risk of bleeding (4) • Use in labor and delivery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4, 7) • Heart Failure and Edema: Avoid use of SPRIX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of SPRIX in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: SPRIX is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) • Serious Skin Reactions: Discontinue SPRIX at first appearance of skin rash or other signs of hypersensitivity. (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including SPRIX, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. Do not use SPRIX in patients for whom hemostasis is critical. (5.12, 7) • Limitations of Use: SPRIX should not be used concomitantly with IM/IV or oral ketorolac, aspirin, or other NSAIDs. (5.16) ____________________ADVERSE REACTIONS____________________ Most common adverse reactions (incidence ≥2%) in patients treated with SPRIX and occurring at a rate at least twice that of placebo are nasal discomfort, rhinalgia, increased lacrimation, throat irritation, oliguria, rash, bradycardia, decreased urine output, increased ALT and/or AST, hypertension, and rhinitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Zyla Life Sciences US Inc. at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking SPRIX with drugs that interfere with hemostasis. Concomitant use of SPRIX and analgesic doses of aspirin is not generally recommended. (7) • ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with SPRIX may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) • ACE Inhibitors and ARBs: Concomitant use with SPRIX in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) • Digoxin: Concomitant use with SPRIX can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) USE IN SPECIFIC POPULATIONS _______________ Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of SPRIX in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482839 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Administration 2.3 Adult Patients < 65 Years of Age 2.4 Reduced Doses for Special Populations 2.5 Discard Used SPRIX Bottle after 24 Hours 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Fetal Toxicity 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Eye Exposure 5.16 Limitations of Use 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Postoperative Pain 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482839 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • SPRIX® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE SPRIX is indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level. Limitations of Use • Sprix is not for use in pediatric patients less than 2 years of age. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. The total duration of use of SPRIX alone or sequentially with other formulations of ketorolac (IM/IV or oral) must not exceed 5 days because of the potential for increasing the frequency and severity of adverse reactions associated with the recommended doses [see Warnings and Precautions (5.15)]. Do not use SPRIX concomitantly with other formulations of ketorolac or other NSAIDs [see Warnings and Precautions (5.15)]. 2.2 Administration SPRIX is not an inhaled product. Do not inhale when administering this product. Instruct patients to administer as follows: 1. First hold the finger flange with fingers, and remove the clear plastic cover with opposite hand; then remove the blue plastic safety clip. Keep the clear plastic cover; and throw away the blue plastic safety clip. 2. Before using the bottle for the FIRST time, activate the pump. To activate the pump, hold the bottle at arm’s length away from the body with index finger and middle finger resting on the top of the finger flange and thumb supporting the base. Press down evenly and release the pump 5 times. Patient may not see a spray the first few times he/she presses down. The bottle is now ready to use. There is no need to activate the pump again if more doses are used from the bottle. 3. It’s important to get the medication to the correct place in the nose so it will be most effective. - Blow nose gently to clear nostrils. - Sit up straight or stand. Tilt head slightly forward. Reference ID: 5482839 - Insert the tip of the container into your right nostril. - Point the container away from the center of your nose. - Hold your breath and spray once into your right nostril, pressing down evenly on both sides. - Immediately after administration, resume breathing through mouth to reduce expelling the product. Also pinch the nose to help retain the spray if it starts to drip. If only one spray per dose is prescribed, administration is complete; skip to Step 5 below. 4. If a dose of 2 sprays is prescribed, repeat the process in Step 3 for the left nostril. Again, be sure to point the spray away from the center of nose. Spray once into the left nostril. 5. Replace the clear plastic cover and place the bottle in a cool, dry location out of direct sunlight, such as inside a medication cabinet. Keep out of reach of children. 2.3 Adult Patients < 65 Years of Age The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg (four doses). 2.4 Reduced Doses for Special Populations For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the recommended dose is 15.75 mg SPRIX (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg (four doses) [see Warnings and Precautions (5.2, 5.6)]. 2.5 Discard Used SPRIX Bottle after 24 Hours Do not use any single SPRIX bottle for more than one day as it will not deliver the intended dose after 24 hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if the bottle still contains some liquid. 3 DOSAGE FORMS AND STRENGTHS SPRIX (ketorolac tromethamine) Nasal spray: 15.75 mg of ketorolac tromethamine in each 100 µL spray. Each 1.7 g bottle contains 8 sprays. 4 CONTRAINDICATIONS SPRIX is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ketorolac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] • Use in patients with active peptic ulcer disease and in patients with recent gastrointestinal bleeding or perforation [see Warnings and Precautions (5.2)] • Use as a prophylactic analgesic before any major surgery [see Warnings and Precautions (5.11)] • Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion [see Warnings and Precautions (5.6)] • Use in labor and delivery. Through its prostaglandin synthesis inhibitory effect, ketorolac may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage [see Use in Specific Populations (8.1)] • Use in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or those for whom hemostasis is critical [see Warnings and Precautions (5.11), Drug Interactions (7)] • Concomitant use with probenecid [see Drug Interactions (7)] • Concomitant use with pentoxifylline [see Drug Interactions (7)] Reference ID: 5482839 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ketorolac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of SPRIX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SPRIX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation SPRIX is contraindicated in patients with active peptic ulcers and/or GI bleeding and in patients with recent gastrointestinal bleeding or perforation [see Contraindications (4)]. NSAIDs, including ketorolac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly Reference ID: 5482839 or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, consider alternate therapies other than NSAIDs. Do not use Sprix in those with active GI bleeding. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SPRIX until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. • Use great care when giving SPRIX to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including ketorolac. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SPRIX immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including SPRIX, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ketorolac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of SPRIX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If SPRIX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Ketorolac and its metabolites are eliminated primarily by the kidneys. Patients with reduced creatinine clearance will have diminished clearance of the drug [see Clinical Pharmacology (12.3)]. SPRIX is contraindicated in patients with advanced renal impairment [see Contraindications (4)]. Reference ID: 5482839 Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of SPRIX in patients with advanced renal disease. The renal effects of SPRIX may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating SPRIX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of SPRIX [see Drug Interactions (7)]. Avoid the use of SPRIX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If SPRIX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Ketorolac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ketorolac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin- sensitive patients, SPRIX is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When SPRIX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including ketorolac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens- Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of SPRIX at the first appearance of skin rash or any other sign of hypersensitivity. SPRIX is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as SPRIX. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue SPRIX and evaluate the patient immediately. Reference ID: 5482839 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including SPRIX, in pregnant women at about 30 weeks gestation and later. NSAIDs, including SPRIX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including SPRIX, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit SPRIX use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if SPRIX treatment extends beyond 48 hours. Discontinue SPRIX if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Population (8.1)] 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with SPRIX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Do not use SPRIX in patients for whom hemostasis is critical [see Contraindications (4), Drug Interactions (7)]. NSAIDs, including SPRIX, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. The concurrent use of ketorolac and therapy that affects hemostasis, including prophylactic low dose heparin (2500 to 5000 units q12h), warfarin and dextrans, has not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, carefully weigh the benefits against the risks and use such concomitant therapy in these patients only with extreme caution. Monitor patients receiving therapy that affects hemostasis closely. In clinical trials, serious adverse events related to bleeding were more common in patients treated with SPRIX than placebo. In clinical trials and in postmarketing experience with ketorolac IV and IM dosing, postoperative hematomas and other signs of wound bleeding have been reported in association with peri-operative use. Therefore, use SPRIX with caution in the postoperative setting when hemostasis is critical. 5.13 Masking of Inflammation and Fever The pharmacological activity of SPRIX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Eye Exposure Avoid contact of SPRIX with the eyes. If eye contact occurs, wash out the eye with water or saline, and consult a physician if irritation persists for more than an hour. Reference ID: 5482839 5.16 Limitations of Use The total duration of use of SPRIX alone or sequentially with other forms of ketorolac is not to exceed 5 days. SPRIX must not be used concomitantly with other forms of ketorolac or other NSAIDs [see Dosage and Administration (2.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to SPRIX in patients enrolled in placebo-controlled efficacy studies of acute pain following major surgery. The studies enrolled 828 patients (183 men, 645 women) ranging from 18 years to over 75 years of age. The patients in the postoperative pain studies had undergone major abdominal, orthopedic, gynecologic, or other surgery; 455 patients received SPRIX (31.5 mg) three or four times a day for up to 5 days, and 245 patients received placebo. Most patients were receiving concomitant opioids, primarily PCA morphine. The most frequently reported adverse reactions were related to local symptoms, i.e., nasal discomfort or irritation. These reactions were generally mild and transient in nature. The most common drug-related adverse events leading to premature discontinuation were nasal discomfort or nasal pain (rhinalgia). Table 1: Post-Operative Patients with Adverse Reactions Observed at a Rate of 2% or More and at Least Twice the Incidence of the Placebo Group. SPRIX (N = 455) Placebo (N = 245) Nasal discomfort 15% 2% Rhinalgia 13% <1% Lacrimation increased 5% 0% Throat irritation 4% <1% Oliguria 3% 1% Rash 3% <1% Bradycardia 2% <1% Urine output decreased 2% <1% ALT and/or AST increased 2% 1% Hypertension 2% 1% Rhinitis 2% <1% Reference ID: 5482839 In controlled clinical trials in major surgery, primarily knee and hip replacements and abdominal hysterectomies, seven patients (N=455, 1.5%) treated with SPRIX experienced serious adverse events of bleeding (4 patients) or hematoma (3 patients) at the operative site versus one patient (N=245, 0.4%) treated with placebo (hematoma). Six of the seven patients treated with SPRIX underwent a surgical procedure and/or blood transfusion and the placebo patient subsequently required a blood transfusion. Adverse Reactions Reported in Clinical Trials with Other Dosage Forms of Ketorolac or Other NSAIDs Adverse reaction rates increase with higher doses of ketorolac. It is necessary to remain alert for the severe complications of treatment with ketorolac, such as GI ulceration, bleeding, and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure. These complications can be serious in certain patients for whom ketorolac is indicated, especially when the drug is used inappropriately. In patients taking ketorolac or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) experiences including: abdominal pain constipation/diarrhea dyspepsia flatulence GI fullness GI ulcers (gastric/duodenal) gross bleeding/perforation heartburn nausea stomatitis vomiting Other experiences: abnormal renal function anemia dizziness drowsiness edema elevated liver enzymes headache* hypertension increased bleeding time injection site pain pruritus purpura rash tinnitus sweating *Incidence greater than 10% Additional adverse experiences reported occasionally (<1% in patients taking ketorolac or other NSAIDs in clinical trials) include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, palpitation, pallor, tachycardia, syncope Digestive System: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia Metabolic and Nutritional: weight change Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise Respiratory: asthma, dyspnea, pulmonary edema, rhinitis Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ketorolac or other NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 5482839 Other observed reactions (reported from postmarketing experience in patients taking ketorolac or other NSAIDs) are: Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema, myalgia Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens- Johnson syndrome, fixed drug eruption (FDE), and toxic epidermal necrolysis Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion) Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia Nervous System: aseptic meningitis, convulsions, coma, psychosis Respiratory: bronchospasm, respiratory depression, pneumonia Special Senses: conjunctivitis Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with ketorolac. Table 2: Clinically Significant Drug Interactions with Ketorolac Drugs that Interfere with Hemostasis Clinical Impact: • Ketorolac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ketorolac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone [see Clinical Pharmacology (12.3)]. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. • When ketorolac is administered concurrently with pentoxifylline, there is an increased risk of bleeding. Intervention: Monitor patients with concomitant use of SPRIX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Concomitant use of SPRIX and pentoxifylline is contraindicated [see Contraindications (4) and Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of SPRIX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. SPRIX is not a substitute for low dose aspirin for cardiovascular protection. Reference ID: 5482839 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of SPRIX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of SPRIX and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of SPRIX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of ketorolac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of SPRIX and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of SPRIX and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of SPRIX and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of SPRIX and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of SPRIX and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ketorolac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Intervention: The concomitant use of ketorolac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of SPRIX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Reference ID: 5482839 Intervention: During concomitant use of SPRIX and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: Concomitant administration of oral ketorolac and probenecid results in increased half-life and systemic exposure. [see Clinical Pharmacology (12.3)]. Intervention: Concomitant use of SPRIX and probenecid is contraindicated. Antiepileptic Drugs Clinical Impact: Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine). Intervention: During concomitant use of SPRIX and antiepileptic drugs, monitor patients for seizures. Psychoactive Drugs Clinical Impact: Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam). Intervention: During concomitant use of SPRIX and psychoactive drugs, monitor patients for hallucinations. Nondepolarizing Muscle Relaxants Clinical Impact: In postmarketing experience there have been reports of a possible interaction between ketorolac and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac with muscle relaxants has not been formally studied. Intervention: During concomitant use of SPRIX and nondepolarizing muscle relaxants, monitor patients for apnea. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including SPRIX, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SPRIX use between about 20 and 30 weeks of gestation, and avoid SPRIX use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including SPRIX, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Reference ID: 5482839 Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rabbits and rats tested at 0.6 and 1.5 times the human systemic exposure, respectively, at the recommended maximum IN dose of 31.5 mg four times a day, there was no evidence of teratogenicity or other adverse developmental outcomes (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ketorolac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SPRIX, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If SPRIX treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SPRIX and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.6 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg qid, based on area-under-the-plasma-concentration curve [AUC]) in rabbits and at 10 mg/kg Reference ID: 5482839 (1.5 times the human AUC) in rats. These studies did not reveal evidence of teratogenicity or other adverse developmental outcomes. However, because animal dosing was limited by maternal toxicity, these studies do not adequately assess ketorolac’s potential to cause adverse developmental outcomes in humans. 8.2 Lactation Risk Summary Ketorolac is excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SPRIX and any potential adverse effects on the breastfed infant from the SPRIX or from the underlying maternal condition. Clinical Considerations Exercise caution when administering SPRIX to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infant’s health care provider if they note any adverse events. Data Limited data from one published study involving ten nursing mothers 2-6 days postpartum showed low levels of ketorolac in breast milk. Levels were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg ketorolac, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk to plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400-1000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight adjusted dose. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including SPRIX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including SPRIX, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Sprix is not for use in pediatric patients less than 2 years of age. The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established. 8.5 Geriatric Use Exercise caution when treating the elderly (65 years and older) with SPRIX. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Dosage and Administration (2.4), Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14), Clinical Pharmacology (12.3)]. After observing the response to initial therapy with SPRIX, adjust the dose and frequency to suit an individual patient’s needs. Ketorolac and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Reference ID: 5482839 0 OH • 0 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. There has been no experience with overdosage of SPRIX. In controlled overdosage studies with IM ketorolac injection, daily doses of 360 mg given for five days (approximately 3 times the maximum daily dose of SPRIX) caused abdominal pain and peptic ulcers, which healed after discontinuation of dosing. Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION SPRIX (ketorolac tromethamine) Nasal Spray is a member of the pyrrolo-pyrrole group of nonsteroidal anti- inflammatory drugs, available as a clear, colorless to yellow solution packaged in a glass vial with a snap on spray pump that delivers 15.75 mg ketorolac tromethamine per spray and is intended for intranasal administration. The chemical name is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2 (hydroxymethyl)-1,3-propanediol (1:1). The molecular weight is 376.41. Its molecular formula is C19H24N2O6(C15H13NO3•C4H11NO3), and it has the following chemical structure. Ketorolac tromethamine is highly water-soluble, allowing its formulation in an aqueous nasal spray product at pH 7.2. The inactive ingredients in SPRIX include: edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ketorolac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of SPRIX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2), an early component of the arachidonic acid cascade, resulting in the reduced synthesis of prostaglandins, thromboxanes, and prostacyclin. Ketorolac is a potent inhibitor of prostaglandin synthesis in vitro. Ketorolac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ketorolac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics The half-lives of ketorolac by the IN and IM routes were similar. The bioavailability of ketorolac by the IN route of administration of a 31.5 mg dose was approximately 60% compared to IM administration. (See Table 3). Reference ID: 5482839 Table 3: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration Ketorolac Tromethamine Cmax (SD) ng/mL tmax (range) hours AUC 0-∞ (SD) ng•h/mL T½ (SD) hours 30 mg IM (1.0 mL of a 30 mg/mL solution) 2382.2 (432.7) 0.75 (0.25-1.03) 11152.8 (4260.1) 4.80 (1.18) 31.5 mg IN (SPRIX) (2 x 100 µL of a 15% w/w solution) 1805.8 (882.8) 0.75 (0.50-2.00) 7477.3 (3654.4) 5.24 (1.33) 15 mg IM (0.5 mL of a 30 mg/mL solution) 1163.4 (279.9) 0.75 (0.25-1.50) 5196.3 (2076.7) 5.00 (1.72) Cmax = maximum plasma concentration; tmax = time of Cmax; AUC0-∞ = complete area under the concentration-time curve; T½ = half-life; SD = standard deviation. All values are means, except tmax, for which medians are reported. Absorption In a study in which SPRIX (31.5 mg) was administered to healthy volunteers four times daily for 5 days, the Cmax, tmax, and AUC values following the final dose were comparable to those obtained in the single-dose study. Accumulation of ketorolac has not been studied in special populations, geriatric, pediatric, renal failure or hepatic disease patients. Distribution Scintigraphic assessment of drug disposition of ketorolac following SPRIX intranasal dosing demonstrated that most of the ketorolac was deposited in the nasal cavity and pharynx, with less than 20% deposited in the esophagus and stomach, and zero or negligible deposition in the lungs (<0.5%). The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be highly protein bound (99.2%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac tromethamine is excreted in human milk. Elimination Metabolism Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine. There is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. Excretion The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac tromethamine (n = 9) demonstrated that the S enantiomer is cleared approximately two times faster than the R-enantiomer and that the clearance was independent of the route of administration. This means that the ratio of S/R plasma concentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. Reference ID: 5482839 The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours. Specific Populations Geriatric: A single-dose study was conducted to compare the pharmacokinetics of SPRIX (31.5 mg) in subjects ≥ age 65 to the pharmacokinetics in subjects < age 65. Exposure to ketorolac was increased by 23% for the ≥ 65 population as compared to subjects < 65. Peak concentrations of 2028 and 1840 ng/mL were observed for the elderly and nonelderly adult populations, respectively, at 0.75 h after dosing. In the elderly population a longer terminal half-life was observed as compared to the nonelderly adults (4.5 h vs. 3.3 h, respectively). Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients with liver disease compared to healthy volunteers. Renal Impairment: Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects. Allergic Rhinitis: Comparison of the pharmacokinetics of SPRIX in subjects with allergic rhinitis to data from a previous study in healthy subjects showed no differences that would be of clinical consequence for the efficacy or safety of SPRIX. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Other Nasal Spray Products: A study was conducted in subjects with symptomatic allergic rhinitis to assess the effects of the commonly used nasal spray products oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of SPRIX. Subjects received a single dose of oxymetazoline nasal spray followed by a single dose (31.5 mg) of SPRIX 30 min later. Subjects also received fluticasone nasal spray (200 mcg as 2 x 50 mcg in each nostril) for seven days, with a single dose (31.5 mg) of SPRIX on the 7th day. Administration of these common intranasal products had no effect of clinical significance on the rate or extent of ketorolac absorption. Probenecid: Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL), and terminal half-life increased approximately twofold from 6.6 to 15.1 hours [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An 18-month study in mice with oral doses of ketorolac at 2 mg/kg/day (approximately 1.3 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg four times a day, based on area-under-the plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (approximately 0.8 times the human AUC) showed no evidence of tumorigenicity. Reference ID: 5482839 Mutagenesis Ketorolac was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, or in forward mutation assays. Ketorolac did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 µg/mL and at higher concentrations, ketorolac increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (approximately 1.3 times the human AUC) and 16 mg/kg (approximately 2.4 times the human AUC) of ketorolac, respectively. 14 CLINICAL STUDIES 14.1 Postoperative Pain The effect of SPRIX on acute pain was evaluated in two multi-center, randomized, double-blind, placebo-controlled studies. In a study of adults who had undergone elective abdominal or orthopedic surgery, 300 patients were randomized and treated with SPRIX or placebo administered every 8 hours and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX required 36% less morphine over 48 hours than patients treated with placebo. In a study of adults who had undergone elective abdominal surgery, 321 patients were randomized and treated with SPRIX or placebo administered every 6 hours and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX required 26% less morphine over 48 hours than patients treated with placebo. 16 HOW SUPPLIED/STORAGE AND HANDLING SPRIX (ketorolac tromethamine) Nasal Spray, 15.75 mg/spray, are single-day preservative-free spray bottles, supplied as: NDC 69344-144-43 Carton containing 5 single-day nasal spray bottles NDC 69344-144-53 Carton containing 1 single-day nasal spray bottle Each single-day nasal spray bottle contains a sufficient quantity of solution to deliver 8 sprays for a total of 126 mg of ketorolac tromethamine. Each spray delivers 15.75 mg of ketorolac tromethamine. The delivery system is designed to administer precisely metered doses of 100 µL per spray. Storage Protect from light and freezing. Store unopened SPRIX between 2°C to 8°C (36°F to 46°F). During use, keep containers of SPRIX Nasal Spray at controlled room temperature, between 15°C to 30°C (59°F to 86°F), out of direct sunlight. Bottles of SPRIX should be discarded within 24 hours of priming. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) that accompanies each prescription dispensed. Instruct all patients to read and closely follow the FDA-approved SPRIX Patient Instructions to ensure proper administration of SPRIX. When prescribing SPRIX, inform patients or their caregivers of the potential risks of ketorolac treatment, instruct patients to seek medical advice if they develop treatment-related adverse events, advise patients not to give SPRIX to other family members, and advise patients to discard any unused drug. Inform patients, families, or their caregivers of the following information before initiating therapy with SPRIX and periodically during the course of ongoing therapy. Reference ID: 5482839 Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Contraindications (4), Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop SPRIX and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking SPRIX immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including SPRIX, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of SPRIX and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with SPRIX is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of SPRIX with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with SPRIX until they talk to their healthcare provider [see Drug Interactions (7)]. Renal Effects SPRIX is eliminated by the kidneys. Advise patients to maintain adequate fluid intake and request medical advice if urine output decreases significantly [see Contraindications (4), Warnings and Precautions (5.6)]. Reference ID: 5482839 Limitations of Use Instruct patients not to use SPRIX for more than 5 days. Use of SPRIX alone or in combination with any other ketorolac product for more than 5 days increases the risk for serious complications including GI bleeding and renal injury [see Dosage and Administration (2)]. Single-Day Container Instruct patients not to use any single bottle of SPRIX for more than one day [see Dosage and Administration (2.5)]. Nasal Discomfort Advise patients that they may experience transient, mild to moderate nasal irritation or discomfort upon dosing. Manufactured for and Distributed by: Zyla Life Sciences US Inc. Wayne, PA 19087 LBL # 101.05 Reference ID: 5482839 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant.. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482839 What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and sticky like tar • diarrhea • unusual weight gain • itching • skin rash or blisters with fever • your skin or eyes look yellow • swelling of the arms, legs, hands and feet • indigestion or stomach pain • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Zyla Life Sciences US Inc., Wayne, PA 19087 Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 For more information, go to www.sprix.com or call 1-800-518-1084. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: 04/2021 Reference ID: 5482839 Clear Plastic Cover Finger Flange Safety Clip- Instructions for Use SPRIX® (spriks) (ketorolac tromethamine) Nasal Spray Read this Instructions for Use before you start using SPRIX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Important information: • SPRIX is for use in your nose only. Do not breathe in (inhale) SPRIX. • Each SPRIX bottle has enough pain medicine for 1 day. • Throw away each SPRIX bottle within 24 hours of taking your first dose, even if the bottle still contains unused medicine. Your healthcare provider has prescribed SPRIX to treat moderate to severe pain. • Use SPRIX exactly as your healthcare provider tells you to use it. • Your healthcare provider will tell you how many sprays you should use each time you use SPRIX. • Do not use SPRIX for more than 5 days. If you still have pain after 5 days, contact your healthcare provider. • Do not use SPRIX more than every 6 hours. • It is important that you drink plenty of fluids while you are using SPRIX. Tell your healthcare provider if you urinate less while using SPRIX. You may have discomfort or irritation in your nose when using SPRIX. This usually lasts for a short time. Do not breathe in (inhale) SPRIX while spraying. Using SPRIX Nasal Spray Parts of your SPRIX bottle Follow the instructions below to use SPRIX. Before you use SPRIX for the first time, you will need to prime the bottle. Priming SPRIX: Step 1. Hold the finger flange with your fingers (see Figure A), and remove the clear plastic cover with your opposite hand. Keep the clear plastic cover for later. Remove and throw away the blue plastic safety clip. Reference ID: 5482839 Figure A If the clear plastic cover is improperly removed, the tip of the bottle may be pulled off of the glass vial. If this happens, place the tip back onto the glass vial by lining it up carefully and gently pushing it back on until it is back in the correct position (see Figure B). The SPRIX bottle should work properly again. Figure B Step 2. Hold the SPRIX bottle upright at arm’s length away from you with your index finger and middle finger resting on the top of the finger flange and your thumb supporting the base (see Figure C). Press down on the finger flange and release the pump 5 times. You may not see a spray the first few times you press down. Now the pump is primed and ready to use. You do not need to prime the pump again if you use more doses from this bottle. Figure C Step 3. Blow your nose to clear your nostrils. Step 4. Sit up straight or stand. Step 5. Keep your head tilted downward toward your toes. Step 6. Place the tip of the SPRIX bottle into your right nostril. Step 7. Hold the SPRIX bottle upright and aim the tip toward the back of your nose (see Figure D). Reference ID: 5482839 Figure D Step 8. Hold your breath and spray 1 time into your right nostril, pressing down on both sides of the finger flange (see Figure D). Step 9. Breathe in gently through your mouth after you use SPRIX. You may also pinch your nose to help keep the medicine in your nose. Step 10. If your healthcare provider has prescribed only 1 spray per dose for you, you have now finished your dose, skip to Step 12 below. Step 11. If your healthcare provider has prescribed 2 sprays for you, repeat steps 3 - 9 above for your left nostril. Be sure to point the spray away from the center of your nose. Spray 1 time into your left nostril. Step 12. When you are finished using SPRIX, put the clear plastic cover back on the SPRIX bottle. How should I store SPRIX? • Store unopened SPRIX bottles between 36°F to 46°F (2°C to 8°C). • Keep opened bottles of SPRIX at room temperature. • Keep SPRIX out of direct sunlight. • Do not freeze SPRIX. • SPRIX does not contain a preservative. Throw away each SPRIX bottle within 24 hours of taking your first dose, even if the bottle still contains unused medicine. Keep SPRIX and all medicines out of the reach of children. General information about the safe and effective use of SPRIX. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not give SPRIX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SPRIX that is written for health professionals. What are the ingredients in SPRIX? Active ingredient: ketorolac tromethamine Inactive ingredient: edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Zyla Life Sciences US Inc. Wayne, PA 19087 LBL # 102.04 Revised: 04/2021 Reference ID: 5482839	custom-source	2025-02-12T15:47:11.532270	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022382s022lbl.pdf', 'application_number': 22382, 'submission_type': 'SUPPL ', 'submission_number': 22}
80,393	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZORVOLEX® safely and effectively. See full prescribing information for ZORVOLEX. ZORVOLEX (diclofenac) capsules, for oral use Initial U.S. Approval: 1988 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • ZORVOLEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events(5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE ZORVOLEX is a nonsteroidal anti-inflammatory drug indicated for • management of mild to moderate acute pain (1) • management of osteoarthritis pain.(1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2) • The dosage for acute pain is 18 mg or 35 mg orally three times a day. (2) • The dosage for osteoarthritis pain is 35 mg orally three times a day. (2) DOSAGE FORMS AND STRENGTHS ZORVOLEX (diclofenac) capsules: 18 mg and 35 mg (3) CONTRAINDICATIONS • Known hypersensitivity to diclofenac or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop(5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of ZORVOLEX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZORVOLEX in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function(5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: ZORVOLEX is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity)(5.8) • Serious Skin Reactions: Discontinue ZORVOLEX at first appearance of skin rash or other signs of hypersensitivity(5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including ZORVOLEX, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (incidence ≥2%) are edema, nausea, headache, dizziness, vomiting, constipation, pruritus, diarrhea, flatulence, pain in extremity, abdominal pain, sinusitis, alanine aminotransferase increased, blood creatinine increased, hypertension, and dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Zyla Life Sciences US Inc., at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ZORVOLEX with drugs that interfere with hemostasis. Concomitant use of ZORVOLEX and analgesic doses of aspirin is not generally recommended(7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with ZORVOLEX may diminish the antihypertensive effect of these drugs. Monitor blood pressure(7) • ACE Inhibitors and ARBs: Concomitant use with ZORVOLEX in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with ZORVOLEX can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of ZORVOLEX in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482840 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Dosage Adjustments in Patients with Hepatic Impairment 2.3 Non-Interchangeability with Other Formulations of Diclofenac 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, andPerforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to AspirinSensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482840 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • ZORVOLEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE ZORVOLEX is indicated for: • Management of mild to moderate acute pain • Management of osteoarthritis pain 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of ZORVOLEX and other treatment options before deciding to use ZORVOLEX. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. The effectiveness of ZORVOLEX when taken with food has not been studied in clinical studies. Taking ZORVOLEX with food may cause a reduction in effectiveness compared to taking ZORVOLEX on an empty stomach [see Clinical Pharmacology (12)]. Acute Pain For management of mild to moderate acute pain, the dosage is 18 mg or 35 mg orally three times daily. Osteoarthritis Pain For management of osteoarthritis pain, the dosage is 35 mg orally three times daily. Reference ID: 5482840 2.2 Dosage Adjustments in Patients with Hepatic Impairment Patients with hepatic disease may require reduced doses of ZORVOLEX compared to patients with normal hepatic function [see Clinical Pharmacology (12)]. As with other diclofenac products, start treatment at the lowest dose. If efficacy is not achieved with the lowest dose, discontinue use. 2.3 Non-Interchangeability with Other Formulations of Diclofenac ZORVOLEX capsules are not interchangeable with other formulations of oral diclofenac even if the milligram strength is the same. ZORVOLEX capsules contain diclofenac free acid whereas other diclofenac products contain a salt of diclofenac, i.e., diclofenac potassium or sodium. A 35 mg dose of ZORVOLEX is approximately equal to 37.6 mg of sodium diclofenac or 39.5 mg of potassium diclofenac. Therefore, do not substitute similar dosing strengths of other diclofenac products without taking this into consideration. 3 DOSAGE FORMS AND STRENGTHS ZORVOLEX (diclofenac) capsules: 18 mg - blue body and light green cap (imprinted IP-203 on the body and 18 mg on the cap in white ink). ZORVOLEX (diclofenac) capsules: 35 mg - blue body and green cap (imprinted IP-204 on the body and 35 mg on the cap in white ink). 4 CONTRAINDICATIONS ZORVOLEX is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. Reference ID: 5482840 To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ZORVOLEX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ZORVOLEX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Reference ID: 5482840 Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ZORVOLEX until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more then 90 days. Reference ID: 5482840 Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with ZORVOLEX, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), ZORVOLEX should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ZORVOLEX immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with ZORVOLEX, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing ZORVOLEX with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, and anti-epileptics). 5.4 Hypertension NSAIDs, including ZORVOLEX, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of ZORVOLEX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ZORVOLEX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Reference ID: 5482840 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of ZORVOLEX in patients with advanced renal disease. The renal effects of ZORVOLEX may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating ZORVOLEX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ZORVOLEX [see Drug Interactions (7)]. Avoid the use of ZORVOLEX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ZORVOLEX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ZORVOLEX is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ZORVOLEX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 5482840 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life- threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ZORVOLEX at the first appearance of skin rash or any other sign of hypersensitivity. ZORVOLEX is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ZORVOLEX. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ZORVOLEX and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDS, including ZORVOLEX, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including ZORVOLEX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including ZORVOLEX, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ZORVOLEX use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ZORVOLEX treatment extends beyond 48 hours. Discontinue ZORVOLEX if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ZORVOLEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including ZORVOLEX, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, concomitant use of warfarin, other anticoagulants, Reference ID: 5482840 antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of ZORVOLEX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Patients with Acute Pain Two-hundred sixteen (216) patients received ZORVOLEX in the completed, 48-hour, double-blind, placebo-controlled, clinical trial of acute pain following bunionectomy. The most frequent adverse reactions in this study are summarized in Table 1. Table 1 Summary of Adverse Reactions (≥2% in ZORVOLEX 18 mg or 35 mg group) – Phase 3 Study in Patients With Postsurgical Pain ZORVOLEX 18 mg or 35 mg Adverse Reactions three times daily* Placebo* N = 216 N = 106 Edema 33% 32% Nausea 27% 37% Headache 13% 15% Dizziness 10% 16% Vomiting 9% 12% Constipation 8% 4% Pruritus 7% 6% Flatulence 3% 2% Reference ID: 5482840 Pain in Extremity 3% 1% Dyspepsia 2% 1% One tablet of hydrocodone/acetaminophen 10 mg/325 mg was permitted every 4 to 6 hours as rescue medication for pain management. There was a greater use of concomitant opioid rescue medication in placebo-treated patients than in ZORVOLEX-treated patients. About 82% of patients in the ZORVOLEX 35 mg group, 85% of the patients in the ZORVOLEX 18 mg group, and 97% of patients in the placebo group took rescue medication for pain management during the study. Adverse Reactions in Patients with Osteoarthritis Pain Two-hundred two (202) patients received ZORVOLEX in the completed, 12-week, double- blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 2. Table 2 Summary of Adverse Reactions (≥2%) – 12-week Phase 3 Study in Patients With Osteoarthritis Pain Adverse Reactions ZORVOLEX 35 mg N=202 Placebo N=103 Nausea 7% 2% Diarrhea 6% 3% Headache 4% 3% Abdominal Pain Upper 3% 1% Sinusitis 3% 1% Vomiting 3% 1% Alanine Aminotransferase Increased 2% 0 Blood Creatinine Increased 2% 0 Dyspepsia 2% 1% Flatulence 2% 0 Hypertension 2% 1% * Adverse reactions that occurred in >2% of patients treated with ZORVOLEX and occurred more frequently than in patients treated with placebo Six-hundred one (601) patients received ZORVOLEX 35 mg either twice or three times daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of those, 360 (60%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 3. Table 3 Summary of Adverse Reactions (≥2%) – 52-week Open-label Study in Patients with Osteoarthritis Pain ZORVOLEX 35 mg Adverse Reactions N=601 Upper respiratory tract infection 8% Headache 8% Urinary tract infection 7% Diarrhea 6% Nasopharyngitis 6% Nausea 6% Constipation 5% Sinusitis 5% Osteoarthritis 5% Cough 4% Alanine aminotransferase increased 4% Reference ID: 5482840 Back pain 3% Dyspepsia 3% Procedural pain 3% Bronchitis 3% Hypertension 3% Abdominal pain upper 3% Influenza 3% Arthralgia 3% Contusion 3% Vomiting 3% Abdominal discomfort 2% Aspartate aminotransferase increased 2% Dizziness 2% Fall 2% Abdominal pain 2% Adverse reactions reported for diclofenac and other NSAIDs: In patients taking other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus. Additional adverse reactions reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses: blurred vision Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic Reference ID: 5482840 anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses: conjunctivitis, hearing impairment 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of diclofenac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 4 for clinically significant drug interactions with diclofenac. Table 4 Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ZORVOLEX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of ZORVOLEX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. ZORVOLEX is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Reference ID: 5482840 Intervention: • During concomitant use of ZORVOLEX and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of ZORVOLEX and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ZORVOLEX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ZORVOLEX and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ZORVOLEX and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ZORVOLEX and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of ZORVOLEX and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of ZORVOLEX and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of ZORVOLEX and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Reference ID: 5482840 Intervention: During concomitant use of ZORVOLEX and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Inhibitors or Inducers of Cytochrome P450 2C9 Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co- administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including ZORVOLEX, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ZORVOLEX use between about 20 and 30 weeks of gestation, and avoid ZORVOLEX use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDS, including ZORVOLEX, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, and rabbits given diclofenac during the period of organogenesis at doses approximately 1, 1, and 2 times, respectively, the maximum recommended human dose (MRHD) of ZORVOLEX despite the presence of maternal and fetal toxicity at these doses [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or Reference ID: 5482840 other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ZORVOLEX, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ZORVOLEX treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ZORVOLEX and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD] of ZORVOLEX, 105 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 1 and 2 times, respectively, the MRHD based on BSA comparison). In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been Reference ID: 5482840 shown to cross the placental barrier in mice, rats, and humans. 8.2 Lactation Risk Summary Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZORVOLEX and any potential adverse effects on the breastfed infant from the ZORVOLEX or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ZORVOLEX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including ZORVOLEX, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of ZORVOLEX in pediatric patients has not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in Reference ID: 5482840 OH symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). 11 DESCRIPTION ZORVOLEX (diclofenac) capsules are a nonsteroidal anti-inflammatory drug, available as hard gelatin capsules of 18 mg and 35 mg for oral administration. The chemical name is 2 [(2, 6-dichlorophenyl) amino] benzeneacetic acid. The molecular weight is 296.15. Its molecular formula is C14H11Cl2NO2, and it has the following chemical structure. Diclofenac acid is a white to slight yellowish crystalline powder. Diclofenac acid has a pKa of 4.18 and a logP of 3.03. It is practically insoluble in water and sparingly soluble in ethanol. The inactive ingredients in ZORVOLEX include a combination of lactose monohydrate, sodium lauryl sulfate, microcrystalline cellulose, croscarmellose sodium and sodium stearyl fumarate. The capsule shells contain gelatin, titanium dioxide, and dyes FD&C blue #1, FD&C blue #2, FDA/E172 Yellow Iron Oxide and FDA/E172 Black Iron Oxide. The imprinting on the gelatin capsules is white edible ink. The 18 mg capsules have a blue body imprinted with IP-203 and light green cap imprinted with 18 mg in white ink. The 35 mg capsules have a blue body imprinted with IP-204 and green cap imprinted with 35 mg in white ink. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of ZORVOLEX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics The relative bioavailability of ZORVOLEX 35 mg capsules was compared to diclofenac potassium immediate-release (IR) tablets 50 mg in 39 healthy subjects under fasted and fed conditions in a single-dose crossover study. Reference ID: 5482840 ZORVOLEX 35 mg capsules do not result in an equivalent systemic exposure to 50 mg diclofenac potassium IR tablets. When taken under fasted conditions, a 20% lower dose of diclofenac in ZORVOLEX capsules resulted in a 23% lower mean systemic exposure (AUCinf) and a 26% lower mean peak concentration (Cmax) compared to diclofenac potassium IR tablets. The time to reach peak concentration (Tmax) was similar for ZORVOLEX and diclofenac potassium IR tablets and was ~1 hour for both. When taken under fed conditions, a 20% lower dose of diclofenac in ZORVOLEX capsules resulted in a 23% lower mean systemic exposure (AUCinf) and a 48% lower mean Cmax compared to diclofenac potassium IR tablets. The Tmax for ZORVOLEX was delayed by approximately 1 hour compared to diclofenac potassium IR tablets (3.32 hours vs. 2.33 hours, respectively). When taken under fed conditions, ZORVOLEX capsules resulted in an 11% lower mean systemic exposure (AUCinf) and a 60% lower mean Cmax compared to fasted conditions. Whereas diclofenac potassium IR tablets under fed conditions resulted in 8% - 10% lower mean systemic exposure (AUCinf) and 28% - 43% lower mean Cmax compared to fasted conditions, based on the results from two individual food effect studies. The Tmax for ZORVOLEX was delayed by approximately 2.32 hours under fed conditions compared to fasted conditions (3.32 hours vs. 1.00 hour, respectively), while the Tmax for diclofenac potassium IR tablets was delayed by approximately 1.00 - 1.33 hours under fed conditions compared to fasted conditions (1.70 vs. 0.74 hours and 2.33 vs. 1.00 hours, respectively in two studies). There were no differences in elimination half-life between ZORVOLEX and diclofenac potassium IR tablets under fasted or fed conditions. Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of diclofenac in plasma occurred. Administration of ZORVOLEX capsules 18 mg and 35 mg was associated with dose proportional pharmacokinetics. Taking ZORVOLEX with food causes a significant decrease in the rate but not the overall extent of systemic absorption of diclofenac compared with taking ZORVOLEX on an empty stomach. ZORVOLEX capsules results in 60% lower Cmax, 11% lower AUCinf, and 2.32 hours delayed Tmax (1.0 hour during fasted versus 3.32 hours during fed) under the fed condition compared to the fasted condition. The effectiveness of ZORVOLEX when taken with food has not been studied in clinical studies. The decreased Cmax may be associated with decreased effectiveness. Taking ZORVOLEX with food may cause a reduction in effectiveness compared to taking ZORVOLEX on an empty stomach. Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 mg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Reference ID: 5482840 Elimination Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. The terminal half-life of unchanged diclofenac is approximately 2 hours. Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3' hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy-diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Specific Populations Pediatric: The pharmacokinetics of ZORVOLEX has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race/ethnicity have not been identified. Hepatic Impairment: No dedicated diclofenac pharmacokinetics studies in patients with hepatic impairment were conducted. Hepatic metabolism accounts for almost 100% of diclofenac elimination. Therefore, in patients with hepatic impairment, start with the lowest dose and if efficacy is not achieved, consider use of an alternate product [see Warnings and Precautions (5.3)]. Renal Impairment: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and less than 30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 4 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Reference ID: 5482840 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.2 times the maximum recommended human dose [MRHD] of ZORVOLEX based on body surface area [BSA] comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.014 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.04 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential. Mutagenesis Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.4 times the MRHD based on BSA comparison) did not affect fertility. 14 CLINICAL STUDIES Acute Pain The efficacy of ZORVOLEX in the management of acute pain was demonstrated in a single multicenter, randomized, double-blind, placebo-controlled, parallel arm study comparing ZORVOLEX 18 mg and 35 mg taken three times a day, placebo, and celecoxib in patients with pain following bunionectomy. The study enrolled 428 patients with a mean age of 40 years (range 18 to 65 years) and a minimum pain intensity rating of at least 40 mm on a 100-mm visual analog scale (VAS) during the 9-hour period after discontinuation of the anesthetic block following bunionectomy surgery. Patients were randomized equally across the treatment groups. The mean and range (in parenthesis) of pain intensities on the VAS at baseline were 74 mm (44 to 100 mm), 77 mm (41 to 100 mm), and 76 mm (40 to 100 mm) for the ZORVOLEX 35 mg, ZORVOLEX 18 mg, and placebo groups, respectively. One tablet of hydrocodone/acetaminophen 10 mg/325 mg was permitted every 4 to 6 hours as rescue medication. About 82% of patients in the ZORVOLEX 35 mg group, 85% of the patients in the ZORVOLEX 18 mg group, and 97% of patients in the placebo group took rescue medication for pain management during the study. The average pain intensities over time are depicted for the treatment groups in Figure 1. Both ZORVOLEX 18 mg and 35 mg demonstrated efficacy in pain intensity reduction compared with placebo, as measured by the sum of pain intensity difference over 0 to 48 hours after the first dose. Figure 1 Average Pain Intensity Over 48 Hours for ZORVOLEX 18 mg, ZORVOLEX 35 mg, and Placebo Groups Reference ID: 5482840 00 90 cg ... 0 80 ~ ?: 70 "iii C 60 !I .5 so .s "' ~ 40 i 30 C "' 20 cg :E 10 0 0 4 8 12 6 20 24 28 32 36 40 44 48 Time IHours) ~ Zorvolex Capsules 35 mg TCD ~ Zorvolex Capsules 18 mg TID -.-Placebo Osteoarthritis Pain The efficacy of ZORVOLEX in the management of osteoarthritis pain was demonstrated in a single multicenter, randomized, double-blind, placebo-controlled, parallel-arm study comparing ZORVOLEX 35 mg taken twice a day or three times a day and placebo in patients with osteoarthritis of the knee or hip. The study enrolled 305 patients with a mean age of 62 (range 41 to 90 years). Osteoarthritis pain was measured using the Western Ontario and McMaster University Osteoarthritis Index Pain Subscale (WOMAC Pain Subscale). Mean baseline WOMAC Pain Subscale Score across treatment groups was 75 mm using a 0 to 100 mm visual analog scale. The primary efficacy parameter was the change from baseline at 12 weeks in the WOMAC Pain Subscale. ZORVOLEX 35 mg three times a day reduced osteoarthritis pain compared with placebo, as measured by WOMAC Pain Subscale Score. The distribution (%) of patients achieving various percentage reductions in pain intensity at Week 12 are depicted in Figure 2. Reference ID: 5482840 ----. "'I-"- '"""'L, ................... "'"\..._ ...... , -,_ "'\. "I..,_ ..,_ "\ "'I- ..... "\, ...,_ ..... ',.; 0 Figure 2 Distribution (%) of Patients Achieving Various Percentage Reductions in Pain Intensity at Week 12 100 90 80 70 60 50 40 30 20 10 ≥0 ≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 ≥100 % Reduction from Baseline in WOMAC Pain Subscale Scores Zorvolex Capsules 35 mg TID Placebo Proportion (%) of Patients Achieving Reduction 16 HOW SUPPLIED/STORAGE AND HANDLING ZORVOLEX (diclofenac) capsules are supplied as: • 18 mg - blue body and light green cap (imprinted IP-203 on the body and 18 mg on the cap in white ink) • NDC (69344-203-29), Bottles of 90 capsules • 35 mg - blue body and green cap (imprinted IP-204 on the body and 35 mg on the cap in white ink) • NDC (69344-204-29), Bottles of 90 capsules Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with ZORVOLEX and periodically during the course of ongoing therapy. Reference ID: 5482840 Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop ZORVOLEX and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking ZORVOLEX immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including ZORVOLEX, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of ZORVOLEX and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with ZORVOLEX is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of ZORVOLEX with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Reference ID: 5482840 Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with ZORVOLEX until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured (under license from iCeutica Pty Ltd.) for and Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 ©2019 Zyla Life Sciences. All rights reserved. US Patent Nos. 8679544, 8999387, 9017721, 9173854, 9180095, 9180096, and 9186328 LBL# 501.02 Reference ID: 5482840 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: opast history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs otaking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks ofpregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with h h d i id ff D ki di i ith lki What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) Reference ID: 5482840 • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: •shortness of breath or trouble breathing •slurred speech •chest pain •swelling of the face or throat •weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: •nausea • vomit blood •more tired or weaker than usual • there is blood in your bowel movement or •diarrhea it is black and sticky like tar •itching • unusual weight gain •your skin or eyes look yellow • skin rash or blisters with fever • indigestion orstomach pain • swelling of the arms, legs, hands and •flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach andintestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 For more information, go to WWW.ZORVOLEX.COM or call 1-800-518-1084. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 Reference ID: 5482840	custom-source	2025-02-12T15:47:11.858323	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/204592s014lbl.pdf', 'application_number': 204592, 'submission_type': 'SUPPL ', 'submission_number': 14}
80,390	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CALDOLOR® safely and effectively. See full prescribing information for CALDOLOR. CALDOLOR (ibuprofen injection), for intravenous use Initial U.S. Approval: 1974 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning • Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • CALDOLOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ---------------------------RECENTMAJORCHANGES---------------------------- Warnings and Precautions (5.9) 11/2024 -----------------------------INDICATIONS AND USAGE------------------------- CALDOLOR is a nonsteroidal anti-inflammatory drug indicated in adults and pediatric patients aged 3 months and older for the: • Management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics (1) • Reduction of fever (1) -------------------------DOSAGE AND ADMINISTRATION-------------------- • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (2.1) • CALDOLOR Injection vials must be diluted before administration. (2.1) • CALDOLOR Injection bags are ready to use. (2.1) • Adult Pain: 400 mg to 800 mg intravenously over 30 minutes every 6 hours as necessary. (2.2) • Adult Fever: 400 mg intravenously over 30 minutes, followed by 400 mg every 4 to 6 hours or 100-200 mg every 4 hours as necessary. (2.2) • Pediatric (pain and fever) ages 12 to 17 years of age: 400 mg intravenously over 10 minutes every 4 to 6 hours as necessary. (2.3) • Pediatric (pain and fever) aged 6 months to less than 12 years of age: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. (2.3) • Pediatric (pain and fever) aged 3 months to less than 6 months: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 100 mg. (2.3) ------------------------DOSAGE FORMS AND STRENGTHS------------------ Injection: • 800 mg/8 mL (100 mg/mL) single dose vial (3) • 800 mg/200 mL (4 mg/mL) single dose, ready-to-use, polypropylene flexible bag (3) -------------------------------CONTRAINDICATIONS----------------------------- • Known hypersensitivity to ibuprofen or any component of the drug product (4) • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) -------------------------WARNINGS AND PRECAUTIONS--------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4, 7) • Heart Failure and Edema: Avoid use of CALDOLOR in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of CALDOLOR in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: CALDOLOR is contraindicate d in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) • Serious Skin Reactions: Discontinue CALDOLOR at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.10) • Fetal Toxicity: Limit use of NSAIDs, including CALDOLOR, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.11, 7) -------------------------------ADVERSE REACTIONS----------------------------- The most common adverse reactions are nausea, flatulence, vomiting, headache, hemorrhage and dizziness (>5%). The most common adverse reactions in pediatric patients are infusion site pain, vomiting, nausea, anemia and headache (>2%). (6) To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------------------DRUG INTERACTIONS--------------------------- • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking CALDOLOR with drugs that interfere with hemostasis. Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended. (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with CALDOLOR may diminish the antihypertensive effect of these drugs. Monitor blood pressure .(7) • ACE Inhibitors and ARBs: Concomitant use with CALDOLOR in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) • Digoxin: Concomitant use with CALDOLOR can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7) --------------------------USE IN SPECIFIC POPULATIONS-------------------- Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of CALDOLOR in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 Reference ID: 5482836 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Adults 2.3 Pediatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Ophthalmological Effects 5.16 Aseptic Meningitis 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Analgesia (Pain) 14.2 Antipyretic (Fever) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the Full Prescribing Information are not listed. Reference ID: 5482836 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events •Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. [see Warnings and Precautions (5.1)]. •CALDOLOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration and Perforation •NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE CALDOLOR is indicated in adults and pediatric patients aged 3 months and older for the: • management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics • reduction of fever 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with CALDOLOR, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed 3200 mg total daily dose in adults. Do not exceed 40 mg/kg or 2,400 mg, whichever is less, total daily dose in pediatric patients 6 months to 17 years of age. The dosage is limited to a single dose not to exceed 10 mg/kg or 100 mg, whichever is less, in pediatric patients 3 months to less than 6 months of age. To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of CALDOLOR. CALDOLOR injection 800 mg/8 mL (100 mg/mL) vials MUST BE DILUTED prior to administration. Dilute to a final concentration of 4 mg/mL or less. Appropriate diluents include 0.9% Sodium Chloride Injection USP (normal saline), 5% Dextrose Injection USP (D5W), or Lactated Ringers Solution. • 100 mg dose: Dilute 1 mL of CALDOLOR in at least 100 mL of diluent • 200 mg dose: Dilute 2 mL of CALDOLOR in at least 100 mL of diluent • 400 mg dose: Dilute 4 mL of CALDOLOR in at least 100 mL of diluent • 800 mg dose: Dilute 8 mL of CALDOLOR in at least 200 mL of diluent CALDOLOR injection 800 mg/200 mL (4 mg/mL) polypropylene flexible bags are ready to use, intended for 800 mg doses only. For weight-based dosing at 10 mg/kg ensure that the concentration of CALDOLOR is 4 mg/mL or less. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used. Diluted solutions are stable for up to 24 hours at ambient temperature (approximately 20° C to 25° C) and room lighting. 2.2 Adults For Analgesia (pain): The dose is 400 mg to 800 mg intravenously every 6 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg. Reference ID: 5482836 For Fever: The dose is 400 mg intravenously, followed by 400 mg every 4 to 6 hours or 100 mg to 200 mg every 4 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg. 2.3 Pediatric Patients For Analgesia (pain) and Fever: Ages 12 to 17 years The dose is 400 mg intravenously every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less. Ages 6 months to less than 12 years The dose is 10 mg/kg intravenously up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less. Pediatric Dosing as Necessary for Fever and Pain Age Group Dose Dosing Interval Min infusion time Max daily dose 6 months to less than 12 years 10 mg/kg up to 400 mg max Every 4 to 6 hours as necessary 10 minutes 40 mg/kg or 2,400 mg 12 to 17 years 400 mg Every 4 to 6 hours as necessary 10 minutes 40 mg/kg or 2,400 mg Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less. Ages 3 months to less than 6 months The dose is a single dose at 10 mg/kg intravenously up to a maximum single dose of 100 mg. Infusion time must be at least 10 minutes. 3 DOSAGE FORMS AND STRENGTHS CALDOLOR (ibuprofen injection) is a clear, colorless, non-pyrogenic, aqueous solution intended for intravenous use available in following strengths: • 800 mg/8 mL (100 mg/mL) single dose vial • 800 mg/200 mL (4 mg/mL) single dose, ready-to-use, polypropylene, flexible bag 4 CONTRAINDICATIONS CALDOLOR is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. Reference ID: 5482836 There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of CALDOLOR in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If CALDOLOR is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months and in about 2%-4% of patients treated for one year. However, even short-term therapy is not without risk. Risk Factors for GI Bleeding, Ulceration and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue CALDOLOR until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID- treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs, including ibuprofen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue CALDOLOR immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension Reference ID: 5482836 NSAIDs, including CALDOLOR, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of CALDOLOR in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If CALDOLOR is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of CALDOLOR in patients with advanced renal disease. The renal effects of CALDOLOR may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating CALDOLOR. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of CALDOLOR [see Drug Interactions (7)]. Avoid the use of CALDOLOR in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If CALDOLOR is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronism state. 5.7 Anaphylactic Reactions Ibuprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, CALDOLOR is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When CALDOLOR is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including ibuprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of CALDOLOR at the first appearance of skin rash or any other sign of hypersensitivity. CALDOLOR is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. Reference ID: 5482836 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CALDOLOR. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue CALDOLOR and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including CALDOLOR, in pregnant women at about 30 weeks gestation and later. NSAIDs, including CALDOLOR, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including CALDOLOR, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit CALDOLOR use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if CALDOLOR treatment extends beyond 48 hours. Discontinue CALDOLOR if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with CALDOLOR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including CALDOLOR may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorder, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. CALDOLOR must be diluted prior to use. Infusion of the drug product without dilution can cause hemolysis [see Dosage and Administration (2.1)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of CALDOLOR in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Ophthalmological Effects Blurred or diminished vision, scotomata, and changes in color vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such complaints and refer the patient for an ophthalmologic examination that includes central visual fields and color vision testing. 5.16 Aseptic Meningitis Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have underlying chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen, give consideration to whether or not the signs or symptoms are related to ibuprofen therapy. Reference ID: 5482836 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Population During clinical development, 560 patients were exposed to CALDOLOR, 438 in pain and 122 with fever. In the pain studies, CALDOLOR was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, CALDOLOR was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days. The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal. Pain Studies The incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post operative patients comparing CALDOLOR to placebo in patients also receiving morphine as needed for post-operative pain. Table 1: Post-operative Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in Pain Studies* Event CALDOLOR Placebo (N=287) 400 mg (N=134) 800 mg (N=304) Any Reaction 118 (88%) 260 (86%) 258 (90%) Nausea 77 (57%) 161 (53%) 179 (62%) Vomiting 30 (22%) 46 (15%) 50 (17%) Flatulence 10 (7%) 49 (16%) 44 (15%) Headache 12 (9%) 35 (12%) 31 (11%) Hemorrhage 13 (10%) 13 (4%) 16 (6%) Dizziness 8 (6%) 13 (4%) 5 (2%) Edema peripheral 1 (<1%) 9 (3%) 4 (1%) Urinary retention 7 (5%) 10 (3%) 10 (3%) Anemia 5 (4%) 7 (2%) 6 (2%) Decreased hemoglobin 4 (3%) 6 (2%) 3 (1%) Dyspepsia 6 (4%) 4 (1%) 2 (<1%) Wound hemorrhage 4 (3%) 4 (1%) 4 (1%) Abdominal discomfort 4 (3%) 2 (<1%) 0 Cough 4 (3%) 2 (<1%) 1 (<1%) Hypokalemia 5 (4%) 3 (<1%) 8 (3%) * All patients received concomitant morphine during these studies. Fever Studies Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two CALDOLOR-treated patients included abdominal pain and nasal congestion. In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below. Reference ID: 5482836 7 Table 2: Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in All-Cause Fever Study Event CALDOLOR Placebo N=28 100 mg N=30 200 mg N=30 400 mg N=31 Any Reaction 27 (87%) 25 (83%) 23 (74%) 25 (89%) Anemia 5 (17%) 6 (20%) 11 (36%) 4 (14%) Eosinophilia 7 (23%) 7 (23%) 8 (26%) 7 (25%) Hypokalemia 4 (13%) 4 (13%) 6 (19%) 5 (18%) Hypoproteinemia 3 (10%) 0 4 (13%) 2 (7%) Neutropenia 2 (7%) 2 (7%) 4 (13%) 2 (7%) Blood urea increased 0 0 3 (10%) 0 Hypernatremia 2 (7%) 0 3 (10%) 0 Hypertension 0 0 3 (10%) 0 Hypoalbuminemia 3 (10%) 1 (3%) 3 (10%) 1 (4%) Hypotension 0 2 (7%) 3 (10%) 1 (4%) Diarrhea 3 (10%) 3 (10%) 2 (7%) 2 (7%) Pneumonia bacterial 3 (10%) 1 (3%) 2 (7%) 0 Blood LDH increased 3 (10%) 2 (7%) 1 (3%) 1 (4%) Thrombocythemia 3 (10%) 2 (7%) 1 (3%) 0 Bacteremia 4 (13%) 0 0 0 Pediatric Population A total of 143 pediatric patients ages 6 months and older have received CALDOLOR in controlled clinical trials. The most common adverse reactions (incidence greater than or equal to 2%) in pediatric patients treated with CALDOLOR were infusion site pain, vomiting, nausea, anemia and headache. Twenty-one hospitalized patients ages 3 months to less than 6 months were treated with CALDOLOR for pain or fever in an open-label, non-controlled clinical study; 18 of 21 patients were treated with a single dose. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with ibuprofen. Table 3: Clinically Significant Drug Interactions with Ibuprofen Drugs That Interfere with Hemostasis Clinical Impact: • Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin released by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of CALDOLOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Pharmacodynamic (PD) studies have demonstrated interference with the antiplatelet activity of aspirin when Impact: ibuprofen 400 mg, given three times daily, is administered with enteric-coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology (12.2)]. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an Reference ID: 5482836 NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. CALDOLOR is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of CALDOLOR and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of CALDOLOR and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of CALDOLOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of CALDOLOR and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of CALDOLOR and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of CALDOLOR and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of CALDOLOR and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of CALDOLOR and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of CALDOLOR and pemetrexed, may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: • During concomitant use of CALDOLOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. • NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. • In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Reference ID: 5482836 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including CALDOLOR, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of CALDOLOR use between about 20 and 30 weeks of gestation, and avoid CALDOLOR use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including CALDOLOR, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including CALDOLOR, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If CALDOLOR treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue CALDOLOR and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of CALDOLOR during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable Reference ID: 5482836 estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.04, 0.12, or 0.36-times the maximum recommended human daily dose of 3200 mg of ibuprofen based on body surface area) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.02, 0.06, 0.18, 0.54-times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above. In a published study, rats were orally dosed with 300 mg/kg ibuprofen (0.912-times the maximum human daily dose of 3200 mg based on body surface area) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity. One incidence each of a membranous ventricular septal defect and gastroschisis was noted in fetuses from rabbits treated with 500 mg/kg (3-times the maximum human daily dose) from Gestation Day 9-11. 8.2 Lactation Risk Summary No lactation studies have been conducted with CALDOLOR; however, limited published literature reports that, following oral administration, ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose. There are no reports of adverse effects on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CALDOLOR and any potential adverse effects on the breastfed infant from the CALDOLOR or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including CALDOLOR, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including CALDOLOR in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of CALDOLOR have been established for the treatment of pain and fever in pediatric patients aged 3 months and older. Use of CALDOLOR for these indications is supported by evidence from one open-label and acetaminophen controlled study of fever and additional safety data from four studies in 164 pediatric patients, supportive pediatric data from other approved ibuprofen products, and evidence from adequate and well-controlled studies in adults [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)]. Safety and effectiveness of CALDOLOR in pediatric patients less than 3 months of age for treatment of pain and fever have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Clinical studies of CALDOLOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients are at increased risk for serious GI adverse events. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Reference ID: 5482836 For additional information about overdosage treatment contact a poison control center at 1-800-222-1222. 11 DESCRIPTION CALDOLOR (ibuprofen injection) is a nonsteroidal anti-inflammatory drug, available as an 800 mg/8 mL single dose vial (100 mg/mL) and 800 mg/200 mL (4 mg/mL) polypropylene, single dose, ready-to-use, flexible bag for intravenous administration. The chemical name is ibuprofen, which is (±)-2-(p-isobutylphenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74°C to 77°C. It has a molecular weight of 206.28. It is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is represented below: CALDOLOR 800 mg/8 mL (100 mg/mL) vial: Each 1 mL of solution contains 100 mg of ibuprofen, USP, 78 mg of arginine (at a molar ratio of 0.92:1 arginine:ibuprofen), and 10% arginine solution and hydrochloric acid as pH adjusters in Water for Injection, USP. The solution pH is about 7.4. CALDOLOR 800 mg/200 mL (4 mg/mL) polypropylene flexible bag: Each 1 mL of solution contains 4 mg of ibuprofen, USP, 3.11 mg of dibasic sodium phosphate, as a buffering agent; 6.30 mg sodium chloride as a tonicity agent; and sodium hydroxide as a pH adjuster in Water for Injection, USP. The solution is iso-osmotic with an approximate pH of 7.4. CALDOLOR is sterile and is intended for intravenous administration only. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ibuprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of CALDOLOR, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Ibuprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, ibuprofen 400 mg given once daily, administered 2 hours prior to immediate-release aspirin (81 mg) for 6 days, showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 (TxB2) inhibition at 24 hours following the day-6 aspirin dose [53%]. An interaction was still observed, but minimized, when ibuprofen 400 mg given once- daily was administered as early as 8 hours prior to the immediate-release aspirin dose [90.7%]. However, there was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg, given once daily, was administered 2 hours after (but not concomitantly, 15 min, or 30 min after) the immediate-release aspirin dose [99.2%]. In another study, where immediate-release aspirin 81 mg was administered once daily with ibuprofen 400 mg given three times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, the mean % serum thromboxane B2 (TxB2) inhibition suggested no interaction with the antiplatelet activity of aspirin [98.3%]. However, there were individual subjects with serum TxB2 inhibition below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin, where healthy subjects were administered enteric-coated aspirin 81 mg once daily for 6 days and ibuprofen 400 mg three times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours following the day-6 aspirin dose [67%]. [See Drug Interactions (7)]. 12.3 Pharmacokinetics Ibuprofen is a racemic mixture of [-]R- and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~60%) interconverted into Reference ID: 5482836 the active [+]S species in adults. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. The pharmacokinetic parameters of CALDOLOR determined in a study with volunteers are presented below. Table 4: Pharmacokinetic Parameters of Intravenous Ibuprofen 400 mg* CALDOLOR Mean (SD) 800 mg* CALDOLOR Mean (SD) Number of Patients 12 12 AUC (mcg·h/mL) 109.3 (28.9) 192.8 (35.7) Cmax (mcg/mL) 39.2 (6.09) 72.6 (9.61) KEL (1/h) 0.32 (0.06) 0.29 (0.04) T1/2 (h) 2.22 (0.45) 2.44 (0.31) AUC = Area-under-the-curve Cmax = Peak plasma concentration CV = Coefficient of Variation KEL = First-order elimination rate constant T1/2 = Elimination half-life * = 60 minute infusion time The pharmacokinetic parameters of CALDOLOR determined in a study with febrile pediatric patients are presented in Table 5. It was observed that the median Tmax was at the end of the infusion and that CALDOLOR had a shorter elimination half-life in pediatric patients compared to adults. Table 5: Pharmacokinetic Parameters of 10 mg/kg Intravenous** Ibuprofen, Pediatric Patients, by Age Group 3 months to <6 months^ Mean (SD) 6 months to <2 years Mean (SD) 2 years to <6 years Mean (SD) 6 years to 16 years Mean (SD) Number of Patients 20 5 12 25 AUC (mcg·h/mL) 69.63 (19.28) 71.1 (26.4) 79.2 (29.3) 80.7 (29.8) Cmax (mcg/mL) 59.75 (12.85) 59.2 (20.6) 64.2 (22.1) 61.9 (16.5) Tmax (min)* 10 10 (10-30) 12 (10-46) 10 (10-40) T1/2 (h) 1.3 1.8 (0.5) 1.5 (0.6) 1.55 (0.41) Median (minimum-maximum) ^Open-label study with hospitalized pediatric patients with pain or fever *= 10 minute infusion time Ibuprofen, like most NSAIDs, is highly protein bound (>99% bound at 20 mcg/mL). Protein binding is saturable, and at concentrations >20 mcg/mL binding is nonlinear. Based on oral dosing data, there is an age- or fever-related change in volume of distribution for ibuprofen. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of ibuprofen have not been conducted. Mutagenesis In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Impairment of Fertility In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.06-times the MRHD based on body surface area comparison) did not impact male or female fertility or litter size. In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.0085-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males, but decreased ovulation was reported in females. 14 CLINICAL STUDIES Reference ID: 5482836 103.0 ----------- 102.5, ,_ 102,0, ; 1ou; g, 101.a i 100.!i f; 100.0 ga_:5, 00.0 0 .2 4 6 · ,,,. 100 mg C 8'd□lor • 9 · 200 mg CaAd0IOI' • • · 400 lll!J Ca olor Pleoebo 8 10 12 14 'iG 18 2':l 22 2.q Time ltlOYirs) 14.1 Analgesia (Pain) The effect of CALDOLOR on acute pain was evaluated in three multi-center, randomized, double-blind, placebo-controlled studies. In a study of women who had undergone an elective abdominal hysterectomy, 319 patients were randomized and treated with CALDOLOR 800 mg or placebo administered every 6 hours (started intra-operatively) and morphine administered on an as-needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the mean morphine consumption through 24 hours in patients who received CALDOLOR as compared to those receiving placebo (47 mg and 56 mg, respectively). The clinical relevance of this finding is supported by a greater reduction in pain intensity over 24 hours for patients treated with CALDOLOR, even though morphine was available on an as-needed basis. In a study of patients who had undergone an elective abdominal or orthopedic surgery, 406 patients (87 men, 319 women) were randomized to receive CALDOLOR 400 mg, CALDOLOR 800 mg, or placebo administered every 6 hours (started intra-operatively), and morphine on an as-needed basis. This study failed to demonstrate a statistically significant difference in outcome between patients receiving CALDOLOR 800 mg or 400 mg and placebo, although there were trends favoring the active treatments. An additional study of orthopedic surgical pain confirmed the findings of the study of abdominal surgical pain. A total of 185 patients were randomized and treated with CALDOLOR 800 mg or placebo administered every 6 hours (started pre-operatively) and morphine administered on an as-needed basis. Efficacy was demonstrated as a statistically significant greater reduction in pain intensity over 24 hours post-operatively for patients treated with CALDOLOR as compared to those receiving placebo. 14.2 Antipyretic (Fever) The effect of CALDOLOR on fever was evaluated in two randomized, double-blind studies in adults and in one open-label study in pediatric patients. In a multi-center study, 120 hospitalized patients (88 men, 32 women) with temperatures of 101°F or greater were randomized to CALDOLOR 400 mg, 200 mg, 100 mg or placebo, administered every 4 hours for 24 hours. Each of the three CALDOLOR doses, 100 mg, 200 mg, and 400 mg, resulted in a statistically greater percentage of patients with a reduced temperature (<101°F) after 4 hours, compared to placebo (65%, 73%, 77% and 32%, respectively). The dose response is shown in the figure below. Figure 1: Temperature Reduction by Treatment Group, Hospitalized Febrile Patients In a single-center study, 60 hospitalized patients (48 men, 12 women) with uncomplicated P. falciparum malaria having temperatures >100.4°F were randomized to CALDOLOR 400 mg or placebo, administered every 6 hours for 72 hours of treatment. There was a significant reduction in fever within the first 24 hours of treatment, measured as the area above the temperature 98.6°F vs. time curve for patients treated with CALDOLOR. In a multi-center, open-label study, 100 hospitalized pediatric patients 6 months of age and older with temperatures of 101.0ºF or greater were randomized and treated with 10 mg/kg of CALDOLOR or a low dose of an active comparator every 4 hours as needed for fever. Efficacy was demonstrated as a statistically significant greater reduction in temperature for the primary endpoint, an area under the curve analyses of temperature versus time for the first 2 hours, as well as over the entire dosing interval. Seventy-four percent of CALDOLOR treated patients became afebrile (temperature <99.5ºF) by the end of first dosing interval. 16 HOW SUPPLIED/STORAGE AND HANDLING CALDOLOR (ibuprofen injection) is a clear, colorless, non-pyrogenic, aqueous solution supplied as follows: Reference ID: 5482836 800 mg/8 mL (100 mg/mL) single dose vial. Carton of 25 vials, NDC 66220-287-08. 800 mg/200 mL (4 mg/mL) single dose ready-to-use polypropylene flexible bag. Case of 20 bags, NDC 66220-284-22. Individual bag, NDC 66220-284-11. Storage Store at controlled room temperature 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Discard the unused portion. The stopper in the CALDOLOR vial does not contain natural rubber latex, dry natural rubber, or blends of natural rubber. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with CALDOLOR and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop CALDOLOR and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions including DRESS Advise patients to stop taking CALDOLOR immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including CALDOLOR, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)] Fetal Toxicity Inform pregnant women to avoid use of CALDOLOR and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with CALDOLOR is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours I [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of CALDOLOR with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with CALDOLOR until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 5482836 Manufactured for: Cumberland Pharmaceuticals Inc. Nashville, TN 37203 US Patent Number 6,727,286, 8,871,810, 8,735,452, 9,012,508, 9,072,661, 9,072,710, 9,114,068, 9,138,404, 9,295,639, and 9,649,284 CALDOLOR® is a registered trademark of Cumberland Pharmaceuticals Inc. Reference ID: 5482836	custom-source	2025-02-12T15:47:12.085026	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022348s027lbl.pdf', 'application_number': 22348, 'submission_type': 'SUPPL ', 'submission_number': 27}
80,395	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PENNSAID® safely and effectively. See full prescribing information for PENNSAID. PENNSAID (diclofenac sodium) topical solution 2% w/w, for topical use Initial U.S. Approval: 1988 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal This risk may occur early in treatment and may increase with duration of use (5.1) • PENNSAID is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ----------------------------RECENT MAJOR CHANGES ------------------------- Warnings and Precautions (5.9) 11/2024 ----------------------------INDICATIONS AND USAGE ------------------------- PENNSAID is a nonsteroidal anti-inflammatory drug indicated for the treatment of the pain of osteoarthritis of the knee(s). (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. The recommended dose is 2 pump actuations on each painful knee, 2 times a day. (2) • Apply PENNSAID, to clean, dry skin. (2.1) • Dispense 40 mg (2 pump actuations) directly onto the knee or first into the hand and then onto the knee. Spread evenly around front, back and sides of the knee. (2.1) • Wash hands completely after administering the product. (2.2) • Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances. (2.2) • Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). (2.2) • Do not get PENNSAID in your eyes, nose, or mouth (2.2). --------------------- DOSAGE FORMS AND STRENGTHS -------------------- • PENNSAID (diclofenac sodium) topical solution 2% w/w (3) -------------------------------CONTRAINDICATIONS ---------------------------- • Known hypersensitivity to diclofenac or any components of the drug product. (4) • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. (4) • In the setting of coronary artery bypass graft (CABG) surgery. (4) --------------------WARNINGS AND PRECAUTIONS----------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of PENNSAID in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of PENNSAID in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: PENNSAID is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue PENNSAID at first appearance of skin rash or other signs of hypersensitivity. (5.9, 5.15) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including PENNSAID, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1). • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7). • Exposure to light: Avoid exposure of treated knee(s) to natural or artificial sunlight. (5.15) • Eye Contact: Avoid contact of PENNSAID with eyes and mucosa. (5.16) • Oral Nonsteroidal Anti-inflammatory Drugs: Avoid concurrent use with oral NSAIDs. (5.17) ------------------------------ADVERSE REACTIONS------------------------------ The most common adverse reactions with PENNSAID are application site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Horizon at 1 866-479-6742 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly using PENNSAID with drugs that interfere with hemostasis. Concomitant use of PENNSAID and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB) or Beta-Blockers: Concomitant use with PENNSAID may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with PENNSAID in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with PENNSAID can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of PENNSAID in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482841 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Special Precautions 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Sun Exposure 5.16 Eye Exposure 5.17 Oral Nonsteroidal Anti-Inflammatory Drugs 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7. DRUG INTERACTIONS 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10. OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Study in Osteoarthritis of the Knee 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482841 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. [see Warnings and Precautions (5.1)]. • PENNSAID is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE PENNSAID is indicated for the treatment of the pain of osteoarthritis of the knee(s). 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.2)]. For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day. Apply PENNSAID to clean, dry skin. The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required. After the priming procedure, PENNSAID is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee. Application of PENNSAID in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended. 2.2 Special Precautions • Avoid showering/bathing for at least 30 minutes after the application of PENNSAID to the treated knee. • Wash and dry hands after use. • Do not apply PENNSAID to open wounds. • Avoid contact of PENNSAID with eyes and mucous membranes. • Do not apply external heat and/or occlusive dressings to treated knees. • Avoid wearing clothing over the PENNSAID-treated knee(s) until the treated knee is dry. • Protect the treated knee(s) from natural and artificial sunlight. Reference ID: 5482841 • Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with PENNSAID. • Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). • Do not use combination therapy with PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. 3 DOSAGE FORMS AND STRENGTHS PENNSAID (diclofenac sodium) topical solution: 2% w/w 4 CONTRAINDICATIONS PENNSAID is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of PENNSAID in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If PENNSAID is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Reference ID: 5482841 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue PENNSAID until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac for 2 - 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with oral diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of oral diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold Reference ID: 5482841 adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), PENNSAID should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue PENNSAID immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver-related event in patients treated with PENNSAID, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing PENNSAID with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics). 5.4 Hypertension NSAIDs, including PENNSAID, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of PENNSAID in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If PENNSAID is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Reference ID: 5482841 No information is available from controlled clinical studies regarding the use of PENNSAID in patients with advanced renal disease. The renal effects of PENNSAID may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating PENNSAID. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of PENNSAID [see Drug Interactions (7)]. Avoid the use of PENNSAID in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If PENNSAID is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, PENNSAID is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When PENNSAID is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of PENNSAID at the first appearance of skin rash or any other sign of hypersensitivity. PENNSAID is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. Do not apply PENNSAID to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as PENNSAID. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue PENNSAID and evaluate the patient immediately. Reference ID: 5482841 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including PENNSAID, in pregnant women at about 30 weeks gestation and later. NSAIDs, including PENNSAID, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including PENNSAID, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 and 30 weeks gestation, limit PENNSAID use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if PENNSAID treatment extends beyond 48 hours. Discontinue PENNSAID if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with PENNSAID has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including PENNSAID, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of PENNSAID in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Sun Exposure Instruct patients to avoid exposure to natural or artificial sunlight on treated knee(s) because studies in animals indicated topical diclofenac treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. The potential effects of PENNSAID on skin response to ultraviolet damage in humans are not known. 5.16 Eye Exposure Avoid contact of PENNSAID with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. 5.17 Oral Nonsteroidal Anti-Inflammatory Drugs Concomitant use of oral NSAIDs with PENNSAID 1.5% resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Therefore, do not use combination therapy with PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. Reference ID: 5482841 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. PENNSAID The data described below reflect exposure to PENNSAID of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population’s mean age was approximately 60 years, 85% of patients were Caucasian, 65% were females, and all patients had primary osteoarthritis. The most common adverse events with PENNSAID were application site skin reactions. These events were the most common reason for withdrawing from the study. Application Site Reactions: In this controlled trial, application site reactions were characterized by one or more of the following: dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing (<1%). Other Common Adverse Reactions: Table 1 lists all adverse reactions occurring in >1% of patients receiving PENNSAID, where the rate in the PENNSAID group exceeded vehicle, from a controlled study conducted in patients with osteoarthritis. Table 1: Incidence of Adverse Reactions Occurring in >1% of Subjects with Osteoarthritis Using PENNSAID and More Often than in Subjects with OA Using Vehicle Control (Pooled) Adverse Reaction PENNSAID N=130 n (%) Vehicle Control N=129 n (%) Urinary tract infection 4 (3%) 1 (<1%) Application site induration 2 (2%) 1 (<1%) Contusion 2 (2%) 1 (<1%) Sinus congestion 2 (2%) 1 (<1%) Nausea 2 (2%) 0 Reference ID: 5482841 PENNSAID 1.5% The safety of PENNSAID 2% is based in part, on prior experience with PENNSAID 1.5%. The data described below reflect exposure to PENNSAID 1.5% of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with PENNSAID 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application Site Reactions: In controlled trials, application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of PENNSAID 1.5% and oral diclofenac. In the open-label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%. Other Common Adverse Reactions: In controlled trials, subjects treated with PENNSAID 1.5% experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 2). The combination of PENNSAID 1.5% and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases. Table 2 lists all adverse reactions occurring in ≥1% of patients receiving PENNSAID 1.5%, where the rate in the PENNSAID 1.5% group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence. Table 2: Adverse Reactions Occurring in ≥1% of Patients Treated with PENNSAID 1.5% Topical Solution in Placebo and Oral Diclofenac-Controlled Trials Treatment Group: PENNSAID 1.5% N=911 Topical Placebo N=332 Adverse Reaction N (%) N (%) Dry Skin (Application Site) 292 (32) 17 (5) Contact Dermatitis (Application Site) 83 (9) 6 (2) Dyspepsia 72 (8) 13 (4) Abdominal Pain 54 (6) 10 (3) Flatulence 35 (4) 1 (<1) Pruritus (Application Site) 34 (4) 7 (2) Diarrhea 33 (4) 7 (2) Nausea 33 (4) 3 (1) Pharyngitis 40 (4) 13 (4) Constipation 29 (3) 1 (<1) Edema 26 (3) 0 Rash (Non-Application Site) 25 (3) 5 (2) Infection 25 (3) 8 (2) Ecchymosis 19 (2) 1 (<1) Dry Skin (Non-Application Site) 19 (2) 1 (<1) Contact Dermatitis, vesicles (Application Site) 18 (2) 0 Paresthesia (Non-Application Site) 14 (2) 3 (<1) Accidental Injury 22 (2) 7 (2) Pruritus (Non-Application Site) 15 (2) 2 (<1) Sinusitis 10 (1) 2 (<1) Halitosis 11 (1) 1 (<1) Application Site Reaction (not otherwise specified) 11 (1) 3 (<1) Reference ID: 5482841 6.2 Postmarketing Experience In postmarketing surveillance, the following adverse reactions have been reported during post-approval use of PENNSAID 1.5%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: abdominal pain, accidental injury, allergic reactions, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, neck rigidity, pain Cardiovascular: palpitation, cardiovascular disorder Gastrointestinal: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, lip swelling, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis, swollen tongue Metabolic and Nutritional: creatinine increased Musculoskeletal: leg cramps, myalgia Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis, throat swelling Skin and Appendages: At the Application Site: rash, skin burning sensation; Other Skin and Appendages Adverse Reactions: eczema, skin discoloration, urticaria, exfoliative dermatitis, Stevens- Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion Vascular: blood pressure increased, hypertension 7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with diclofenac. Table 3: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of PENNSAID with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)] Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)] Intervention: Concomitant use of PENNSAID and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. PENNSAID is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually Reference ID: 5482841 reversible. Intervention: • During concomitant use of PENNSAID and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of PENNSAID and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of PENNSAID with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of PENNSAID and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of PENNSAID and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) Intervention: During concomitant use of PENNSAID and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of PENNSAID and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of PENNSAID and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)] Concomitant use of oral NSAIDs with PENNSAID has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%). Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Do not use combination therapy with PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. Pemetrexed Clinical Impact: Concomitant use of PENNSAID and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of PENNSAID and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Reference ID: 5482841 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including PENNSAID, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of PENNSAID use between about 20 and 30 weeks of gestation, and avoid PENNSAID use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including PENNSAID, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations were observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.6, 0.6, and 1.3 times, respectively, the maximum recommended human dose (MRHD) of 162 mg diclofenac sodium via PENNSAID, despite the presence of maternal and fetal toxicity at these doses [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of the Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including PENNSAID, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If PENNSAID treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue PENNSAID and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of PENNSAID during labor or delivery. In animal studies, NSAIDs, including diclofenac inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Reference ID: 5482841 Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.6 times the maximum recommended human dose [MRHD] of PENNSAID, 162 mg diclofenac sodium/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.6 and 1.3-times, respectively, the MRHD based on BSA comparison). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in PENNSAID) are equivocal as to potential teratogenicity. In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.12 and 0.24 times the MRHD, respectively, based on BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats. In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0.06 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3.6 mg/kg, IP; 0.2 times the MRHD based on BSA comparison), and caused adverse effects on the developing testes (6.1 mg/kg, oral; 0.4 times the MRHD based on BSA comparison). 8.2 Lactation Risk Summary Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PENNSAID and any potential adverse effects on the breastfed infant from the PENNSAID or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). 8.3 Females and Males of Reproductive Potential Infertility Females Reference ID: 5482841 Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including PENNSAID, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including PENNSAID, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear [See Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Of the 911 patients treated with PENNSAID 1.5% in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with PENNSAID 1.5% in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to PENNSAID 1.5% for this elderly population. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in PENNSAID. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, contact a poison control center (1-800-222-1222). 11 DESCRIPTION PENNSAID 2% topical solution, contains diclofenac sodium, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug, and is available as a clear, colorless to faintly pink or orange solution for topical application. The chemical name is 2[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following chemical structure. Reference ID: 5482841 Each 1 gram of solution contains 20 mg of diclofenac sodium. The inactive ingredients: dimethyl sulfoxide USP (DMSO, 45.5% w/w), ethanol, purified water, propylene glycol, and hydroxypropyl cellulose. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of PENNSAID, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption: After administration of PENNSAID topical solution (40 mg/knee every 12 h; total daily diclofenac exposure: 80 mg/knee) for 7.5 days, the mean (SD) AUC0-12 and mean (SD) Cmax were 77.27 (49.89) ng•h/mL and 12.16 (7.66) ng/mL, respectively, on Day 1; and 204.58 (111.02) ng•h/mL and 25.24 (12.95) ng/mL, respectively, at steady state on Day 8. After administration of PENNSAID 1.5% topical solution (19.3 mg/knee every 6 h; total daily diclofenac exposure 77.2 mg/knee), the mean (SD) AUC0-12 and mean (SD) Cmax were 27.46 (23.97) ng•h/mL and 2.30 (2.02) ng/mL, respectively, on Day 1; and 141.49 (92.47) ng•h/mL and 17.04 (11.28) ng/mL, respectively, at steady state on Day 8. The pharmacokinetics and effect of PENNSAID were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of PENNSAID under these conditions is not recommended. Distribution: Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Elimination Metabolism: Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5 hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4' hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy diclofenac. Excretion: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Specific Populations: Reference ID: 5482841 Pediatric: The pharmacokinetics of PENNSAID has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been studied. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day approximately 0.85 and 1.7 times, respectively, the maximum recommended human topical dose of PENNSAID (based on apparent bioavailability and body surface area comparison). In a dermal carcinogenicity study conducted in albino mice, daily topical applications of diclofenac sodium for two years at concentrations up to 0.035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in PENNSAID) did not increase neoplasm incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of diclofenac sodium at doses up to 0.035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in PENNSAID) resulted in an earlier median time of onset of tumors. Mutagenesis Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal aberration assay of bone marrow cells. Impairment of Fertility Fertility studies have not been conducted with PENNSAID. Diclofenac sodium administered to male and female rats at doses up to 4 mg/kg/day (approximately 3.4 times the MRHD of PENNSAID based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies conducted in rats found no effect of dermally applied DMSO on fertility, reproductive performance, or offspring performance. However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (0.6 times the MRHD) for 14 days and at 0.25 mg/kg (0.01 times the MRHD) for 30 days produced adverse effects on male reproductive hormones and testes. 13.2 Animal Toxicology and/or Pharmacology Ocular Effects No adverse effects were observed using indirect ophthalmoscopy after multiple-daily dermal application to rats for 26 weeks and minipigs for 52 weeks of DMSO at twice the concentration found in PENNSAID. Published studies of dermal or oral administration of DMSO to rabbits, dogs and pigs described refractive changes of lens curvature and cortical fibers indicative of myopic changes and/or incidences of lens opacity or discoloration when evaluated using slit-lamp biomicroscopy examination, although no ocular abnormalities were observed in rhesus monkeys during daily oral or dermal treatment with DMSO for 9 to 18 months. 14 CLINICAL STUDIES 14.1 Study in Osteoarthritis of the Knee PENNSAID Reference ID: 5482841 The use of PENNSAID for the treatment of pain of osteoarthritis of the knee was evaluated in a single double-blind controlled trial conducted in the US, involving patients treated with PENNSAID at a dose of 2 pumps twice a day for 4 weeks. PENNSAID was compared to topical vehicle, applied directly to the study knee. In this trial, patients treated with PENNSAID experienced a greater reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale compared to patients treated with vehicle. Numerical results of the WOMAC pain subscale are summarized in Table 4. Table 4: Change in Treatment Outcomes after 4 Weeks of Treatment with PENNSAID Efficacy Variable Treatment PENNSAID N=130 Vehicle Control N=129 WOMAC Pain Subscale Baseline Mean Change from Baseline 12.4 -4.5 12.6 -3.6 * WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale. 16 HOW SUPPLIED/STORAGE AND HANDLING PENNSAID (diclofenac sodium) topical solution 2% w/w, is supplied as a clear, colorless to faintly pink or orange solution containing 20 mg of diclofenac sodium per gram of solution, in a white polypropylene-dose pump bottle with a clear cap. Each pump actuation delivers 20 mg of diclofenac sodium in 1 gram of solution. NDC Number & Size 112 g bottle………………………………………….NDC # 75987-040-05 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with PENNSAID and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulceration and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop PENNSAID and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct Reference ID: 5482841 patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop using PENNSAID immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including PENNSAID, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)] Fetal Toxicity Inform pregnant women to avoid use of PENNSAID and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.11)]. If treatment with PENNSAID is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of PENNSAID with other NSAIDs or salicylates (e.g.,diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with PENNSAID until they talk to their healthcare provider [see Drug Interactions (7)]. Eye Exposure Instruct patients to avoid contact of PENNSAID with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. Prevention of Secondary Exposure Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which PENNSAID was applied until the knee(s) is completely dry. Special Application Instructions Instruct patients not to apply PENNSAID to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and reduce tolerability of the drug. Instruct patients to wait until the area treated with PENNSAID is completely dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication. Instruct patients to minimize or avoid exposure of treated knee(s) to natural or artificial sunlight. Distributed by: Horizon Medicines LLC Deerfield, IL 60015 PEN-US-PI-003 Reference ID: 5482841 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDS: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your health care provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your health care provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking new medicine without talking to your health care provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting and dizziness. Reference ID: 5482841 Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your health care provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and • diarrhea sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands, and feet • flu-like symptoms If you take too much of your NSAID, call your health care provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your health care provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your health care provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your health care provider. You can ask your pharmacist or health care provider for information about NSAIDs that is written for health professionals. Distributed by: Horizon Medicines LLC, Deerfield, IL 60015 For more information, go to www.PENNSAID.com or call 1-866-479-6742. This Medication Guide has been approved by the U.S. Food and Drug Administration Revised 01/2022 PEN-US-MG-002 Reference ID: 5482841 Instructions for Use PENNSAID® (pen-sed) (diclofenac sodium topical solution) 2% Read the Medication Guide that comes with PENNSAID first. Be sure that you read, understand and follow these Instructions for Use before you use PENNSAID for the first time. Important: For use on the skin only (topical). Do not get PENNSAID in your eyes, nose or mouth. Before you use PENNSAID: • Apply PENNSAID exactly as your healthcare provider tells you. Talk with your healthcare provider or pharmacist if you are not sure. • Only use PENNSAID to treat pain from osteoarthritis in your knee or knees. • Apply PENNSAID on clean, dry skin that does not have any cuts, infections or rashes. • Use PENNSAID two times a day on your knee or knees asprescribed. • Ifyouget PENNSAID inyour eyes, rinse youreyesright away withwaterorsaline.Call yourhealthcare provider if your eyes areirritated for more than onehour. PENNSAID comes in a pump bottle or in a sample packet from your healthcare provider If you are using a PENNSAID pump bottle follow the steps below: Before you use PENNSAID pump bottle for the first time, you will need to prime the pump. To prime the pump, remove the cap (See Figure A) and fully press the top of the pump all the way down 4 times while holding the bottle in an upright position (See Figure B). Dispense this portion of the medicine into a tissue or paper towel and throw it away in a trash can. The pump is now ready to use. You should not need to prime the pump again. Figure A. Figure B. Steps for using PENNSAID pump bottle: Step 1: Wash your hands with soap and water before applying PENNSAID. Step 2: Remove the bottle cap and press the pump head down firmly and fully to dispense PENNSAID into the palm of your hand. Release the pump head and then press the pump head down firmly and fully a second time. When you use your PENNSAID pump bottle, you can hold the bottle at an angle. Put 2 pumps of PENNSAID on your hand (See Figure C). Reference ID: 5482841 ?l ~ ==m <;:::, ~ I • ""' Figure C. Step 3: Apply PENNSAID evenly around the front, back, and sides of your knee. PENNSAID should be applied without massaging the knee (See Figures D and E). Figure D. Figure E. Step 4: Repeat Steps 2 and 3 for your other knee if your healthcare provider has prescribed PENNSAID for both knees. Step 5: Wash your hands with soap and water right away after applying PENNSAID. Step 6: Replace the cap on the bottle and store in an upright position. If you are using a PENNSAID sample packet follow the steps below: Steps for using a PENNSAID sample packet: Step 1: Wash your hands with soap and water before applying PENNSAID. Step 2: Cut open the sample packet using scissors or completely tear the packet at the notch on the dotted line (See Figure A). Do not use your teeth to open the sample packet (See Figure A). Figure A. Step 3: Squeeze from the bottom of the sample packet to the top to remove contents. Squeeze all of the PENNSAID out of the sample packet into the palm of your hand (See Figure B). Figure B. Reference ID: 5482841 Step 4: Apply PENNSAID evenly around the front, back, and sides of your knee. PENNSAID should be applied without massaging the knee (See Figures C and D). Figure C. Figure D. Step 5: Repeat steps 2 through 4 for your other knee if your healthcare provider has prescribed PENNSAID for both knees. Step 6: Wash your hands with soap and water right away after applying PENNSAID. Step 7: Throw away the empty sample packet into a trash can. After you use PENNSAID: Do not: • cover your knee with clothing until your knee is completely dry. • put sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medicines on your knee until it is completely dry. • take a shower or a bath for at least30 minutes after you put PENNSAID on your knee(s). • use heating pads or cover the treated area with bandages where you have applied PENNSAID. • exercise following application of PENNSAID. • use sunlamp and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in the sunlight. How should I store PENNSAID? • Store PENNSAID at room temperature between 68°F to 77°F (20°C to 25°C). Keep PENNSAID and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Horizon Medicines LLC Deerfield, IL 60015 USA Revised 01/2022 PEN-US-IFU-002 Reference ID: 5482841	custom-source	2025-02-12T15:47:12.244818	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/204623s013lbl.pdf', 'application_number': 204623, 'submission_type': 'SUPPL ', 'submission_number': 13}
80,397	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LICART® safely and effectively. See full prescribing information for LICART. LICART® (diclofenac epolamine) topical system Initial U.S. Approval: 1988 WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use (5.1) • LICART is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ------------------------------ RECENT MAJOR CHANGES----------------------- Warning and Precautions (5.9) 11/2024 ----------------------- INDICATIONS AND USAGE ------------------------------ LICART contains diclofenac epolamine, which is a nonsteroidal anti- inflammatory drug (NSAID), and is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions (1) -------------------- DOSAGE AND ADMINISTRATION ----------------------- • Use the lowest effective dose for shortest duration consistent with individual patient treatment goals (2.1) • See the Full Prescribing Information for important administration instructions (2.1) • Do not apply to damaged or non-intact skin (2.1) • The recommended dose is one (1) LICART to the most painful area once daily (2.2) -------------------- DOSAGE FORMS AND STRENGTHS -------------------- • LICART (diclofenac epolamine) topical system 1.3% for topical use. Each individual LICART is debossed. (3) ----------------------------- CONTRAINDICATIONS ------------------------------ • Known hypersensitivity to diclofenac or any components of the drug product (4) • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) • For use on non-intact or damaged skin (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of LICART in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of LICART in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: LICART is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue LICART at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10 ). • Fetal Toxicity: Limit use of NSAIDs, including LICART, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) --------------------------- ADVERSE REACTIONS-------------------------------- Most common adverse reactions for LICART are application site pruritus and other application site reactions (6.1) To report SUSPECTED ADVERSE REACTIONS, contact IBSA Pharma Inc. at 1-800-587-3513 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------- • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly using LICART with drugs that interfere with hemostasis. Concomitant use of LICART and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with LICART may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with LICART in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with LICART may increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) ---------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of LICART in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482843 ________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Recommended Dose 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Accidental Exposure in Children 5.16 Eye Exposure 5.17 Oral Nonsteroidal Anti-inflammatory Drugs 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Minor Soft Tissue Injuries (Sprain, Contusion) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5482843 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [See Warnings and Precautions (5.1)]. • LICART is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [See Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [See Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE LICART is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. LICART is intended for topical use only. Convey the following important administration instructions to the patient: • If LICART begins to peel-off, the edges of the topical system may be taped down. If problems with adhesion persist, patients may overlay the topical system with a mesh netting sleeve, where appropriate (e.g., to secure topical systems applied to ankles, knees, or elbows). The mesh netting sleeve (e.g., Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (i.e., non-breathable). • Do not apply LICART to non-intact or damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. • Do not wear a LICART topical system when bathing or showering. • Wash your hands after applying, handling, or removing the topical system. • Avoid contact with eyes. • Do not use LICART in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted. * Curad® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc. Reference ID: 5482843 2.2 Recommended Dose The recommended dose is one (1) LICART topical system to the most painful area once daily. 3 DOSAGE FORM AND STRENGTHS Topical System: 1.3% diclofenac epolamine (10 cm x 14 cm) debossed with “LICART (diclofenac epolamine) topical system 1.3%”. 4 CONTRAINDICATIONS LICART is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]. • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]. • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • On non-intact or damaged skin resulting from any etiology, including exudative dermatitis, eczema, infected lesions, burns or wounds. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10– 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause Reference ID: 5482843 mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of LICART in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If LICART is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2% - 4% of patients treated for one year. However, even short- term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-Treated Patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue LICART until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In an open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times Reference ID: 5482843 the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In post-marketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Post- marketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug- induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and post-marketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), LICART should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue LICART immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with LICART, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing LICART with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti- epileptics). 5.4 Hypertension NSAIDs, including LICART, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective- treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish Reference ID: 5482843 National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of LICART in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If LICART is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of LICART in patients with advanced renal disease. The renal effects of LICART may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating LICART. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of LICART [see Drug Interactions (7)]. Avoid the use of LICART in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If LICART is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, LICART is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When LICART is used in patients with preexisting asthma (without Reference ID: 5482843 known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of LICART at the first appearance of skin rash or any other sign of hypersensitivity. LICART is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as LICART. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue LICART and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including LICART, in pregnant women at about 30 weeks gestation and later. NSAIDs, including LICART, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including LICART, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit LICART use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if LICART treatment extends beyond 48 hours. Discontinue LICART if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with LICART has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Reference ID: 5482843 NSAIDs, including LICART, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of LICART in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.15 Accidental Exposure in Children Even a used LICART contains a large amount of diclofenac epolamine (as much as 170 mg). The potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used LICART. It is important for patients to store and dispose of LICART out of the reach of children and pets. 5.16 Eye Exposure Avoid contact of LICART with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. 5.17 Oral Nonsteroidal Anti-inflammatory Drugs Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use LICART in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 874 subjects were exposed to one or more doses of LICART in eleven clinical studies, including approximately 500 subjects who were treated with LICART in six controlled multiple-dose trials. Approximately 400 of these were exposed to the once-a-day 24-hour application, for up to one week in 288 Reference ID: 5482843 subjects and up to two weeks in 121 subjects. Adverse Reactions Leading to Discontinuation of Treatment In the controlled trials, none of the patients given LICART discontinued treatment due to an adverse reaction. Common Adverse Reactions Localized Reactions Overall, the most common adverse reactions associated with LICART treatment were application site skin reactions. Table 1 lists all adverse reactions occurring in ≥ 1% of patients in nine studies (excluding the two dermatologic safety studies) of LICART. A majority of patients treated with LICART experienced adverse reactions with a maximum intensity of “mild” or “moderate”. Table 1. Common Adverse Reactions (by System Organ Class) in ≥ 1% of Patients Treated with LICART or Placebo1 based on Data Pooled from Single-Dose and Multiple-Dose Studies LICART N=573 Placebo N=492 N Percent N Percent General Disorders and Administration Site Conditions 8 1.4 19 3.9 Application Site Pruritus 5 0.9 11 2.2 Other Application Site Reactions2 5 0.9 11 2.2 1 The placebo was comprised of the same ingredients as LICART except for diclofenac and may inform adverse reactions associated with the non-active ingredients contained in LICART. 2 Includes application site irritation (6 subjects), application site erythema (3 subjects), application site reaction (4 subjects), application site rash (1 subject), application site inflammation (1 subject), blister (1 subject). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of LICART or other products containing diclofenac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. LICART Cases suggesting dermal allergic reactions and photoallergic reactions have been reported through foreign post-marketing surveillance. Diclofenac Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE) [see Warnings and Precautions (5.9)]. 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Reference ID: 5482843 Intervention: Monitor patients with concomitant use of LICART with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of LICART and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. LICART is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of LICART and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of LICART and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of LICART with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of LICART and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of LICART and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Reference ID: 5482843 Intervention: During concomitant use of LICART and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of LICART and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of LICART and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of LICART and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of LICART and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including LICART, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of LICART use between about 20 and 30 weeks of gestation, and avoid LICART use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations and Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including LICART, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, diclofenac epolamine administered orally to pregnant rats and rabbits during the period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from the maximum recommended human dose (MRHD) of LICART. In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose. Diclofenac Reference ID: 5482843 epolamine administered orally to both male and female rats prior to mating and throughout the mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including LICART, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If LICART treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue LICART and follow up according to clinical practice (see Data). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed Reference ID: 5482843 to NSAIDs through maternal use is uncertain. Animal Data Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to15. Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3-times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to18. No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 7-times the maximum recommended daily exposure in humans based on a body surface area comparison. Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3-times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight. 8.2 Lactation Risk Summary Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk (see Data). There are no data on the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LICART and any potential adverse effects on the breastfed infant from LICART or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). The relative bioavailability for LICART is < 1% of a single 50 mg diclofenac tablet. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including LICART may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including LICART, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of LICART in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious Reference ID: 5482843 EPOLAMINE Cv 2-(pyrrolidin-1-yl)ethanol N+ I CH2-CH2-OH cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Clinical studies of LICART did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, call a poison control center (1-800-222-1222). 11 DESCRIPTION LICART (diclofenac epolamine) topical system 1.3% is a nonsteroidal anti-inflammatory drug, available for topical application. LICART is a 10 cm x 14 cm topical system comprised of an adhesive material containing 1.3% diclofenac epolamine which is applied to a non-woven polyester felt backing and covered with a polypropylene film release liner. The release liner is removed prior to topical application to the skin. The chemical name of diclofenac epolamine is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, (2 (pyrrolidin-1-yl) ethanol salt, with a molecular formula of C20H24Cl2N2O3 and molecular weight 411.3, an n- octanol/water partition coefficient of 8 at pH 8.5, and the following chemical structure: Each LICART contains 182 mg of diclofenac epolamine in an aqueous base. Each gram of adhesive contains 13 mg of diclofenac epolamine (equivalent to 9.4 mg diclofenac). Each LICART also contains the following inactive ingredients: butylene glycol, carboxymethylcellulose sodium, dihydroxyaluminum aminoacetate, edetate disodium, gelatin, heparin sodium, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium polyacrylate, sorbitol solution, tartaric acid, titanium dioxide, and purified water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because Reference ID: 5482843 diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Heparin sodium is included in the LICART formulation as an inactive ingredient. In one study in healthy human volunteers activated partial thromboplastin time (aPTT), a measure of coagulation, was unchanged following multiple LICART applications. 12.2 Pharmacodynamics LICART applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin. 12.3 Pharmacokinetics Absorption Following application of LICART once-a-day (24-hour application) for four consecutive days on the front part of the thigh, peak plasma concentrations of diclofenac (range 0.4 – 2.9 ng/mL) were noted between 4 – 20 hours of application, with mean plasma concentrations of diclofenac in the range of 0.5 – 0.9 ng/mL during the application period. On average, after 24 hours of application (medial aspect of the upper arm), about 7 mg of diclofenac are released from the topical system. Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with LICART were lower (<1%) than after a single oral 50-mg diclofenac sodium tablet. The pharmacokinetics of LICART have been evaluated in healthy volunteers (1) at rest (i.e., under normal behavior), (2) undergoing moderate exercise (three cycling sessions of 20 minutes each, at 50% of Heart Rate Reserve above heart rate at rest, performed at several minutes and 4 and 8 hours after topical system application), (3) under occlusion (elastic occlusive bandage over the entire topical system during 24 hours of application, except two 1-hour periods of non-occlusion, 5 and 12 hours after topical system application), and (4) exposed to moderate heat (immediately after topical system application and 4, 8 and 12 hours thereafter over four consecutive days, warmed with a heat wrap for 20 minutes, with total heat exposure of 5 hours and 20 minutes). Moderate exercise, occlusion and moderate heat all increased (~ 20%) the peak plasma concentration (Cmax) and the systemic exposure (AUC) of diclofenac (see Table 3). Table 3: Diclofenac pharmacokinetics behavior following various LICART application modalities Parameter Normal Moderate Exercise Under Occlusion Moderate Heat Cmax (ng/mL) 1.01±0.64 1.22±0.76 1.14±0.74 1.23±0.73 Tmax (h) 6 (4–20) 12 (0-24) 6 (0-24) 6 (0-20) AUCτ (ng/mL×h) 18.58±11.63 22.77±14.39 21.94±14.25 23.07±14.29 Cmin (ng/mL) 0.49±0.31 0.62±0.42 0.63±0.47 0.69±0.46 Values are arithmetic means ± SD, except for Tmax: median (min - max). Distribution Diclofenac has a very high affinity (>99%) for human serum albumin. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Elimination Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4' hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’ hydroxy- diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites Reference ID: 5482843 undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac. Excretion The plasma elimination half-life of diclofenac after application of LICART is approximately 12 hours. Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Specific Populations The pharmacokinetics of LICART has not been investigated in children, patients with hepatic or renal impairment, or specific racial groups. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs was reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or LICART. Mutagenesis Diclofenac epolamine is not mutagenic in Salmonella typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats. Impairment of Fertility Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation). Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and post-implantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. 14 CLINICAL STUDIES 14.1 Minor Soft Tissue Injuries (Sprain, Contusion) The efficacy of LICART was demonstrated in two randomized, double-blind, parallel-arm, placebo- and active-controlled studies in patients with minor sprains, strains, and/or contusions. Patients were randomized equally to receive LICART, placebo, or FLECTOR and treatment was applied as a 24-hour, once daily application for 7 or 14 days. FLECTOR was not administered according to its approved twice daily (BID) dosing regimen; therefore, conclusions regarding comparative efficacy between LICART and FLECTOR cannot be made based on these studies. Reference ID: 5482843 100 1: 0 0 UCART I E3 90 E3 Placebo 8' 00 Protocol 05DCz/FHp11 ,... .9 0 70 0 ! 00 50 1 40 C 30 ~ i 20 ~ 10 0 1 4 7 10 13 16 Treatment Day 100 1: 0 0 UCART I E3 90 E3Pll:K:ebo 8' 00 Protocol 06EU/FHp()3 ,... .9 0 70 0 (D 00 I 50 (I,) ~ 40 C 30 ~ I 20 10 0 1 2 3 4 5 6 7 8 Treatment Day One study enrolled 429 adult patients aged 18 to 65 years with ankle sprain who had a mean baseline pain intensity on movement of 72 mm on a 0-100 mm visual analog scale (VAS). The second study enrolled 355 adult patients aged 18-75 years with muscle contusion of the limb who had a mean baseline pain on movement intensity of 68 mm on a 0-100 mm VAS. The primary efficacy endpoint was the mean change from baseline in pain on movement to Day 3 of treatment, where pain on movement was assessed twice daily (i.e., morning and evening) for 7 days in the ankle sprain study (06EU/FHp03) and 14 days in the muscle contusion study (05DCz/FHp11). In both studies, LICART demonstrated a statistically significant difference versus placebo on the primary efficacy endpoint, reduction in pain on movement at Day 3. Figure 1: Pain on movement intensity score differences from baseline in the muscle contusion study (Protocol 05DCz/FHp11). Figure 2: Pain on movement intensity score differences from baseline in the ankle sprain study (Protocol 06EU/FHp03). Reference ID: 5482843 Based on a clinical study in 28 subjects with LICART applied to the lower leg above the ankle, 28 subjects (100%) had adhesion scores of 0 (≥90% adhered) for all evaluations performed every 4 hours during the 24 hour wear period. 16 HOW SUPPLIED/STORAGE AND HANDLING The LICART (diclofenac epolamine) topical system 1.3% is supplied in re-sealable envelopes, each containing 5 topical systems (10 cm x 14 cm EACH) (NDC 71858-0305-4), with 3 envelopes per box (NDC 71858-0305-5). Each LICART is debossed with “LICART (diclofenac epolamine) topical system 1.3%”. • Keep out of reach of children and pets. • Envelopes should be sealed at all times when not in use. Storage Store at 20 °C to 25 ºC (68 °F to 77 ºF); excursions permitted between 15 ºC to 30 ºC (59 ºF to 86 ºF) [see USP Controlled Room Temperature]. Once the envelope has been opened, LICART is stable up to 6 months, if stored at room temperature in the re-sealed envelope. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with LICART and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop LICART and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Reference ID: 5482843 Advise patients to stop using LICART immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9,5.10 )]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including LICART, may delay or prevent rupture of ovarian follicles, which has been associated with a reversible infertility in some women [see Use in Specific Populations (8.3)] Fetal Toxicity Inform pregnant women to avoid use of LICART and other NSAIDs starting at 30 weeks’ gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with LICART is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of other NSAIDs Inform patients that the concomitant use of LICART with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over-the-counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with LICART until they talk to their healthcare provider [see Drug Interactions (7)]. Eye Exposure Instruct patients to avoid contact of LICART with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions (5.15)]. Special Application Instructions • Instruct patients that, if LICART begins to peel-off, the edges of the topical system may be taped down. If problems with adhesion persist, patients may overlay the topical system with a mesh netting sleeve, where appropriate (e.g., to secure topical systems applied to ankles, knees, or elbows). The mesh netting sleeve (e.g., Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non-breathable). • Instruct patients that LICART may not be applied to non-intact or damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. • Instruct patients not to wear LICART when bathing or showering. • Instruct patients to avoid contact with eyes. • Instruct patients to wash hands after applying, handling or removing the topical system. Curad® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc. Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland Distributed by: IBSA Pharma Inc., Parsippany, NJ 07054 USA Reference ID: 5482843 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Reference ID: 5482843 Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland Distributed by: IBSA Pharma Inc., Parsippany, NJ 07054 USA For more information, go to www.licart.com or call 1-800-587-3513 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2022 Reference ID: 5482843	custom-source	2025-02-12T15:47:12.617129	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206976s016lbl.pdf', 'application_number': 206976, 'submission_type': 'SUPPL ', 'submission_number': 16}
80,399	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VIVLODEX™ safely and effectively. See full prescribing information for VIVLODEX. VIVLODEX (meloxicam) capsules, for oral use Initial U.S. Approval: 2000 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE VIVLODEX is a non-steroidal anti-inflammatory drug indicated for management of osteoarthritis (OA) pain. (1) DOSAGE AND ADMINISTRATION • Start with 5 mg orally once daily. May increase dose to 10 mg in patients who require additional analgesia (2.1) • Use the lowest effective dose for shortest duration consistent with individual patient treatment goals (2.1) • VIVLODEX capsules are not interchangeable with other formulations of oral meloxicam even if the milligram strength is the same. (2.2) DOSAGE FORMS AND STRENGTHS VIVLODEX (meloxicam) Capsules: 5 mg or 10 mg (3) CONTRAINDICATIONS • Known hypersensitivity to meloxicam or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of VIVLODEX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of VIVLODEX in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: VIVLODEX is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue VIVLODEX at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including VIVLODEX, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12 7) ADVERSE REACTIONS Most common adverse reactions (incidence ≥2% in controlled clinical trials of VIVLODEX 5 mg or 10 mg group) are diarrhea, nausea, abdominal discomfort. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Egalet US Inc., at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking VIVLODEX with drugs that interfere with hemostasis. Concomitant use of VIVLODEX and analgesic doses of aspirin is not generally recommended (7) • ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with VIVLODEX may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with VIVLODEX in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with VIVLODEX can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of VIVLODEX in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 Reference ID: 5482845 INITIAL U.S. APPROVAL: 2000 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage 2.2 Non-Interchangeability with Other Formulations of Meloxicam 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Osteoarthritis Pain 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Cardiovascular Thrombotic Events Gastrointestinal Bleeding, Ulceration, and Perforation Hepatotoxicity Heart Failure and Edema Anaphylactic Reactions Serious Skin Reactions Fetal Toxicity Avoid Concomitant Use of NSAIDs Use of NSAIDs and Low-Dose Aspirin * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482845 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE VIVLODEX is indicated for management of osteoarthritis pain. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg. In patients on hemodialysis, the maximum daily dosage is 5 mg [see Warnings and Precautions (5.6), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] 2.2 Non-Interchangeability with Other Formulations of Meloxicam VIVLODEX capsules have not shown equivalent systemic exposure to other formulations of oral meloxicam. Therefore, VIVLODEX capsules are not interchangeable with other formulations of oral meloxicam even if the total milligram strength is the same. Do not substitute similar dose strengths of other meloxicam products [see Clinical Pharmacology (12.3)]. Reference ID: 5482845 3 DOSAGE FORMS AND STRENGTHS VIVLODEX (meloxicam) capsules: 5 mg – light pink body with a dark blue cap (imprinted IP-205 on the body and 5 mg on the cap in white ink). VIVLODEX (meloxicam) capsules: 10 mg – pink body and a dark blue cap (imprinted IP-206 on the body and 10 mg on the cap in white ink). 4 CONTRAINDICATIONS VIVLODEX is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Reference ID: 5482845 Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of VIVLODEX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If VIVLODEX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with VIVLODEX. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue VIVLODEX until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. Reference ID: 5482845 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIVLODEX immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including VIVLODEX, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of VIVLODEX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If VIVLODEX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, Reference ID: 5482845 hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of VIVLODEX in patients with advanced renal disease. The renal effects of VIVLODEX may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating VIVLODEX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIVLODEX [see Drug Interactions (7)]. Avoid the use of VIVLODEX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If VIVLODEX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see Contraindications (4), Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIVLODEX is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When VIVLODEX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life- threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of VIVLODEX at the first appearance of skin rash or any other sign of hypersensitivity. VIVLODEX is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as VIVLODEX. Some of these events have been fatal or life- Reference ID: 5482845 threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue VIVLODEX and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDS, including VIVLODEX, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including VIVLODEX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including VIVLODEX, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit VIVLODEX use to the lowest effective dose and shortest duration possssible. Consider ultrasound monitoring of amniotic fluid if VIVLODEX treatment extends beyond 48 hours. Discontinue VIVLODEX if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with VIVLODEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including VIVLODEX, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of VIVLODEX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Reference ID: 5482845 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients with Osteoarthritis Pain Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 – 87 years, were enrolled in two Phase 3 clinical trials and received VIVLODEX 5 mg or 10 mg once daily. Fifty percent (50%) of patients were aged 61 years or older. Two hundred sixty-nine (269) patients received VIVLODEX 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1. Table 1 Summary of Adverse Reactions (≥2%) – 12-Week Phase 3 Study in Patients With Osteoarthritis Pain VIVLODEX Adverse Reactions 5 mg or 10 mg Placebo N=269 N=133 Diarrhea 3% 1% Nausea 2% 0 Abdominal Discomfort 2% 0 Six hundred (600) patients received VIVLODEX 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2. Reference ID: 5482845 Table 2 Summary of Adverse Reactions (≥2%) – 52-Week Open-Label Study in Patients With Osteoarthritis Pain VIVLODEX 10 mg Adverse Reactions N=600 Arthralgia 6% Urinary Tract Infection 6% Osteoarthritis 5% Hypertension 4% Diarrhea 4% Headache 4% Upper Respiratory Tract Infection 4% Back Pain 4% Nasopharyngitis 4% Bronchitis 3% Sinusitis 3% Constipation 3% Dyspepsia 3% Nausea 2% Edema Peripheral 2% Pain in Extremity 2% Additional adverse reactions reported for meloxicam: Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis Central and Peripheral Nervous convulsions, paresthesia, tremor, vertigo System Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative Heart Rate and Rhythm arrhythmia, palpitation, tachycardia Hematologic agranulocytosis, leukopenia, purpura, thrombocytopenia Immune System anaphylactoid reactions (including shock) Reference ID: 5482845 Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis, jaundice, liver failure Metabolic and Nutritional dehydration Psychiatric abnormal dreaming, alterations in mood (such as mood elevation), anxiety, appetite increased, confusion, depression, nervousness, somnolence, Respiratory asthma, bronchospasm, dyspnea Skin and Appendages alopecia, angioedema, bullous eruption, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweating increased, urticaria Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus Urinary System albuminuria, acute urinary retention, BUN increased, creatinine increased, hematuria, interstitial nephritis, renal failure, 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of meloxicam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. Table 3 Clinically Significant Drug Interactions with meloxicam Drugs That Interfere with Hemostasis Clinical Impact: • Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of VIVLODEX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. VIVLODEX is not a substitute for aspirin for cardiovascular prophylaxis. Reference ID: 5482845 Intervention: Concomitant use of VIVLODEX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of VIVLODEX and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VIVLODEX and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VIVLODEX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of VIVLODEX and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VIVLODEX and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of VIVLODEX and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of VIVLODEX and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of VIVLODEX and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of VIVLODEX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of VIVLODEX and pemetrexed, in patients with renal Reference ID: 5482845 impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including VIVLODEX, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of VIVLODEX use between about 20 and 30 weeks of gestation, and avoid VIVLODEX use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including VIVLODEX, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent 1- and 10 times, respectively, the maximum recommended daily dose (MRDD) of VIVLODEX. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 116-times the MRDD. In pre and post-natal reproduction studies, increased incidence of dystocia, delayed parturition, and decreased offspring survival were observed in rats treated with meloxicam at an oral dose equivalent to 0.12-times the MRDD of VIVLODEX. No teratogenic effects were observed in rats treated with meloxicam during organogenesis at an oral dose equivalent to 3.9- times the MRDD [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Reference ID: 5482845 --- Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including VIVLODEX, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If VIVLODEX treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue VIVLODEX and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of VIVLODEX during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcome involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Reference ID: 5482845 Animal data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (3.9-times the maximum recommended daily dose (MRDD) of 10 mg of VIVLODEX based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (116-times the MRDD based on BSA comparison). The no effect level was 20 mg/kg/day (39-times the MRDD based on BSA comparison). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (1- and 10-times the MRDD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.12-times the MRDD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIVLODEX and any potential adverse effects on the breastfed infant from the VIVLODEX or from the underlying maternal condition. Data Animal data Meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including VIVLODEX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including VIVLODEX, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of VIVLODEX in pediatric patients has not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated Reference ID: 5482845 benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Of the total number of patients in clinical studies of VIVLODEX, 291 were age 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Because meloxicam is significantly metabolized in the liver; use VIVLODEX in patients with severe hepatic impairment only if the benefits are expected to outweigh the risks. If VIVLODEX is used in patients with severe hepatic impairment, monitor patients for signs of worsening liver function [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of VIVLODEX in subjects with severe renal impairment is not recommended. In a previous study, the free Cmax plasma concentrations following a single dose of meloxicam were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, the maximum VIVLODEX dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2)]. There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients took 6 to 11 times the highest available dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a previous clinical trial. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). Reference ID: 5482845 11 DESCRIPTION VIVLODEX (meloxicam) capsules are a nonsteroidal anti-inflammatory drug, available as pink and blue capsules containing 5 mg or 10 mg for oral administration. The chemical name is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 dioxide. The molecular weight is 351.4. Its molecular formula is C14H13N3O4S2, and it has the following chemical structure. Meloxicam is a pale yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app=0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. The inactive ingredients in VIVLODEX include: lactose monohydrate, sodium lauryl sulfate, sodium stearyl fumarate, microcrystalline cellulose, and croscarmellose sodium. The capsule shells contain gelatin, titanium dioxide, and dyes FD&C blue #2, FD&C red #40, FD&C yellow #6, and carmine. The imprinting on the gelatin capsules is white edible ink. The 5 mg capsules have a light pink body with “IP-205” imprinted in white ink and a dark blue cap with “5 mg” imprinted in white ink. The 10 mg capsules have a pink body with “IP-206” imprinted in white ink and a dark blue cap with “10 mg” imprinted in white ink. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VIVLODEX has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of VIVLODEX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics The relative bioavailability of VIVLODEX 10 mg capsules compared to meloxicam 15 mg tablets was assessed in 28 healthy subjects under fasted and fed conditions in a single-dose crossover study. Reference ID: 5482845 VIVLODEX 10 mg capsules do not result in an equivalent systemic exposure compared to 15 mg meloxicam tablets. When taken under fasted conditions, a 33% lower dose of meloxicam in VIVLODEX 10 mg capsules resulted in a 33% lower overall systemic exposure (AUCinf) and a comparable mean peak plasma concentration (Cmax) to meloxicam 15 mg tablets. The median time to maximum plasma concentration (Tmax) occurred earlier for VIVLODEX capsules (2 hours for both 5 mg and 10 mg) than for meloxicam tablets (4 hours for 15 mg). Absorption Single oral doses of VIVLODEX 5 mg and 10 mg were associated with dose-proportional pharmacokinetics. Mean Cmax was achieved within 2 hours post-dose for both VIVLODEX 5 mg and 10 mg capsules when taken under fasted conditions. A second meloxicam concentration peak occurs around 8 hours post-dose. Taking VIVLODEX with food causes a decrease in the rate but not the overall extent of systemic meloxicam absorption compared with taking VIVLODEX on an empty stomach. VIVLODEX capsules administered under fed conditions results in 22% lower mean Cmax and a 3 hour delay in median Tmax (5 hours for fed versus 2 hours for fasted) compared to the fasted condition. Significant changes in AUCinf were not observed. VIVLODEX can be administered without regard to timing of meals. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was Reference ID: 5482845 confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t1/2) for VIVLODEX 5 mg and 10 mg is approximately 22 hours. Specific Populations Pediatric: The pharmacokinetics of VIVLODEX have not been investigated in pediatric patients. Hepatic Impairment: Following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see Warnings and Precautions (5.3), Use in Specific Populations (8.6)]. Renal Impairment: Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of VIVLODEX in subjects with severe renal impairment is not recommended. Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see Warnings and Precautions (5.6), Use in Specific Populations (8.7)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical Reference ID: 5482845 doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [see Drug Interactions (7)]. Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam tablets 15 mg once per day every day as compared to subjects receiving lithium alone [see Drug Interactions (7)]. Methotrexate: A previous study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [see Drug Interactions (7)]. Warfarin: The effect of meloxicam tablets on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering VIVLODEX with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.8- and 3.9-times, respectively, the maximum recommended daily dose (MRDD) of 10 mg of VIVLODEX based on body surface area (BSA) comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility In previous studies of meloxicam, there was no impairment of male or female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 8.7 and 4.8-times, respectively, the MRDD based on BSA comparison). 14 CLINICAL STUDIES 14.1 Osteoarthritis Pain The efficacy of VIVLODEX in the management of osteoarthritis pain was demonstrated in a randomized, double-blind, multicenter, parallel-arm, placebo-controlled study comparing VIVLODEX 5 mg or 10 mg taken once daily and placebo in patients with pain due to osteoarthritis of the knee or hip. The study evaluated 402 patients with a mean age of 61 (range 40 to 87 years). Osteoarthritis pain was measured using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Pain Subscale. The mean baseline Reference ID: 5482845 .... l_ L...._ .... '-1 .......... _, '-..,_ WOMAC Pain Subscale Score across treatment groups was 73 mm using a 0 to 100 mm visual analog scale. The primary efficacy endpoint was the change from baseline to Week 12 in the WOMAC Pain Subscale Score. VIVLODEX 5 mg and 10 mg once daily significantly reduced osteoarthritis pain compared with placebo, as measured by changes in WOMAC Pain Subscale Scores. Although both the 5 mg and 10 mg doses significantly reduced pain compared to placebo, the proportion of responders achieving various percentage reductions in pain intensity from baseline to Week 12 is similar for both the 5 mg and 10 mg once daily doses. The proportion (%) of patients in each group who demonstrated reduction in their pain intensity score from baseline to Week 12 is shown in Figure 1. The figure is cumulative, so patients whose change from baseline is, for example, 30%, are also included in every level of pain reduction below 30%. Patients who did not complete the study were classified as non- responders. Figure 1 Proportion (%) of Patients Achieving Various Percentage Reductions in Pain Intensity from Baseline to Week 12 100 90 80 70 60 VIVLODEX Capsules 10 mg VIVLODEX Capsules 5 mg Placebo 50 40 30 20 10 0 ≥0 ≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 ≥100 % Reduction from Baseline in WOMAC Pain Subscale Scores Proportion (%) of Patients Achieving Reduction 16 HOW SUPPLIED/STORAGE AND HANDLING VIVLODEX (meloxicam) capsules are supplied as: • 5 mg - light pink body and dark blue cap (imprinted IP-205 on the body and 5 mg on the cap in white ink) NDC (69344-205-23), Bottles of 30 capsules • 10 mg - pink body and dark blue cap (imprinted IP-206 on the body and 10 mg on the cap in white ink) NDC (69344-206-23), Bottles of 30 capsules Storage Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Reference ID: 5482845 Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with VIVLODEX and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop VIVLODEX and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4), Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking VIVLODEX immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9), (5.10)]. Reference ID: 5482845 Fetal Toxicity Inform pregnant women to avoid use of VIVLODEX and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with VIVLODEX is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of VIVLODEX with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2), Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with VIVLODEX until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured and Distributed by: iCeutica Operations LLC, Princeton, NJ 08540 All rights reserved.US Patent Nos. 9526734, 9649318, 9808468 Reference ID: 5482845 Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?” • new or worse high blood pressure • heart failure Reference ID: 5482845 • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing •slurred speech • chest pain •swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or • diarrhea it is black and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and • flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: iCeutica Operations LLC, Princeton, NJ 08540 For more information, go to WWW.VIVLODEX.COM or call 1-800-518-1084 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 Reference ID: 5482845	custom-source	2025-02-12T15:47:12.966834	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/207233s005lbl.pdf', 'application_number': 207233, 'submission_type': 'SUPPL ', 'submission_number': 5}
80,402	WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) CAMBIA is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CAMBIA safely and effectively. See full prescribing information for CAMBIA. CAMBIA® (diclofenac potassium), for oral solution Initial U.S. Approval: 1988 –––––––––––––––––– RECENT MAJOR CHANGES ––––––––––––––––––– Warnings and Precautions (5.9) 11/2024 –––––––––––––––––– INDICATIONS AND USAGE ––––––––––––––––––– CAMBIA is a non-steroidal anti-inflammatory drug (NSAID) indicated for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older (1) Limitations of Use (1): • CAMBIA is not indicated for the prophylactic therapy of migraine • Safety and effectiveness of CAMBIA not established for cluster headache, which is present in an older, predominantly male population –––––––––––––– DOSAGE AND ADMINISTRATION –––––––––––––––– Single 50 mg dose; mix single packet contents with 1 to 2 ounces (30 to 60 mL) of water prior to administration • Use the lowest effective dose for shortest duration consistent with individual patient treatment goals (2.1) ––––––––––––– DOSAGE FORMS AND STRENGTHS ––––––––––––––– Packets: Each containing buffered diclofenac potassium 50 mg in a soluble powder (3) –––––––––––––––––– CONTRAINDICATIONS ––––––––––––––––––––––– • Known hypersensitivity to diclofenac or NSAIDs or any components of the drug product (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of (CABG) surgery (4) ––––––––––––– WARNINGS AND PRECAUTIONS ––––––––––––––– • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3, 8.6, 12.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of CAMBIA in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of CAMBIA in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: CAMBIA is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue CAMBIA at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Medication Overuse Headache: Detoxification may be necessary. (5.11) • Fetal Toxicity: Limit use of NSAIDs, including Cambia, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus (5.12, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.13, 7) ––––––––––––––––––––– ADVERSE REACTIONS –––––––––––––––––––– Most common adverse reactions (≥1% and >placebo) were nausea and dizziness (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Assertio Therapeutics, Inc. at 866-458-6389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ––––––––––––––––––––– DRUG INTERACTIONS –––––––––––––––––––– • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking CAMBIA with drugs that interfere with hemostasis. Concomitant use of CAMBIA and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors and ARBs: Concomitant use with CAMBIA in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of loop and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with CAMBIA can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) ––––––––––––––– USE IN SPECIFIC POPULATIONS –––––––––––––––– • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of CAMBIA in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482756 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Acute Treatment of Migraine 2.2 Non-Interchangeability with Other Formulations of Diclofenac 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Medication Overuse Headache 5.12 Fetal Toxicity 5.13 Hematologic Toxicity 5.14 Masking of Inflammation and Fever 5.15 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482756 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • CAMBIA is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE CAMBIA is indicated for the acute treatment of migraine attacks with or without aura in adults (18 years of age or older). Limitations of Use: • CAMBIA is not indicated for the prophylactic therapy of migraine. • The safety and effectiveness of CAMBIA have not been established for cluster headache, which is present in an older, predominantly male population. 2 DOSAGE AND ADMINISTRATION 2.1 Acute Treatment of Migraine Administer one packet (50 mg) of CAMBIA for the acute treatment of migraine. Empty the contents of one packet into a cup containing 1 to 2 ounces (30 to 60 mL) of water, mix well and drink immediately. Do not use liquids other than water. Taking CAMBIA with food may cause a reduction in effectiveness compared to taking CAMBIA on an empty stomach [see Clinical Pharmacology (12.3)]. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. The safety and effectiveness of a second dose have not been established. 2.2 Non-Interchangeability with Other Formulations of Diclofenac Different formulations of oral diclofenac (e.g., CAMBIA, diclofenac sodium enteric-coated tablets, diclofenac sodium extended-release tablets, or diclofenac potassium immediate-release tablets) may not be bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulation of diclofenac to CAMBIA. 3 DOSAGE FORMS AND STRENGTHS CAMBIA is available in individual packets each designed to deliver a 50 mg dose when mixed in water. Reference ID: 5482756 4 CONTRAINDICATIONS CAMBIA is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10- 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all- cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of CAMBIA in patients with a recent MI unless the benefits are expected to outweigh the Reference ID: 5482756 risk of recurrent CV thrombotic events. If CAMBIA is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short- term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRI); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risk in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue CAMBIA until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of one or more liver tests may occur during therapy with CAMBIA. These laboratory abnormalities may progress, may persist, or may only be transient with continued therapy. Borderline elevations (less than 3 times the upper limit of the normal [ULN] range) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during treatment (ALT was not measured in all studies). In an open-label, controlled trial of 3,700 patients treated for 2–6 months, patients were monitored at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (>8 times the ULN) in about 1% of the 3,700 patients. In this open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3–8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Almost Reference ID: 5482756 all meaningful elevations in transaminases were detected before patients became symptomatic [see Warnings and Precautions (5.15)]. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug- induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue CAMBIA immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver-related event in patients treated with CAMBIA, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing CAMBIA with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, antiepileptics). Caution patients to avoid taking nonprescription acetaminophen- containing products while using CAMBIA. 5.4 Hypertension NSAIDs, including CAMBIA, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including CAMBIA, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective- treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of CAMBIA in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If CAMBIA is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose- Reference ID: 5482756 dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of CAMBIA in patients with advanced renal disease. The renal effects of CAMBIA may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating CAMBIA. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of CAMBIA [see Drug Interactions (7)]. Avoid the use of CAMBIA in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If CAMBIA is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, CAMBIA is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When CAMBIA is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of CAMBIA at the first appearance of skin rash or any other sign of hypersensitivity. CAMBIA is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CAMBIA. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Reference ID: 5482756 Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue CAMBIA and evaluate the patient immediately. 5.11 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, nonsteroidal anti-inflammatory drugs or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.12 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including CAMBIA, in pregnant women at about 30 weeks gestation and later. NSAIDs, including CAMBIA, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including CAMBIA, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit CAMBIA use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if CAMBIA treatment extends beyond 48 hours. Discontinue CAMBIA if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Population (8.1)]. 5.13 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with CAMBIA has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including CAMBIA, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients and any patient who may be adversely affected by alterations in platelet function for signs of bleeding [see Drug Interactions (7)]. 5.14 Masking of Inflammation and Fever The pharmacological activity of CAMBIA in reducing inflammation, and possibly fever, may diminish Reference ID: 5482756 the utility of diagnostic signs in detecting infections. 5.15 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Discontinue CAMBIA if abnormal liver tests or renal tests persist or worsen. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10)] • Medication Overuse Headache [see Warnings and Precautions (5.11)] • Hematologic Toxicity [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of a single dose of CAMBIA was evaluated in 2 placebo-controlled trials with a total of 634 migraine patients treated with CAMBIA for a single migraine headache. Following treatment with diclofenac potassium (either CAMBIA or diclofenac potassium immediate-release tablets [as a control]), 5 subjects (0.8%) withdrew from the studies; following placebo exposure, 1 subject (0.2%) withdrew. The most common adverse reactions (i.e., that occurred in 1% or more of CAMBIA-treated patients) and more frequent with CAMBIA than with placebo were nausea and dizziness (see Table 1). Table 1: Adverse Reactions With Incidence >1% and Greater Than Placebo in Studies 1 and 2 Combined Adverse Reactions CAMBIA N=634 Placebo N=646 Gastrointestinal Nausea 3% 2% Nervous System Dizziness 1% 0.5% Reference ID: 5482756 The most common adverse events resulting in discontinuation of patients following CAMBIA dosing in controlled clinical trials were urticaria (0.2%) and flushing (0.2%). No withdrawals were due to a serious reaction. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of diclofenac or other NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions Reported With Diclofenac and Other NSAIDs In patients taking diclofenac or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1%-10% of patients are: GI reactions (including abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers [gastric/duodenal], and vomiting), abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus. Other less frequently occurring adverse reactions identified during post approval use of diclofenac and other NSAIDs include fixed drug eruption [see Warnings and Precautions (5.9)]. Additional adverse reactions reported in patients taking NSAIDs include occasionally: Body as a Whole: Fever, infection, sepsis Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope Digestive System: Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: Ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: Weight changes Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: Asthma, dyspnea Skin and Appendages: Alopecia, photosensitivity, sweating increased Special Senses: Blurred vision Urogenital System: Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions in patients taking NSAIDs, which occur rarely, are: Body as a Whole: Anaphylactic reactions, appetite changes, death Cardiovascular System: Arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: Colitis, eructation, liver failure, pancreatitis Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: Hyperglycemia Nervous System: Convulsions, coma, hallucinations, meningitis Respiratory System: Respiratory depression, pneumonia Skin and Appendages: Angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative Reference ID: 5482756 dermatitis, Stevens-Johnson syndrome [see Warnings and Precautions (5.9)], urticaria Special Senses: Conjunctivitis, hearing impairment 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of CAMBIA with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.13)] Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Intervention: Concomitant use of CAMBIA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.13)]. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of CAMBIA and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of CAMBIA and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. Diuretics Reference ID: 5482756 Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of CAMBIA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of CAMBIA and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of CAMBIA and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of CAMBIA and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of CAMBIA and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of CAMBIA and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of CAMBIA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NSAIDs and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Reference ID: 5482756 Inhibitors of Cytochrome P450 2C9 Clinical Impact: Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co- administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [see Clinical Pharmacology (12.3)] Intervention: During concomitant use of CAMBIA and drugs that inhibit CYP2C9, an increase in the duration between CAMBIA doses for subsequent migraine attacks may be necessary. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including CAMBIA, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of CAMBIA use between about 20 and 30 weeks of gestation, and avoid CAMBIA use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including CAMBIA, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal studies, oral administration of diclofenac sodium to pregnant mice, rats, and rabbits resulted in adverse effects on development (embryofetal mortality, reduced fetal growth) at doses similar to those used clinically. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac potassium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Several studies have suggested that women with migraine may be at increased risk of preeclampsia and Reference ID: 5482756 gestational hypertension during pregnancy. Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including CAMBIA, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If CAMBIA treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue CAMBIA and follow up according to clinical practice (see Data). Labor or Delivery The effects of CAMBIA on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Oral administration of diclofenac sodium to pregnant mice and rabbits during organogenesis resulted in embryofetal toxicity at oral doses of up to 20 and 10 mg/kg/day (up to approximately 2 and 4 times, respectively, the recommended human dose [RHD] of 50 mg/day, based on body surface area [mg/m2]). In rats, oral administration of diclofenac at doses of up to 10 mg/kg/day (up to approximately 2 times the RHD on a mg/m2 basis) during organogenesis resulted in increased embryofetal mortality and reduced fetal body weights. Reference ID: 5482756 8.2 Lactation Risk Summary Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMBIA and any potential adverse effects on the breastfed infant from CAMBIA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including CAMBIA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including CAMBIA, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.15)]. Clinical studies of CAMBIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment Because hepatic metabolism accounts for almost 100% of diclofenac elimination, patients with hepatic impairment should be considered for treatment with CAMBIA only if the benefits outweigh the risks. There is insufficient information available to support dosing recommendations for CAMBIA in patients with hepatic insufficiency [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No information is available from controlled clinical studies regarding the use of CAMBIA in patients with advanced renal disease. Therefore, treatment with CAMBIA is not recommended in patients with advanced renal disease. If CAMBIA therapy must be initiated, close monitoring of the patient’s renal function is advisable. Reference ID: 5482756 10 OVERDOSAGE Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and, coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). Anaphylactic reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. 11 DESCRIPTION CAMBIA (diclofenac potassium) for oral solution is a nonsteroidal anti-inflammatory drug, available as a buffered soluble powder, designed to be mixed with water prior to oral administration. CAMBIA is a white to off-white, buffered, flavored powder for oral solution packaged in individual unit dose packets. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid monopotassium salt. The molecular weight is 334.25. Its molecular formula is C14H10Cl2NKO2, and it has the following structure. The inactive ingredients in CAMBIA include: flavoring agents (anise and mint), glycerol behenate, mannitol, potassium bicarbonate, and sucralose. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action CAMBIA has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of CAMBIA, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of Reference ID: 5482756 prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to intravenous administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. In fasting volunteers, measurable plasma levels were observed within 5 minutes of dosing with CAMBIA. Peak plasma levels were achieved at approximately 0.25 hour in fasting normal volunteers, with a range of 0.17 to 0.67 hours. High fat food had no significant effect on the extent of diclofenac absorption, but there was a reduction in peak plasma levels of approximately 70% after a high fat meal. Decreased Cmax may be associated to decreased effectiveness. Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses. Elimination Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4’- hydroxy-, 5-hydroxy-, 3’-hydroxy-, 4’,5-dihydroxy- and 3’-hydroxy-4’-methoxy diclofenac. The major diclofenac metabolite, 4’-hydroxydiclofenac, has very weak pharmacologic activity. The formation of 4’- hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac. In patients with renal impairment, peak concentrations of metabolites 4’- hydroxy-and 5- hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Specific Populations Race: There are no pharmacokinetic differences due to race. Hepatic Impairment: The liver metabolizes almost 100% of diclofenac; there is insufficient information available to support dosing recommendations for CAMBIA in patients with hepatic insufficiency [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Renal Impairment: In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6) and Use in Specific Populations (8.7)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with Reference ID: 5482756 aspirin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Long term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (less than the recommended human dose [RHD] of 50 mg/day on a body surface area [mg/m2] basis) have revealed no significant increases in tumor incidence. There was a slight increase in benign mammary fibroadenomas in mid- dose treated (0.5 mg/kg/day or 3 mg/m2/day) female rats (high-dose females had excessive mortality), but the increase was not significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (less than the RHD on a mg/m2 basis) in males and 1 m/kg/day (less than the RHD on a mg/m2 basis) in females did not reveal any oncogenic potential. Mutagenesis Diclofenac sodium was not genotoxic in in vitro (reverse mutation in bacteria [Ames], mouse lymphoma tk) or in in vivo (including dominant lethal and male germinal epithelial chromosomal aberration in Chinese hamster) assays. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (less than the RHD on a mg/m2 basis) did not affect fertility. 14 CLINICAL STUDIES The efficacy of CAMBIA in the acute treatment of migraine headache was demonstrated in two randomized, double-blind, placebo-controlled trials. Patients enrolled in these two trials were predominantly female (85%) and white (86%), with a mean age of 40 years (range: 18 to 65). Patients were instructed to treat a migraine of moderate to severe pain with 1 dose of study medication. Patients evaluated their headache pain 2 hours later. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated. In addition, the proportion of patients who were “sustained pain free”, defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours post- dose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours post-dose, was also evaluated. In these studies, the percentage of patients achieving pain freedom 2 hours after treatment and sustained pain freedom from 2 to 24 hours post-dose was significantly greater in patients who received CAMBIA compared with those who received placebo (see Table 3). The percentage of patients achieving pain relief 2 hours after treatment (defined as a reduction in headache severity from moderate or severe pain to mild or no pain) was also significantly greater in patients who received CAMBIA compared with those who received placebo (see Table 3). Table 3: Percentage of Patients with 2-Hour Pain Freedom, Sustained Pain Freedom 2-24 Hours, and 2-Hour Pain Relief Following Treatment Study 1 CAMBIA (n=265) Placebo (n=257) 2-Hour Pain Free 24% 13% 2-24h Sustained Pain Free 22% 10% Reference ID: 5482756 2-Hour Pain Relief 48% 27% Study 2 CAMBIA (n=343) Placebo (n=347) 2-Hour Pain Free 25% 10% 2-24h Sustained Pain Free 19% 7% 2-Hour Pain Relief 65% 41% The estimated probability of achieving migraine headache pain freedom within 2 hours following treatment with CAMBIA is shown in Figure 1. Figure 1. Percentage of Patients with Initial Headache Pain Freedom within 2 Hours There was a decreased incidence of nausea, photophobia and phonophobia following administration of CAMBIA, compared to placebo. The efficacy and safety of CAMBIA was unaffected by age or gender of the patient. 16 HOW SUPPLIED/STORAGE AND HANDLING CAMBIA (diclofenac potassium) 50 mg, is a white to off-white, buffered, flavored powder for oral solution, supplied as one or more sets of three perforated co-joined individual dose packets. Each individual packet is designed to deliver a dose of 50 mg diclofenac potassium when mixed in water. NDC 13913-012-01 Individual CAMBIA Packets NDC 13913-012-03 Boxes of nine (9) CAMBIA Packets Storage Store at 25°C (77°F). Excursions permitted from 15°C-30°C (59°F-86°F). [See USP Controlled Room Temperature] 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with CAMBIA and periodically during the course of ongoing therapy. Reference ID: 5482756 Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation CAMBIA, like other NSAIDS, can cause GI discomfort and more serious GI adverse events such as ulcers and bleeding, which may result in hospitalization and even death. Inform patients of the increased risk, and advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. Inform patients of the importance of follow-up in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop CAMBIA and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, Including DRESS Advise patients to stop taking CAMBIA immediately if they develop any type of rash, blisters, fever or other signs of hypersensitivity such as itching and to contact their healthcare provider as soon as possible. CAMBIA, like other NSAIDs, can cause serious skin reactions such as exfoliative dermatitis, Steven-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and DRESS, which may result in hospitalizations and even death [see Warnings and Precautions (5.9, 5.10)]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.11)]. Fetal Toxicity Inform pregnant women to avoid use of CAMBIA and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with CAMBIA is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1)]. Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)]. Female Fertility Reference ID: 5482756 Advise females of reproductive potential who desire pregnancy that NSAIDs, including CAMBIA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of CAMBIA with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with CAMBIA until they talk to their healthcare provider [see Drug Interactions (7)]. Distributed by: Assertio Therapeutics, Inc. 100 South Saunders Road Lake Forest, IL 60045 United States of America Manufactured and Distributed Under License from APR Applied Pharma Research SA, Balerna, Switzerland U.S. Patents: 6,974,595; 7,482,377; 7,759,394; 8,097,651 CAM-003-C.8 ©2023 Assertio Therapeutics, Inc. Reference ID: 5482756 Medication Guide CAMBIA (Cam-bē-ə or Cam-bē-a) (diclofenac potassium) for oral solution What is the most important information I should know about Cambia? CAMBIA contains diclofenac (a non-steroidal anti-inflammatory drug or NSAID). NSAIDs, including CAMBIA, can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs, including CAMBIA, right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs, including CAMBIA, after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems CAMBIA should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What is CAMBIA? CAMBIA is a prescription medicine used to treat migraine attacks in adults. It does not prevent or lessen the number of migraines you have, and it is not for other types of headaches. CAMBIA contains diclofenac potassium (a non-steroidal anti-inflammatory drug or NSAID). How should I take CAMBIA? Take CAMBIA exactly as your healthcare provider tells you to take it. Take 1 dose of CAMBIA to treat your migraine headache: • remove one single dose packet from a set of three packets • open packet only when you are ready to use it • empty contents of packet into 1 to 2 ounces (30 to 60 mL) of water • mix well and drink the water and powder mixture • throw away empty packet in a safe place and out of the reach of children. • taking CAMBIA with food may cause a reduction in effectiveness compared to taking CAMBIA on an empty stomach • do not take more CAMBIA than directed by your healthcare provider. In case of overdose, get medical help or contact a Poison Control Center right away Reference ID: 5482756 Who should not take CAMBIA? Do not take CAMBIA: • if you have had an asthma attack, hives, or other allergic reaction with aspirin, diclofenac, or any other NSAIDs. • right before or after heart bypass surgery. Before taking CAMBIA, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have a history of stomach ulcer or bleeding in your stomach or intestines • have any allergies to any medicines • have chest pain, shortness of breath, irregular heartbeats • have high blood pressure • have asthma • are pregnant, think you might be pregnant, or are trying to become pregnant. Taking NSAIDs, including CAMBIA, at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breastfeed. • have a headache that is different from your usual migraine Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs, like CAMBIA, and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Especially tell your doctor if you take: • aspirin • any anticoagulant medicines (warfarin, Coumadin, Jantoven) Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. What are the possible side effects of CAMBIA? CAMBIA can cause serious side effects, including: See “What is the most important information I should know about CAMBIA?” • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • asthma attacks in people who have asthma • medication overuse headaches. Some people who use too much CAMBIA may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with CAMBIA. • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking CAMBIA and call your healthcare provider right away if you get any of the following symptoms • nausea that seems out of proportion to your migraine • vomit blood • sudden or severe pain in your belly • there is blood in your bowel movement or it is black and sticky like tar • more tired or weaker than usual • unusual weight gain • diarrhea • more tired or weaker than usual • itching • skin rash or blisters with fever Reference ID: 5482756 • your skin or eyes look yellow • swelling of the arms, legs, hands and feet • indigestion or stomach pain • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Assertio Therapeutics, Inc., 100 South Saunders Road, Lake Forest, IL 60045 For more information go to www.CambiaRx.com or call 1-866-458-6389 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 4/2024 CAM-004-C.6 Reference ID: 5482756	custom-source	2025-02-12T15:47:13.156200	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022165s016lbl.pdf', 'application_number': 22165, 'submission_type': 'SUPPL ', 'submission_number': 16}
80,401	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZYNRELEF® safely and effectively. See full prescribing information for ZYNRELEF. ZYNRELEF (bupivacaine and meloxicam) extended-release solution, for instillation use Initial U.S. Approval: 2021 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) -----------------------------RECENT MAJOR CHANGES------------------------ Indications and Usage (1) 01/2024 Dosage and Administration (2.1, 2.3, 2.4) 01/2024 Warnings and Precautions (5.10, 5.14) 11/2024 -----------------------------INDICATIONS AND USAGE------------------------- ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: • soft tissue surgical procedures • orthopedic surgical procedures − foot and ankle procedures − other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10)] Limitations of Use Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large 4 or more level spinal, and head and neck procedures (1). ------------------------DOSAGE AND ADMINISTRATION--------------------- • ZYNRELEF is intended for single-dose administration only (2.1). Administer ZYNRELEF via instillation only. • The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF (2.1). • ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit (2.1). • ZYNRELEF is applied without a needle into the surgical site following final irrigation and suction and prior to suturing (2.1). − The recommended dose of ZYNRELEF is up to a maximum dose of 400 mg/12 mg (14 mL) (2.4). • See Full Prescribing Information for important preparation and administration instructions, dose selection, and compatibility considerations (2.2, 2.3, 2.4, 2.5). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- ZYNRELEF (bupivacaine and meloxicam) extended-release solution is available in four dosage strengths as single-dose glass vials: • 400 mg bupivacaine and 12 mg meloxicam • 300 mg bupivacaine and 9 mg meloxicam • 200 mg bupivacaine and 6 mg meloxicam • 60 mg bupivacaine and 1.8 mg meloxicam -------------------------------CONTRAINDICATIONS----------------------------- ZYNRELEF is contraindicated for: • Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF (4) • Patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (4) • Patients undergoing obstetrical paracervical block anesthesia (4) • Patients undergoing coronary artery bypass graft (CABG) surgery (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after application of ZYNRELEF (5.3). When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours (5.3). Hepatotoxicity: If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient (5.5). Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.6, 7). Heart Failure and Edema: Avoid use of ZYNRELEF in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.7). Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.8). Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.9). Risk of Joint Cartilage Necrosis and Degeneration with Unapproved Intra- articular Use: Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration (5.10, 13.2). Chondrolysis: Limit exposure to articular cartilage due to the potential risk of chondrolysis (5.11). Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use (5.12). Serious Skin Reactions: NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically (5.14). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): If symptoms are present, evaluate clinically (5.15). Fetal Toxicity: Limit use of NSAIDs, including ZYNRELEF, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus (5.16, 8.1). Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.17). -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (incidence ≥5%) are: • Soft tissue procedures: vomiting (6.1). • Orthopedic procedures: constipation and headache (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Heron Therapeutics, Inc. at 1-844-437-6611 and www.ZYNRELEF.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ZYNRELEF with drugs that interfere with hemostasis (7.2). ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Concomitant use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7.2). ACE Inhibitors and ARBs: Concomitant use with ZYNRELEF in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7.2). Reference ID: 5482849 Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effect (7.2). --------------------------USE IN SPECIFIC POPULATIONS-------------------- Infertility: NSAIDs are associated with reversible infertility. Consider avoidance of ZYNRELEF in women who have difficulties conceiving (8.3). Severe Hepatic Impairment: Only use if benefits are expected to outweigh risks; monitor for signs of worsening liver function (8.6). Severe Renal Impairment: Not recommended (8.7). See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Preparation Instructions 2.3 Administration Instructions 2.4 Dosing Instructions 2.5 Compatibility Considerations 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular (CV) Thrombotic Events with NSAID Use 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID Use 5.3 Dose-Related Toxicity 5.4 Risk of Use in Patients with Impaired Cardiovascular Function 5.5 Hepatotoxicity 5.6 Hypertension 5.7 Heart Failure and Edema 5.8 Renal Toxicity and Hyperkalemia 5.9 Anaphylactic Reactions 5.10 Risk of Joint Cartilage Necrosis with Unapproved Intra-articular Use 5.11 Chondrolysis 5.12 Methemoglobinemia 5.13 Exacerbation of Asthma Related to Aspirin Sensitivity 5.14 Serious Skin Reactions 5.15 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.16 Fetal Toxicity 5.17 Hematologic Toxicity 5.18 Masking of Inflammation and Fever 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Bupivacaine Drug Interactions 7.2 Meloxicam Drug Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Poor Metabolizers of CYP2C9 Substrates 10 OVERDOSAGE 10.1 Bupivacaine 10.2 Meloxicam 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482849 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: • soft tissue surgical procedures • orthopedic surgical procedures − foot and ankle procedures − other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10)] Limitations of Use Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large 4 or more level spinal, and head and neck procedures. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information ADMINISTER ZYNRELEF VIA INSTILLATION ONLY. • ZYNRELEF should not be administered via the following routes. - Epidural - Intrathecal - Intravascular - Intra-articular [see Warnings and Precautions (5.10), Nonclinical Toxicology (13.2)] Reference ID: 5482849 - Regional nerve blocks - Pre-incisional or pre-procedural locoregional anesthetic techniques. • ZYNRELEF is intended for single-dose administration only. • As there is a potential risk of severe, life-threatening adverse reactions associated with the administration of bupivacaine, ZYNRELEF should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurologic or cardiac toxicity [see Overdosage (10)]. • The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. • Avoid intravascular administration of ZYNRELEF. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products. • Limit exposure to articular cartilage due to the potential risk of chondrolysis [see Warnings and Precautions (5.11)]. • ZYNRELEF is a viscous solution supplied as a kit consisting of a single-dose glass vial, and the following sterile components: Luer Lock syringe(s), a vented vial spike, Luer Lock cone-shaped applicator(s), and syringe tip cap(s). ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit. See the ZYNRELEF Instructions for Use included in the kit for complete administration instructions with illustrations. • The contents of the ZYNRELEF vial are sterile. The vial exterior is not sterile. Follow your facility’s standard operating procedures regarding aseptic drug preparation. • Each ZYNRELEF vial contains overfill to compensate for residual amounts that remain in the vial, vented vial spike, Luer lock applicator, and syringe(s) during drug withdrawal and administration. • ZYNRELEF is applied without a needle into the surgical site after placement of implant(s) (if applicable), following final irrigation and suctioning, and prior to suturing of each layer, when multiple tissue layers are involved. • When ZYNRELEF comes in contact with moisture in the tissues, it becomes more viscous, allowing it to stay in place. • ZYNRELEF does not degrade sutures. When tying knots with monofilament sutures, contact with ZYNRELEF may cause knots to loosen or untie due to the viscosity of ZYNRELEF. In vitro studies showed an increase in elasticity with monofilament sutures exposed to ZYNRELEF with unknown clinical significance. Minimize administration of ZYNRELEF near the incision line and wipe off excess ZYNRELEF from the skin prior to suturing. Three (3) or more knots ending in a multi-throw knot (e.g., a Surgeon’s knot) are recommended with monofilament sutures. Braided or barbed sutures are recommended, especially for closure of deeper layers. Reference ID: 5482849 2.2 Preparation Instructions 1. ZYNRELEF is a clear, pale yellow to yellow, viscous liquid. Visually inspect the ZYNRELEF vial for particulate matter and discoloration. Obtain a new vial if particulate matter or discoloration is observed. 2. Prepare vial for filling of syringe(s) by attaching vented vial spike. 3. Prepare syringe by filling with air then attach to vented vial spike. 4. Invert to allow product to fill the vial neck and push air into vial. Withdraw dose of ZYNRELEF into syringe. (The dose volume takes into account the potential residual volume in the components.) Nominal Dose of Bupivacaine / Meloxicam Number of Syringes and LLAs* Per Dose Volume to be Withdrawn 60 mg/ 1.8 mg 1 2.3 mL (using 3 mL syringe provided) 200 mg / 6 mg 1 7 mL (using 12 mL syringe provided) 300 mg/ 9 mg 1 10.5 mL (using 12 mL syringe provided) 400 mg/ 12 mg 2 14 mL (using two 12 mL syringes provided, 7 mL ZYNRELEF per syringe) LLA: Luer lock cone-shaped applicator 5. Repeat steps 1-3 for more than one syringe. 6. Prepare product immediately prior to use and apply syringe tip cap until product delivery. 2.3 Administration Instructions Before administration, remove the syringe tip cap and attach the Luer lock cone-shaped applicator to the syringe. 1. Using the Luer lock cone-shaped applicator attached to the syringe, apply ZYNRELEF to the tissues within the surgical site as follows: • For soft tissue procedures, apply ZYNRELEF into the wound prior to closure of each layer within the surgical space. − For abdominal procedures, apply after closure of the peritoneum (if applicable) and avoid administration below the peritoneum. • In general for orthopedic procedures, apply ZYNRELEF into the wound and on the periosteum from the proximal to the distal ends of the wound (i.e., beyond the boney repair). - For total joint arthroplasty, apply ZYNRELEF directly into the joint capsule, onto the periosteum, and the antero-, medial-, and lateral tissues (if applicable), after placement of the component(s). - For spinal procedures, apply ZYNRELEF after closure of the paraspinal musculature and again after closure of the subcutaneous fascia. ZYNRELEF must not be applied to the dura or spinal cord. 2. Only apply ZYNRELEF to the tissue layers below the skin incision and not directly onto the subdermal layer or the skin. Minimize administration of ZYNRELEF near the incision line. 3. Use only the amount necessary to coat the tissues, such that ZYNRELEF does not leak from the surgical wound after closure. Wipe off excess ZYNRELEF from the skin prior to or during closure of the wound. Reference ID: 5482849 2.4 Dosing Instructions As a general guidance in selecting the proper dosing of ZYNRELEF, the following examples of dosing are provided: • For soft tissue surgical procedures, such as: − open inguinal herniorrhaphy: up to 10.5 mL to deliver 300 mg of bupivacaine and 9 mg of meloxicam [see Clinical Studies (14)]; − abdominoplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14)]; − Cesarean section: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14)]; − augmentation mammoplasty: up to 7 mL per side to deliver total of 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14)]. • For orthopedic surgical procedures, such as: − bunionectomy: up to 2.3 mL to deliver 60 mg of bupivacaine and 1.8 mg of meloxicam [see Clinical Studies (14)]; − total knee arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14)]; − total shoulder arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14)]; − 1- to 3-level spinal surgery: up to 7 mL to deliver 200 mg bupivacaine and 6 mg meloxicam [see Clinical Studies (14)]. 2.5 Compatibility Considerations • Do not dilute ZYNRELEF. • ZYNRELEF is a nonaqueous solution. It cannot be mixed with water, saline, or other local anesthetics as the product will become more viscous and difficult to administer. • When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, the site should be allowed to dry before a local anesthetic, including ZYNRELEF, is administered into the site. • When administered in recommended doses and concentrations, ZYNRELEF does not ordinarily produce irritation or tissue damage. ZYNRELEF is compatible with: • All components of the ZYNRELEF kit, including syringes, Luer lock cone-shaped applicator, vented vial spike, and syringe tip caps. • Surgical mesh materials, including polypropylene (Prolene®), Gore-tex, and polyester. • Silicone membranes. • Bone cement. • Metal alloys used in surgical implants. Reference ID: 5482849 3 DOSAGE FORMS AND STRENGTHS ZYNRELEF (bupivacaine and meloxicam) extended-release solution is a sterile, clear, pale-yellow to yellow, viscous liquid in a single-dose vial containing 29.25 mg/mL bupivacaine and 0.88 mg/mL meloxicam and is available in the following four presentations: • 14 mL containing 400 mg bupivacaine and 12 mg meloxicam • 10.5 mL containing 300 mg bupivacaine and 9 mg meloxicam • 7 mL containing 200 mg bupivacaine and 6 mg meloxicam • 2.3 mL containing 60 mg bupivacaine and 1.8 mg meloxicam 4 CONTRAINDICATIONS ZYNRELEF is contraindicated in: • Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF [see Warnings and Precautions (5.9, 5.14)]. • Patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.9)]. • Patients undergoing obstetrical paracervical block anesthesia. The use of bupivacaine in this technique has resulted in fetal bradycardia and death [see Use in Specific Populations (8.1)]. • Patients undergoing coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular (CV) Thrombotic Events with NSAID Use Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. The risk of these events following single-dose local application of ZYNRELEF is uncertain. To minimize the potential risk for an adverse CV event in NSAID-treated patients, do not exceed the recommended dose. Physicians and patients should remain alert for the development of such events following treatment with ZYNRELEF, even in the absence of previous CV symptoms. Inform patients about the signs and symptoms of serious CV events and the steps to take if they occur. Reference ID: 5482849 There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. ZYNRELEF is contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all- cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ZYNRELEF in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ZYNRELEF is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. The risk of these events following single-dose local application of ZYNRELEF is uncertain. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID Use NSAIDs, including meloxicam in ZYNRELEF, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most post marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Reference ID: 5482849 Strategies to Minimize the GI Risks in NSAID-treated Patients • Use the recommended dose for each indicated surgical procedure. • Avoid administration of analgesic doses of more than one NSAID at a time. If additional NSAID medication is indicated in the postoperative period, monitor patients for signs and symptoms of NSAID-related GI adverse reactions. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding following treatment with ZYNRELEF. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Dose-Related Toxicity The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. The toxic effects of local anesthetics are additive. Avoid additional local anesthetic administration within 96 hours following ZYNRELEF instillation. If additional local anesthetic administration with ZYNRELEF cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after administration of ZYNRELEF. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. 5.4 Risk of Use in Patients with Impaired Cardiovascular Function Patients with impaired cardiovascular function (e.g., hypotension, heart block) may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by ZYNRELEF. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.5 Hepatotoxicity Local Anesthetics, Including Bupivacaine Because amide-type local anesthetics such as bupivacaine are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. NSAIDs Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, Reference ID: 5482849 cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. The risk of these events following single-dose local application of ZYNRELEF is uncertain. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), perform a clinical evaluation of the patient [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.6 Hypertension NSAIDs, including meloxicam in ZYNRELEF, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) after administration of ZYNRELEF. 5.7 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo- treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. The risk of these events following single-dose local application of ZYNRELEF is uncertain. Avoid the use of ZYNRELEF in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ZYNRELEF is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.8 Renal Toxicity and Hyperkalemia Renal Toxicity ZYNRELEF is a single-use product that contains an NSAID. Long-term administration of NSAIDs has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired Reference ID: 5482849 renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of meloxicam may hasten the progression of renal dysfunction in patients with preexisting renal disease. Because some meloxicam metabolites are excreted by the kidney, monitor patients for signs of worsening renal function. Correct volume status in dehydrated or hypovolemic patients prior to initiating ZYNRELEF. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ZYNRELEF [see Drug Interactions (7)]. Avoid the use of ZYNRELEF in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ZYNRELEF is used in patients with advanced renal disease, monitor patients for signs of worsening renal function [see Clinical Pharmacology (12.3)]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.9 Anaphylactic Reactions NSAIDs Meloxicam, contained in ZYNRELEF, has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see Contraindications (4)]. Seek emergency help if an anaphylactic reaction occurs. 5.10 Risk of Joint Cartilage Necrosis with Unapproved Intra-articular Use The safety and effectiveness of intra-articular use of ZYNRELEF in orthopedic surgical procedures other than for foot and ankle procedures have not been established, and ZYNRELEF is not approved for use via other intra-articular administration routes. Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration [see Nonclinical Toxicology (13.2)]. 5.11 Chondrolysis Limit exposure to articular cartilage due to the potential risk of chondrolysis. Intra-articular infusions of local anesthetics, following arthroscopic and other surgical procedures is an unapproved use, and there have been post marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of glenohumeral chondrolysis have been described in pediatric patients and adult patients following intra- articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are associated with chondrolysis. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. Reference ID: 5482849 5.12 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue any oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.13 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include: chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NSAIDs are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ZYNRELEF is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for exacerbation of asthma symptoms. 5.14 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions. ZYNRELEF is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.15 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ZYNRELEF. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, evaluate the patient immediately and treat as clinically indicated. Reference ID: 5482849 5.16 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including ZYNRELEF, in pregnant women at about 30 weeks gestation and later. NSAIDs, including ZYNRELEF, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including ZYNRELEF, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ZYNRELEF use to the lowest effective dose. Because meloxicam can be detected in plasma beyond 48 hours after administration of ZYNRELEF, consider ultrasound monitoring for oligohydramnios. If oligohydramnios occurs, follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.17 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ZYNRELEF has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.18 Masking of Inflammation and Fever The pharmacological activity of ZYNRELEF in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with bupivacaine HCl or meloxicam and are discussed in greater detail in other sections of the labeling: • Cardiovascular System Reactions [see Warnings and Precautions (5.1, 5.4)] • Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] • Dose-Related Toxicity [see Warnings and Precautions (5.3)] • Hepatotoxicity [see Warnings and Precautions (5.5)] • Hypertension [see Warnings and Precautions (5.6)] • Heart Failure and Edema [see Warnings and Precautions (5.7)] Reference ID: 5482849 • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.8)] • Anaphylactic Reactions [see Warnings and Precautions (5.9)] • Chondrolysis [see Warnings and Precautions (5.11)] • Methemoglobinemia [see Warnings and Precautions (5.12)] • Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.13)] • Serious Skin Reactions [see Warnings and Precautions (5.14)] • Drug Reaction with Eosinophilia and Systemic Toxicity (DRESS) [see Warnings and Precautions (5.15)] • Fetal Toxicity [see Warnings and Precautions (5.16)] • Hematologic Toxicity [see Warnings and Precautions (5.17)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of ZYNRELEF has been evaluated in a total of 1627 patients undergoing various surgical procedures across 14 clinical studies including 7 randomized, double-blind, bupivacaine- and placebo- controlled and saline placebo-controlled studies designed to investigate ZYNRELEF to reduce postoperative pain for 72 hours and the need for opioid analgesics, of whom 1183 received ZYNRELEF by instillation. Patients treated with ZYNRELEF ranged in age from 18 to 85 years (median age 51 years), with 53.0% female, 82.1% White, 13.7% African-American, and 4.3% all other races. Common Adverse Reactions The safety of ZYNRELEF has been evaluated in 1064 patients who received ZYNRELEF in single doses up to 400 mg/12 mg via instillation into the surgical site, including 533 patients undergoing a soft tissue surgical procedure (herniorrhaphy, abdominoplasty, augmentation mammoplasty, or Cesarean section) and 531 patients undergoing an orthopedic surgical procedure (bunionectomy, total knee arthroplasty, total shoulder arthroplasty, or lumbar spinal surgery). The most common adverse reactions (incidence greater than or equal to 5% and higher than placebo) following ZYNRELEF administration among patients undergoing soft tissue procedures was vomiting and among patients undergoing orthopedic procedures were constipation and headache. The safety of ZYNRELEF as part of a scheduled, non-opioid multimodal analgesic regimen including 1 or more other NSAIDs has been evaluated in a total of 473 patients undergoing soft tissue procedures or orthopedic procedures. NSAIDs included ibuprofen, ketorolac, and celecoxib. In these studies, the most common adverse reactions (incidence of greater than or equal to 2%) potentially associated with NSAIDs were pruritus and postoperative anemia. Rare but clinically serious NSAID-related adverse events, including peptic ulcer hemorrhage, gastritis requiring hospitalization, hematemesis and melena, gastrointestinal hemorrhage, and increased hepatic enzymes, were observed in subjects with predisposing risk factors (i.e., concomitant comorbidities and/or on concomitant medications such as anticoagulant and/or antiplatelet medications) that increased the risk for NSAID-related gastrointestinal toxicity. Reference ID: 5482849 Adverse Reactions Reported in Phase 3 and 2b Placebo-controlled Trials Three randomized, bupivacaine-controlled and saline placebo-controlled studies were conducted in patients undergoing bunionectomy (STUDY 1, Table 1 and Table 2), open inguinal herniorrhaphy (STUDY 2, Table 3), and total knee arthroplasty (STUDY 3, Table 4). The bunionectomy procedures in STUDY 1 were performed under regional anesthesia, a lidocaine Mayo block, and intravenous sedation. The herniorrhaphy procedures in STUDY 2 were performed under general anesthesia. The total knee arthroplasty procedures in STUDY 3 were performed under either general or spinal anesthesia. Patients in STUDY 1 and STUDY 2 were allowed opioid rescue with intravenous (IV) morphine and oral oxycodone, and/or non-opioid rescue with oral acetaminophen. Patients in STUDY 3 were pretreated with oral pregabalin and acetaminophen, and allowed opioid rescue with IV morphine and oral oxycodone postoperatively. Table 1. Adverse Reactions with ZYNRELEF in Study 1 (Bunionectomy) Occurring with ≥5% Incidence and Higher than with Saline Placebo Preferred Term Saline Placebo (N=101), % Bupivacaine HCl 50 mg (N=154), % ZYNRELEF 60 mg/1.8 mg (N=157), % Dizziness 18 23 22 Incision site edema 13 14 17 Headache 10 13 14 Incision site erythema 8 12 13 Bradycardia 6 8 8 Impaired healing 1 4 6 Muscle twitching 5 5 6 In STUDY 1, bone healing was assessed by X-ray on Days 28 and 42. There was no clinically meaningful difference in bone healing between treatment groups. A total of 4 subjects had delayed bone healing: 1 in the ZYNRELEF group, 1 in the saline placebo group, and 2 in the bupivacaine HCl group. The incidence of local inflammatory adverse events was higher in the ZYNRELEF group than in either control group (Table 2). Table 2. Incidence of Local Inflammatory Adverse Events with ZYNRELEF in Study 1 (Bunionectomy) Occurring with ≥2% Incidence and Higher than with Saline Placebo Saline Placebo (N=101), % Bupivacaine HCl 50 mg (N=154), % ZYNRELEF 60 mg/1.8 mg (N=157), % Incision site edema 13 14 17 Incision site erythema 8 12 13 Impaired healing 1 4 6 Incision site cellulitis 1 1 4 Wound dehiscence 2 1 4 Incision site infection 0 1 3 Reference ID: 5482849 Table 3. Adverse Reactions with ZYNRELEF in Study 2 (Herniorrhaphy) Occurring with ≥5% Incidence and Higher than with Saline Placebo Preferred Term Saline Placebo (N=82), % Bupivacaine HCl 75 mg (N=173), % ZYNRELEF 300 mg/9 mg (N=163), % Headache 12 14 13 Bradycardia 7 9 9 Dysgeusia 4 12 9 Skin odor abnormala 1 1 8 a All TEAEs of skin odor abnormal were recorded at a single site. Table 4. Adverse Reactions with ZYNRELEF in Study 3 (Total Knee Arthroplasty) Occurring with ≥5% Incidence and Higher than with Saline Placebo Preferred Term Saline Placebo (N=53), % Bupivacaine HCl 125 mg (N=55), % ZYNRELEF 400 mg/12 mg (N=58), % Nausea 47 55 50 Constipation 23 33 24 Vomiting 19 27 26 Hypertension 15 13 19 Pyrexia 4 15 14 Leukocytosis 0 2 7 Pruritis 2 5 7 Headache 0 7 7 Anemia 2 0 5 Hyperhidrosis 4 0 5 Hypotension 4 2 5 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZYNRELEF or other products containing NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. ZYNRELEF Injury, Poisoning, and Procedural Complications: Wound necrosis, wound dehiscence. Surgical and Medical Procedures: Post-procedural drainage. NSAIDs Skin and Appendages: Exfoliative dermatitis, SJS, TEN, and FDE [see Warnings and Precautions (5.14)]. Reference ID: 5482849 7 DRUG INTERACTIONS 7.1 Bupivacaine Drug Interactions In clinical studies, other local anesthetics (including ropivacaine and lidocaine) have been administered before, during, or after application of ZYNRELEF without evidence of local anesthetic systemic toxicity. Administration of ZYNRELEF with other formulations of local anesthetics, including bupivacaine liposome injectable suspension, has not been studied [see Warnings and Precautions (5.3)]. The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. If co-administration cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1), Warnings and Precautions (5.1) and Overdosage (10)]. Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics (Table 5). Table 5. Examples of Drugs Associated with Methemoglobinemia Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.2 Meloxicam Drug Interactions See Table 6 for clinically significant drug interactions with meloxicam. Table 6. Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ZYNRELEF with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.17)]. Reference ID: 5482849 Aspirin Clinical Impact: In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: If aspirin is indicated in the postoperative period, monitor patients for signs and symptoms of GI bleeding [see Clinical Pharmacology (12.3)]. ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of ZYNRELEF and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of ZYNRELEF and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs have reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention: During concomitant use of ZYNRELEF with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Digoxin Clinical Impact: The concomitant use of NSAIDS with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ZYNRELEF and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients on lithium for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ZYNRELEF and methotrexate, monitor patients for methotrexate toxicity. Reference ID: 5482849 Cyclosporine Clinical Impact: Concomitant use of NSAIDs and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of ZYNRELEF and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.2)]. Intervention: If additional NSAID or salicylate medication is indicated in the postoperative period, monitor patients for signs and symptoms of GI toxicity [see Clinical Pharmacology (12.3)]. Pemetrexed Clinical Impact: Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of ZYNRELEF and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available human data on use of ZYNRELEF in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, there are available data on the individual components of ZYNRELEF, bupivacaine and meloxicam. Bupivacaine The available data on bupivacaine use in pregnant women for epidural anesthesia (excluding paracervical block) are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are no adequate and well-controlled studies with bupivacaine in pregnant women. In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at a comparable bupivacaine dose level of 400 mg at the maximum recommended human dose (MRHD) of ZYNRELEF. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a comparable bupivacaine dose to the MRHD (see Data). Based on animal data, pregnant women should be advised of the potential risks to a fetus. Meloxicam Use of NSAIDs, including ZYNRELEF, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ZYNRELEF use between about 20 and 30 weeks of Reference ID: 5482849 gestation and avoid ZYNRELEF use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ZYNRELEF, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.8 and 8 times, respectively, the meloxicam dose level of 12 mg at the MRHD of ZYNRELEF. Increased incidence of septal heart defects was observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 97 times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.1 times the MRHD. No malformations were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 3.2 and 32 times, respectively, the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Meloxicam Premature Closure of the Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ZYNRELEF, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. Because meloxicam can be detected in plasma beyond 48 hours after administration of ZYNRELEF, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, follow up according to clinical practice (see Data). Reference ID: 5482849 --- Labor or Delivery Bupivacaine Bupivacaine is contraindicated in obstetrical paracervical block anesthesia. The use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death [see Contraindications (4)]. Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity [see Clinical Pharmacology (12.3)]. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Meloxicam There are no studies on the effects of meloxicam during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Meloxicam Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Reproduction studies have not been conducted with ZYNRELEF. Reference ID: 5482849 Bupivacaine Bupivacaine HCl was administered subcutaneously to rats at doses of 4.4, 13.3, and 40 mg/kg and to rabbits at doses of 1.3, 5.8, and 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily MRHD of 400 mg on a mg/m2 (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 0.3 times the MRHD on a BSA basis. In a rat pre- and post-natal developmental study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, and 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg on a BSA basis. Meloxicam Meloxicam did not cause malformations when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (3.2 times the meloxicam dose level of 12 mg at the MRHD of ZYNRELEF based on BSA comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (97 times the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (32 times the MRHD based on BSA comparison). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.8 and 8 times the MRHD, respectively, based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.1 times the MRHD based on BSA comparison). 8.2 Lactation Risk Summary Limited published literature reports that bupivacaine and its primary metabolite, pipecoloxylidine (PPX), are present in human milk at low levels. There are no human data available on whether meloxicam is present in human milk. There is no available information on effects of bupivacaine or meloxicam in the breastfed infant or effects of the drugs on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZYNRELEF and any potential adverse effects on the breastfed infant from ZYNRELEF or from the underlying maternal condition. Data Animal Data Following administration of ZYNRELEF to lactating pigs, bupivacaine and meloxicam were detected in milk, but only bupivacaine was detected in the plasma of piglets allowed to suckle milk from the treated animals. Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma. Reference ID: 5482849 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs and avoidance of ZYNRELEF in women who have difficulties conceiving or who are undergoing investigation of infertility. Males In a published study, oral administration of meloxicam to male rats for 35 days resulted in decreased sperm count and motility and histopathological evidence of testicular degeneration at 0.8 times the MRHD based on BSA comparison [see Nonclinical Toxicology (13.1)]. It is not known if these effects on fertility are reversible. The clinical relevance of these findings is unknown. 8.4 Pediatric Use Safety and effectiveness of ZYNRELEF in pediatric patients has not been established. 8.5 Geriatric Use Of the total number of patients undergoing various surgical procedures who were exposed to ZYNRELEF in clinical studies (N=1627), 288 patients (17.7%) were ≥ 65 years old, while 83 (5.1%) were ≥75 years old. No overall differences in safety or efficacy were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions, although the applicability of this to a single administration of low-dose meloxicam in ZYNRELEF is uncertain [see Warnings and Precautions (5.1, 5.2, 5.8)]. In clinical studies, differences in various pharmacokinetic parameters have been observed with bupivacaine HCl between elderly and younger patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to bupivacaine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in ZYNRELEF dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Consider reducing the dose of ZYNRELEF for elderly patients. 8.6 Hepatic Impairment Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Because meloxicam is primarily metabolized in the liver and hepatotoxicity may occur, monitor patients with hepatic impairment for signs and symptoms of worsening disease. Meloxicam has not been adequately studied in patients with severe hepatic impairment. Reference ID: 5482849 No dose adjustment of ZYNRELEF is necessary in patients with mild to moderate hepatic impairment. ZYNRELEF should only be used in patients with severe hepatic impairment if the benefits are expected to outweigh the risks; monitor patients for signs of worsening liver function. Consider increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease [see Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Because bupivacaine and meloxicam and their metabolites are excreted by the kidney, the risk of toxic reactions to these drugs may be greater in patients with impaired renal function. This should be considered when performing dose selection of ZYNRELEF. Consider reducing the dose of ZYNRELEF for patients with mild to moderate renal impairment. Patients with severe renal disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Patients with severe renal impairment have not been studied. The use of ZYNRELEF in patients with severe renal impairment is not recommended. Meloxicam is not dialyzable. When using ZYNRELEF in patients on hemodialysis do not exceed maximum recommended dose or use with other meloxicam-containing products [see Clinical Pharmacology (12.3)]. 8.8 Poor Metabolizers of CYP2C9 Substrates In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin or phenytoin), consider dose reduction, as these patients may have abnormally high plasma levels of meloxicam due to reduced metabolic clearance. Monitor these patients for adverse effects. 10 OVERDOSAGE No data are available with regard to overdose of ZYNRELEF. Findings related to the individual active substances are listed below. 10.1 Bupivacaine Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [see (Warnings and Precautions (5.3) and Adverse Reactions (6)]. Following administration of ZYNRELEF (400 mg/12 mg) by instillation, a highest individual maximum plasma concentration (Cmax) of bupivacaine of 1830 ng/mL was reported. No apparent bupivacaine related systemic toxicity was observed. Signs and symptoms of overdose include CNS symptoms (dizziness, sensory and visual disturbances, and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia, and asystole). Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,000 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL. Management of Local Anesthetic Overdose At the first sign of change, oxygen should be administered. Reference ID: 5482849 The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs, and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. 10.2 Meloxicam Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.2, 5.6, 5.8)]. There is limited experience with meloxicam overdosage. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, call a poison control center (1-800-222-1222). 11 DESCRIPTION ZYNRELEF (bupivacaine and meloxicam) extended-release solution, for soft tissue or periarticular instillation use, contains bupivacaine, an amide local anesthetic, and meloxicam, a nonsteroidal anti- inflammatory drug (NSAID). Reference ID: 5482849 Bupivacaine Bupivacaine is a white to off-white crystalline powder, crystals, or granules. The chemical name for bupivacaine is (±)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide, and its empirical formula is C18H28N2O. The molecular weight of bupivacaine is 288.4. Bupivacaine is sparingly soluble in water and freely soluble in alcohol. Bupivacaine has a log Pow of 1.82 and a pKa of 8.1. Bupivacaine has the following structural formula: H3C H3C O N N H CH3 Meloxicam Meloxicam is a pale yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2 benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula: CH3 OH O S N N H N S CH3 O O ZYNRELEF is a sterile, clear, pale yellow to yellow, viscous liquid provided in single-dose vials (10 mL or 20 mL) for instillation into the surgical site. Each mL of the solution contains active ingredients bupivacaine 29.25 mg and meloxicam 0.88 mg; and inactive ingredients tri(ethylene glycol) poly(orthoester) (730 mg), triacetin (293 mg), dimethyl sulfoxide (117 mg), and maleic acid (0.59 mg). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ZYNRELEF is a fixed-dose combination of bupivacaine and meloxicam. Bupivacaine Local anesthetics block the generation and the conduction of nerve impulses presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Reference ID: 5482849 Meloxicam The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics Additional pharmacodynamic data in clinical studies Additional pharmacodynamic data for ZYNRELEF was evaluated in patients undergoing abdominoplasty, Cesarean section, total shoulder arthroplasty, and 1- to 3-level lumbar spinal surgery. Refer to Dosage and Administration for specific doses used for each study [see Dosage and Administration (2.4)]. Contribution of Meloxicam and Bupivacaine to Activity of ZYNRELEF The contribution of each active ingredient in ZYNRELEF was demonstrated in Phase 2 double-blind, randomized, active- and placebo-controlled clinical studies in subjects undergoing herniorrhaphy or bunionectomy, utilizing ZYNRELEF and formulations of meloxicam alone or bupivacaine alone in the ZYNRELEF vehicle. In both studies, meloxicam alone demonstrated negligible local analgesia and bupivacaine alone demonstrated greater analgesia compared with placebo through 24 hours post surgery, despite exposure to bupivacaine for approximately 72 hours. Compared with bupivacaine alone in both studies, ZYNRELEF (at the same bupivacaine doses) demonstrated greater and longer analgesia through 24, 48, and 72 hours. Effect on Cardiac Repolarization The effect of ZYNRELEF on cardiac repolarization as assessed by the QTc interval was evaluated following a single administration in patients undergoing surgical procedures. ZYNRELEF, at single doses up to the maximum recommended dose, did not demonstrate an effect on the QTc interval. Bupivacaine Systemic absorption of local anesthetics, including bupivacaine, produces effects on the cardiovascular and central nervous systems (CNS), which can be serious at toxic blood concentrations [see Warnings and Precautions (5.3)]. At blood concentrations achieved with normal therapeutic doses, manifestations of CNS stimulation and depression or changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. Clinical reports and animal research suggest that cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. 12.3 Pharmacokinetics The instillation of ZYNRELEF into the surgical site results in systemic plasma levels of bupivacaine and meloxicam for up to the duration as described in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy. Reference ID: 5482849 Absorption The rate of systemic absorption of bupivacaine or meloxicam from ZYNRELEF is dependent upon the total dose of drug administered and the vascularity of the administration site. Pharmacokinetic parameters of bupivacaine and meloxicam after single dose administration by instillation of ZYNRELEF were evaluated following multiple surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative ZYNRELEF doses are provided in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures. Table 7. Summary of Pharmacokinetic Parameters for Bupivacaine and Meloxicam After Single Dose Administration of ZYNRELEF by Instillation for Soft Tissue Surgical Procedures Active Ingredient Parameter Herniorrhaphy: 300 mg/9 mg ZYNRELEF (N=16) Abdominoplasty: 400 mg/12 mg ZYNRELEF (N=22) Augmentation Mammoplasty: 400 mg/12 mg ZYNRELEF (N=49) Cesarean Section: 400 mg/12 mg ZYNRELEF (N=11) Bupivacaine Cmax (ng/mL) 271 (147) 382 (149) 710 (246) 291 (70) Tmax (h) 18 (3, 30) 31 (20, 54) 3.6 (1.3, 35) 24 (1.1, 48) AUC(0-t) a (h×ng/mL) 15174 (8545) 24411 (10072) 27363 (9227) 17923 (5069) AUC(inf) (h×ng/mL) 15524 (8921) 24930 (10105) 31072 (17998) 17983 (5065) t½ (h) 16 (9) 20 (8) 25 (20) 10 (2) C72h (ng/mL) 96 (75) 202 (118) 149 (68) b 127 (56) C96h (ng/mL) 37 (43) 86 (52) c NS 27 (16) C144h (ng/mL) NS 16 (11) c NS 0.8 (1.0) d Meloxicam Cmax (ng/mL) 225 (96) 116 (62) 527 (149) 114 (49) Tmax (h) 54 (24, 96) 24 (4.0, 72) 20 (5.6, 49) 60 (8.5, 73) AUC(0-t) (h×ng/mL) 18721 (7923) 7924 (4197) 30499 (9460) 9710 (4560) AUC(inf) (h×ng/mL) NR 8304 (4422) 41809 (38414) 9778 (4592) t½ (h) NR 21 (9) 42 (70) 21 (9) C72h (ng/mL) 197 (95) 70 (44) 214 (105) b 86 (43) C96h (ng/mL) 146 (86) 33 (25) c NS 48 (32) C144h (ng/mL) NS 7.1 (10) c NS 11 (12) d Note: Arithmetic mean (standard deviation) except Tmax where it is median (min, max). Doses of ZYNRELEF are shown as bupivacaine dose (mg)/meloxicam dose (mg). a AUC(0-t): 0 to 120 h post-dose for herniorrhaphy, augmentation mammoplasty, and Cesarean section; 0 to 144 h post-dose for abdominoplasty. b N=48; c N=21; d N=10 NS = not sampled; NR= not reported, since the terminal elimination phase was not adequately characterized in sufficient number of patients. Reference ID: 5482849 Table 8. Summary of Pharmacokinetic Parameters for Bupivacaine and Meloxicam After Single Dose Administration of ZYNRELEF by Instillation for Orthopedic Surgical Procedures Active Ingredient Parameter Bunionectomy: 60 mg/1.8 mg ZYNRELEF (N=17) Total Knee Arthroplasty: 400 mg/12 mg ZYNRELEF (N=53) Total Shoulder Arthroplasty: 400 mg/12 mg ZYNRELEF (N=20) 1-Level Spinal Surgery: 92 mg/2.8 mg ZYNRELEF (N=13) 2- or 3-Level Spinal Surgery: 191 mg/5.7 mg ZYNRELEF (N=13) Bupivacaine Cmax (ng/mL) 54 (33) 695 (411) 372 (165) 95 (105) 163 (67) Tmax (h) 3.0 (1.6, 24) 21 (4, 59) 20 (1.8, 48) 23 (1.9, 38) 24 (4.1, 69) AUC(0-t) a (h×ng/mL) 1681 (1154) 35889 (28399) 21132 (12331) 4467 (4977) 8488 (4086) AUC(inf) (h×ng/mL) 1718 (1211) 38173 (29401) b 21193 (12329) 5535 (6091) c 8659 (4288) d t½ (h) 15 (8) 17 (7) b 10 (3) 25 (25) c 14 (5) d C72h (ng/mL) 5.0 (5.3) 227 (283) 145 (117) 34 (48) d 61 (49) c C96h (ng/mL) 1.7 (2.9) e NS 30 (32) 5.2 (7.3) d 24 (27) d C144h (ng/mL) NS 5.3 (21) f 1.1 (2.2) g NS NS Meloxicam Cmax (ng/mL) 26 (14) e 275 (134) 248 (125) h 53 (41) i 90 (36) c Tmax (h) 18 (8, 60) e 36 (12, 72) 57 (12, 72) h 18 (12, 72) i 43 (23, 69) c AUC(0-t) (h×ng/mL) 1621 (927) e 19525 (12259) 22292 (12250) h 3556 (2665) 6269 (3133) c AUC(inf) (h×ng/mL) 2079 (1631) e 25673 (17666) j 24133 (15285) k 3826 (3890) d 8265 (5874) l t½ (h) 33 (36) e 42 (37) j 29 (11) k 35 (15) d 38 (22) l C72h (ng/mL) 13 (9) e 202 (120) 228 (131) h 44 (44) d 69 (37) d C96h (ng/mL) 7.7 (5.8) m NS 158 (126) h 21 (23) d 43 (28) l C144h (ng/mL) NS 28 (37) n 52 (56) k NS NS Note: Arithmetic mean (standard deviation) except Tmax where it is median (min, max). Doses of ZYNRELEF are shown as bupivacaine dose (mg)/meloxicam dose (mg). For spinal surgery, ZYNRELEF mean doses for single-level and multilevel surgeries are shown; individual doses ranged from 45 mg/1.4 mg to 248 mg/7.4 mg. a AUC(0-t): 0 to 120 h post-dose for bunionectomy and lumbar spinal decompression; 0 to 144 h post-dose for total knee arthroplasty and total shoulder arthroplasty. b N=50; c N=12; d N=11; e N=16; f N=32; g N=19; h N=18; i N=13; j N=35; k N=17; l N=10; m N=15; n N=28 NS = not sampled. Distribution After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, their distribution is expected to be the same as for other bupivacaine HCl solution formulations or meloxicam oral formulation. Bupivacaine Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma proteins. Reference ID: 5482849 Local anesthetics including bupivacaine appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs, such as bupivacaine, readily enter the fetal blood from the maternal circulation. Meloxicam Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range of oral meloxicam. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Bupivacaine Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecoloxylidine is the major metabolite of bupivacaine. The elimination of drug from tissue distribution depends largely upon the ability of plasma protein binding sites in the circulation to carry it to the liver where it is metabolized [see Use in Specific Populations (8.6)]. Meloxicam Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P450 mediated metabolism formed by oxidation of an intermediate metabolite 5'‑hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, their excretion is expected to be the same as for other bupivacaine HCl solution formulations or meloxicam oral formulations. Bupivacaine The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. Reference ID: 5482849 When administered in recommended doses and concentrations, bupivacaine HCl does not ordinarily produce irritation or tissue damage. The mean apparent terminal half-life (t1/2) for bupivacaine from ZYNRELEF is approximately 10 to 25 hours. Meloxicam Meloxicam excretion is predominately in the form of metabolites, and occurs to equal extents in the urine and feces. Following oral meloxicam, only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg oral meloxicam doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean apparent terminal half-life (t1/2) for meloxicam from ZYNRELEF is approximately 21 to 42 hours. Specific Populations Effect of Age, Sex, Race, and Ethnicity on Pharmacokinetics Based on the population pharmacokinetic analysis, age, sex, race, and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of bupivacaine and meloxicam in ZYNRELEF [see Use in Special Populations (8.5)]. Hepatic Impairment After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, the effects of hepatic impairment are expected to be the same as for other bupivacaine and meloxicam formulations [see Warnings and Precautions (5.5)]. Bupivacaine Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics [see Use in Specific Populations (8.6)]. Meloxicam Following a single 15 mg dose of oral meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of oral meloxicam was not affected by hepatic impairment. No dosage adjustment of ZYNRELEF is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see Use in Specific Populations (8.6)]. Renal Impairment After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, the effects of renal impairment are expected to be the same as for other bupivacaine and meloxicam formulations. Reference ID: 5482849 Bupivacaine Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow [see Warnings and Precautions (5.8) and Use in Specific Populations (8.7)]. Meloxicam Meloxicam pharmacokinetics with oral meloxicam have been investigated in patients with mild and moderate renal impairment. Following oral meloxicam, total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in patients with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment of ZYNRELEF is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of ZYNRELEF in patients with severe renal impairment is not recommended [see Warnings and Precautions (5.8) and Use in Specific Populations (8.7)]. Hemodialysis: Following a single oral dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma. Meloxicam is not dialyzable [see Use in Specific Populations (8.7)]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 6 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of oral meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for oral meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single- dose pharmacokinetics of 30 mg oral meloxicam. Digoxin: Oral meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Lithium: In a study conducted in healthy patients, mean pre-dose lithium concentration and AUC were increased by 21% in patients receiving lithium doses ranging from 804 to 1072 mg twice daily with oral meloxicam 15 mg QD every day as compared to patients receiving lithium alone [see Drug Interactions (7)]. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Reference ID: 5482849 Warfarin: The effect of oral meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy patients receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these patients, oral meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one patient showed an increase in INR from 1.5 to 2.1. Caution should be used when administering oral meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. 12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic variants such as CYP2C92 and CYP2C93 polymorphisms. Limited data from three published reports showed that meloxicam AUC was substantially higher in individuals with reduced CYP2C9 activity, particularly in poor metabolizers (e.g., 3/3), compared to normal metabolizers (1/1). The frequency of CYP2C9 poor metabolizer genotypes varies based on racial/ethnic background but is generally present in <5% of the population. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility The maximum recommended human dose (MRHD) of ZYNRELEF is 400 mg and 12 mg of bupivacaine and meloxicam, respectively. Carcinogenesis Bupivacaine Long-term studies in animals to evaluate the carcinogenic potential of ZYNRELEF or bupivacaine have not been conducted. Meloxicam There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) or mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.6 and 3.2 times, respectively, the meloxicam dose level of 12 mg at the MRHD of ZYNRELEF based on BSA comparison). Mutagenesis Bupivacaine The mutagenic potential of bupivacaine has not been determined. Meloxicam Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Bupivacaine The effect of ZYNRELEF and bupivacaine on fertility has not been determined. Reference ID: 5482849 Meloxicam Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 7.3 and 4 times, respectively, the MRHD based on BSA comparison). In a published study, oral administration of 1 mg/kg (0.8 times the MRHD) meloxicam to male rats for 35 days resulted in decreased sperm count and motility and histopathological evidence of testicular degeneration. The clinical relevance of these findings is unknown. 13.2 Animal Toxicology and/or Pharmacology Necrosis and degeneration of cartilage and chondrocytes were observed following intra-articular injection of a single dose of ZYNRELEF in the knee joint of rabbits. Cartilage degeneration was also observed following intra-articular injection of a single dose of ZYNRELEF in the knee joints of dogs. 14 CLINICAL STUDIES The efficacy of ZYNRELEF was established in 3 double-blind, controlled studies in patients undergoing bunionectomy (Study 1), unilateral open inguinal herniorrhaphy (Study 2), and total knee arthroplasty (Study 3). Refer to 12.2 for additional supportive pharmacodynamic data for ZYNRELEF [see Pharmacodynamics (12.2)]. Based on the extrapolation of efficacy of ZYNRELEF across the 3 double-blind, controlled studies in patients undergoing bunionectomy, unilateral open inguinal herniorrhaphy, and total knee arthroplasty, and the pharmacokinetic profiles across surgical procedures with varied characteristics, such as anatomic location, tissue type, length and depth of surgical area, and vascularity, the pharmacokinetic profile and effectiveness of ZYNRELEF are not expected to be clinically significantly different when ZYNRELEF is administered at an appropriate dose in other soft tissue and orthopedic surgical procedures [see Dosage and Administration (2.4), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Study 1 In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial (NCT03295721), 412 patients undergoing unilateral simple bunionectomy with a lidocaine Mayo block were randomized to 1 of the following 3 treatment groups in a 3:3:2 ratio (respectively): ZYNRELEF 60 mg/1.8 mg, bupivacaine HCl 50 mg, or saline placebo. The mean patient age was 47 years (range 18 to 77) and patients were predominantly female (86%). ZYNRELEF was applied directly into the surgical site, using the cone-shaped applicator, at the end of the procedure, after final irrigation and suction but prior to closure. Bupivacaine HCl and saline placebo were administered by injection and instillation, respectively. Pain intensity was rated by patients using an 11-point numeric rating scale (NRS) out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen; however, patients were allowed rescue medication as needed, and included oxycodone 10 mg orally every 4 hours, morphine 10 mg IV every 2 hours, and/or acetaminophen 1000 mg orally every 6 hours. The primary endpoint was the mean area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) with activity over the 72-hour period for the ZYNRELEF treatment group compared to the saline placebo treatment group. Secondary endpoints included mean AUC of NRS pain intensity scores over the 72-hour period for the ZYNRELEF treatment group compared to the bupivacaine HCl treatment group, proportion of patients who did not receive opioid analgesia, and total opioid consumption. Reference ID: 5482849 10 --- ZYNRELEF 60 mg/1.8 mg (N=l57) ----'i'-- Bupivacaine HCI 50 mg (N=l55) --.l•k-- Saline Placebo (N=lOO) ,___ 9 ~ Cl'.) -tj 8 i::: ~ <I) ~ 7 '-' <I) ... 6 0 <.) Cl'.) -~ 5 cJJ i::: <I) 4 -.s .s 3 ~ p.. -< 2 I Cl'.) ~ 0 1 2 4 8 12 24 36 48 60 72 Hours Post Study Drng Administration Patients treated with ZYNRELEF demonstrated a significant reduction in pain intensity compared to those treated with either bupivacaine HCl or saline placebo for up to 72 hours (Figure 1). A significant proportion of patients treated with ZYNRELEF did not receive opioid analgesia (29%) over 72 hours compared to those treated with either bupivacaine HCl (11%) or saline placebo (2%). Figure 1. Mean Pain Intensity with Activity Over 72 Hours for STUDY 1 (Bunionectomy) Study 2 In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial (NCT03237481), 418 patients undergoing unilateral open inguinal herniorrhaphy with mesh under general anesthesia were randomized to 1 of the following 3 treatment groups in a 2:2:1 ratio (respectively): ZYNRELEF 300 mg/9 mg, bupivacaine HCl 75 mg, or saline placebo. The mean patient age was 49 years (range 18 to 83) and patients were predominantly male (94%). ZYNRELEF was applied directly into the surgical site, using the cone-shaped applicator, at the end of the procedure, following irrigation and suction of each fascial layer but prior to closure. Bupivacaine HCl and saline placebo were administered by injection and instillation, respectively. Pain intensity was rated by patients using an 11-point NRS out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen; however, patients were allowed rescue medication as needed, which included oxycodone 10 mg orally every 4 hours, morphine 10 mg IV every 2 hours, and/or acetaminophen 1000 mg orally every 6 hours. The primary endpoint was the mean AUC of the NRS pain intensity scores (cumulative pain scores) with activity over the 72-hour period for the ZYNRELEF treatment group compared to the saline placebo treatment group. Secondary endpoints included mean AUC of NRS pain intensity scores over the 72-hour period for the ZYNRELEF treatment group compared to the bupivacaine HCl treatment group, proportion of patients who did not receive opioid analgesia, and total opioid consumption. Patients treated with ZYNRELEF demonstrated a statistically significant reduction in pain intensity compared to those treated with either bupivacaine HCl or saline placebo for up to 72 hours (Figure 2). A Reference ID: 5482849 10 _.,_ ZYNRELEF 300 mg/9 mg (N=164) ____...,_ Bupivacaine HCl 75 mg (N=172) _._ Saline Placebo (N=82) ""' 9 i:.i:i v'l -tj 8 i:: "' "' ::;s 7 '-' "' ... 6 0 (.) v'l -~ 5 C/l i:: "' 4 .s .s 3 "' ~ -< 2 I v'l ~ 0 1 2 4 8 12 24 36 48 60 72 Hours Post Study Drug Administration significant proportion of patients treated with ZYNRELEF did not receive opioid analgesia (51%) over 72 hours compared to those treated with either bupivacaine HCl (40%) or saline placebo (22%). A significant reduction in total opioid consumption over 72 hours was also observed for patients treated with ZYNRELEF (median consumption 0 mg) compared to those treated with either bupivacaine HCl (7.3 mg) or saline placebo (11.3 mg). Figure 2. Mean Pain Intensity with Activity Over 72 Hours for STUDY 2 (Herniorrhaphy) Study 3 In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical study (NCT03015532), 222 patients undergoing primary unilateral total knee arthroplasty under general anesthesia were randomized to one of the following treatment groups in a 1:1:1:1 ratio; ZYNRELEF 400 mg/12 mg, ZYNRELEF 400 mg/12 mg plus ropivacaine 50 mg (injected into the posterior capsule), bupivacaine HCl 125 mg, or saline placebo. The mean age was 62 years (range 33 to 85) and 51% of patients were female. ZYNRELEF was administered, using the cone-shaped applicator, onto the posterior capsule, the anteromedial tissues and periosteum, and the anterolateral tissues and periosteum after cementation of the components. Preoperatively, patients were administered pregabalin 150 mg as a single oral dose and acetaminophen up to 1 g IV. Pain intensity was rated by the patients using an 11-point NRS out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen, and patients were allowed only opioid rescue medication as needed (10 mg oxycodone orally every 4 hours, and/or 10-15 mg morphine IV every 2 hours). The primary endpoint was the AUC of the NRS pain intensity scores (cumulative pain scores) at rest collected over the first 48 hours. Patients treated with ZYNRELEF demonstrated a significant reduction in pain intensity compared to patients treated with saline placebo for the first 48-hour and 72-hour postoperative periods (Figure 3). There were two patients who did not receive opioid analgesia over 72 hours; one in the ZYNRELEF 400 mg/12 mg + ropivacaine treatment group and one in the bupivacaine HCl treatment group. Reference ID: 5482849 10 --+- ZYNRELEF 400 mg/12 mg (N=58) - •- ZYNRELEF 400 mg/12 mg + Ropivacaine 50 mg (N=56) ___.,.__ Saline Placebo (N=53) 9 ~ CZl 8 -jj = "' 7 (I) 6 (I) 6 .... 0 0 CZl ~ I i~ ... t < - - - -,---+I ----r!---------I! , ,,~ ---i-------f~, l f- ; ,... ~1-------1 .€ 5 en = ] 4 ·= "' 3 P.. ~ CZl 2 ~ 0 I 2 4 6 8 12 24 36 48 60 72 Hours Post Study Drug Administration Figure 3. Mean Pain Intensity at Rest Over 72 Hours for STUDY 3 (Total Knee Arthroplasty) 16 HOW SUPPLIED/STORAGE AND HANDLING ZYNRELEF® (bupivacaine and meloxicam) extended-release solution is a clear, pale-yellow to yellow viscous liquid available in 4 presentations. Each single-dose glass vial is filled with a solution of 29.25 mg/mL bupivacaine and 0.88 mg/mL meloxicam. Each presentation described below is supplied in the ZYNRELEF kit containing a vial (packaged in an individual carton) along with sterile, individually packaged components for administration. Product Presentation Vented Vial Spike Provided Luer Lock Syringe(s) Provided Luer Lock Applicator(s) Provided Syringe Tip Cap(s) Provided NDC Bupivacaine/ Meloxicam Net Quantity Volume 47426-301-02 400 mg/12 mg 14 mL 1 2 x 12 mL 2 2 47426-302-02 300 mg/9 mg 10.5 mL 1 1 x 12 mL 1 1 47426-303-01 200 mg/6 mg 7 mL 1 1 x 12 mL 1 1 47426-304-01 60 mg/1.8 mg 2.3 mL 1 1 x 3 mL 1 1 * Each ZYNRELEF vial contains overfill to compensate for residual amounts that remain in the vial, vented vial spike, Luer lock applicator, and syringe(s) during drug withdrawal and administration Reference ID: 5482849 The following replacement components are individually supplied separate from the kit: • Carton containing 5 vented vial spikes • Carton containing 10 Luer lock applicators • Carton containing 10 sterile 3 mL Luer lock syringes • Carton containing 8 sterile 12 mL Luer lock syringes Storage Store ZYNRELEF kits at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. If ZYNRELEF vials are removed from the kit, store them at controlled room temperature. Protect from light during storage. 17 PATIENT COUNSELING INFORMATION Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Warnings and Precautions (5.9)]. Serious Skin Reactions, including DRESS Advise patients to contact their healthcare provider as soon as possible if they develop any type of rash or fever [see Warnings and Precautions (5.14, 5.15)]. Methemoglobinemia Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.12)]. Fetal Toxicity Inform pregnant women of the risk of the premature closing of the fetal ductus arteriosus if ZYNRELEF or other NSAIDs are used starting at 30 weeks gestation because of the risk of the premature closing of Reference ID: 5482849 the fetal ductus arteriosus. If treatment with ZYNRELEF is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios because meloxicam can be detected in plasma beyond 48 hours after administration [see Warnings and Precautions (5.16) and Use in Specific Populations (8.1)]. Temporary Loss of Sensation Near the Surgical Site Inform patients in advance that ZYNRELEF can cause temporary loss of sensation near the surgical site. Use of NSAIDs Inform patients of the increased risk of gastrointestinal toxicity if an NSAID or salicylate (e.g., diflunisal, salsalate) is used in the postoperative period following administration of ZYNRELEF [see Drug Interactions (7)]. Manufactured for: Heron Therapeutics, Inc., 4242 Campus Point Court, Suite 200, San Diego, CA, 92121, USA. Patent: https://www.herontx.com/patents/ ZYNRELEF® is a registered trademark of Heron Therapeutics, Inc. Copyright © 2021 - 2024 Heron Therapeutics, Inc. All rights reserved. Reference ID: 5482849	custom-source	2025-02-12T15:47:13.898080	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/211988s018lbl.pdf', 'application_number': 211988, 'submission_type': 'SUPPL ', 'submission_number': 18}
80,404	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ELYXYB safely and effectively. See full prescribing information for ELYXYB. ELYXYB (celecoxib) oral solution Initial U.S. Approval: 1998 WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. (5.1) • ELYXYB is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024 INDICATIONS AND USAGE ELYXYB is a nonsteroidal anti-inflammatory drug indicated for the acute treatment of migraine with or without aura in adults (1) Limitations of Use ELYXYB is not indicated for the preventive treatment of migraine. (1) DOSAGE AND ADMINISTRATION • The recommended dose of ELYXYB is 120 mg taken orally, with or without food (2.1) • The maximum dosage in a 24-hour period is 120 mg (2.1) • Use ELYXYB for the fewest number of days per month, as needed (2.1) • Hepatic Impairment: The recommended and maximum dose is 60 mg (2.4 mL) in patients with moderate hepatic impairment (Child-Pugh Class B) (2.2, 8.6, 12.3) • Poor Metabolizers of CYP2C9 Substrates: The recommended and maximum dose is 60 mg (2.4 mL) in patients who are known or suspected to be CYP2C9 poor metabolizers (2.3, 8.8, 12.5) DOSAGE FORMS AND STRENGTHS Oral solution, 120 mg/4.8 mL (25 mg/mL) (3) CONTRAINDICATIONS • Known hypersensitivity to celecoxib, any components of the drug product, or sulfonamides (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) • Heart Failure and Edema: Avoid use of ELYXYB in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ELYXYB in patients with severe renal impairment unless benefits are expected to outweigh risk of worsening renal function (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: ELYXYB is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) • Serious Skin Reactions: Discontinue ELYXYB at first appearance of skin rash or other signs of hypersensitivity (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Medication Overuse Headache: Detoxification may be necessary (5.11) • Fetal Toxicity: Limit use of NSAIDs, including ELYXYB, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.12, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.13, 7) ADVERSE REACTIONS Most common adverse reaction (at least 3% and greater than placebo) is dysgeusia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact SCILEX Pharmaceuticals Inc. at 1-866-SCILEX3 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ELYXYB with drugs that interfere with hemostasis. Concomitant use of ELYXYB and analgesic doses of aspirin is not generally recommended (7) • ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with ELYXYB may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) • ACE Inhibitors and ARBs: Concomitant use with ELYXYB in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function (7) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) • Digoxin: Concomitant use with ELYXYB can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of ELYXYB in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 11/2024 Reference ID: 5482759 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Dosage Modification in Patients with Hepatic Impairment 2.3 Dosage Modification in CYP2C9 Poor Metabolizers 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Medication Overuse Headache 5.12 Fetal Toxicity 5.13 Hematological Toxicity 5.14 Masking of Inflammation and Fever 5.15 Laboratory Monitoring 5.16 Disseminated Intravascular Coagulation (DIC) 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Poor Metabolizers of CYP2C9 Substrates 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482759 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • ELYXYB is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE ELYXYB is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use ELYXYB is not indicated for the preventive treatment of migraine. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dose of ELYXYB is 120 mg taken orally, with or without food [see Clinical Pharmacology (12.3)]. The maximum dosage in a 24-hour period is 120 mg. The safety and effectiveness of a second dose in a 24-hour period have not been established. Use ELYXYB for the fewest number of days per month, as needed. Reference ID: 5482759 2.2 Dosage Modification in Patients with Hepatic Impairment The recommended and maximum dose in patients with moderate hepatic impairment (Child- Pugh Class B) is 60 mg (2.4 mL) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device. Use of ELYXYB in patients with severe hepatic impairment is not recommended. 2.3 Dosage Modification in CYP2C9 Poor Metabolizers The recommended and maximum dose in patients who are known or suspected to be CYP2C9 poor metabolizers is 60 mg (2.4 mL) [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.5)]. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device. 3 DOSAGE FORMS AND STRENGTHS Dosage form: Clear colorless oral solution Strength: 120 mg/4.8 mL (25 mg/mL) 4 CONTRAINDICATIONS ELYXYB is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product [see Warnings and Precautions (5.7, 5.9)]. • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]. • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • In patients who have demonstrated allergic-type reactions to sulfonamides [see Warnings and Precautions (5.7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. Reference ID: 5482759 In a trial with celecoxib capsules, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use ELYXYB for the fewest number of days per month as needed, based on individual treatment goals. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ELYXYB, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID administered in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs, including ELYXYB, are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ELYXYB in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ELYXYB is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration and Perforation NSAIDs, including ELYXYB, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with celecoxib. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these Reference ID: 5482759 risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with severe liver impairment and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ELYXYB until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs, including ELYXYB. In controlled clinical trials of celecoxib capsules, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., nausea, fatigue, pruritus, jaundice, right upper quadrant tenderness, and/or flu-like symptoms), discontinue ELYXYB immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including ELYXYB, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including ELYXYB, with caution in patients with hypertension. Monitor blood pressure (BP) during the initiation of ELYXYB treatment and throughout the course of therapy. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Reference ID: 5482759 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ELYXYB may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. In a clinical study, the cumulative rates at 9 months of peripheral edema in patients on celecoxib capsules 400 mg twice daily, ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily were 4.5%, 6.9%, and 4.7%, respectively. Avoid the use of ELYXYB in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ELYXYB is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs, including celecoxib, the active ingredient in ELYXYB, has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of celecoxib in patients with severe renal impairment. The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating ELYXYB. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ELYXYB [see Drug Interactions (7)]. ELYXYB is not recommended in patients with severe renal impairment. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Reference ID: 5482759 5.7 Anaphylactic Reactions Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see Contraindications (4) and Warnings and Precautions (5.8)]. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ELYXYB is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ELYXYB is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions (5.10)], acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE), which may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE). These serious events may occur without warning and can be fatal. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ELYXYB at the first appearance of skin rash or any other sign of hypersensitivity. ELYXYB is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ELYXYB. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ELYXYB and evaluate the patient immediately. 5.11 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, nonsteroidal anti- inflammatory drugs or combination of these drugs for 10 or more days per month), including ELYXYB, may lead to exacerbation of headache (medication overuse headache). Medication Reference ID: 5482759 overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.12 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including ELYXYB, in pregnant women at about 30 weeks gestation and later. NSAIDs, including ELYXYB, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including ELYXYB, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ELYXYB use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ELYXYB treatment extends beyond 48 hours. Discontinue ELYXYB if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.13 Hematological Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ELYXYB has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. In controlled clinical trials of celecoxib capsules, the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with ELYXYB should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. NSAIDs, including ELYXYB, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.14 Masking of Inflammation and Fever The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Reference ID: 5482759 5.15 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID, including ELYXYB, treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. In controlled clinical trials with celecoxib capsules, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. 5.16 Disseminated Intravascular Coagulation (DIC) ELYXYB is not indicated in pediatric patients or for the treatment of juvenile rheumatoid arthritis (JRA). Disseminated intravascular coagulation has occurred with use of celecoxib capsules in pediatric patients with systemic onset JRA, which required monitoring for signs and symptoms of abnormal clotting or bleeding. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.8)] • Serious Skin Reactions [see Warnings and Precautions (5.9)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10)] • Medication Overuse Headache [see Warnings and Precautions (5.11)] • Fetal Toxicity [see Warnings and Precautions (5.12)] • Hematologic Toxicity [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. Reference ID: 5482759 The safety of ELYXYB was evaluated in 815 patients who received at least one dose of ELYXYB in two, randomized, double-blind, placebo-controlled trials (Study 1 and 2) in adult patients with migraine [see Clinical Studies (14)]. The most common (at least 2% of patients who received ELYXYB and greater than placebo) adverse reaction in Study 1 and Study 2 was dysgeusia, which occurred in 3% of patients who received ELYXYB compared to 1% of patients who received placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of celecoxib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular: Vasculitis, deep venous thrombosis General: Anaphylactic reaction, angioedema Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure Hemic and lymphatic: Agranulocytosis, aplastic anemia, pancytopenia, leucopenia Metabolic: Hypoglycemia, hyponatremia Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage Renal: Interstitial nephritis Skin and Appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE) [see Warnings and Precautions (5.9)]. 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with celecoxib. Table 1: Clinically Significant Drug Interactions with Celecoxib Drugs That Interfere with Hemostasis Clinical Impact • Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention Monitor patients with concomitant use of ELYXYB with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.13)]. Aspirin Clinical Impact • In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. • In two studies in healthy volunteers and in patients with established heart disease respectively, celecoxib (200 mg to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 mg to 325 mg). Reference ID: 5482759 Intervention Concomitant use of ELYXYB and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.13)]. ELYXYB is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact • NSAIDs may diminish the antihypertensive effect of ACE inhibiters, ARBs, or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention • During concomitant use of ELYXYB and ACE inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of ELYXYB and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention During concomitant use of ELYXYB with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention During concomitant use of ELYXYB and digoxin, monitor serum digoxin levels. Lithium Clinical Impact NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention During concomitant use of ELYXYB and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. Intervention During concomitant use of ELYXYB and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention During concomitant use of ELYXYB and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.2)]. Intervention The concomitant use of ELYXYB with other NSAIDs or salicylates is not recommended. Reference ID: 5482759 Pemetrexed Clinical Impact Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention CYP2C9 Inhibitors o Clinical Impact • During concomitant use of ELYXYB and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal, and GI toxicity. • NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. • In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. r inducers Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of ELYXYB with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of ELYXYB. Intervention CYP2D6 substrates Clinical Impact Evaluate each patient's medical history when consideration is given to prescribing ELYXYB. A dosage adjustment may be warranted when ELYXYB is administered with CYP2C9 inhibitors or inducers. In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. Intervention Corticosteroids Clinical Impact Evaluate each patient's medical history when consideration is given to prescribing ELYXYB. A dosage adjustment may be warranted when ELYXYB is administered with CYP2D6 substrates. Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. Intervention Monitor patients with concomitant use of ELYXYB with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including ELYXYB, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ELYXYB use between about 20 and 30 weeks of gestation, and avoid ELYXYB use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ELYXYB, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Reference ID: 5482759 Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, administration of celecoxib during pregnancy resulted in adverse effects on development, including increases in embryonic death and fetal malformations, at doses or maternal plasma drug exposures greater than those used clinically (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post- implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ELYXYB, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ELYXYB treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ELYXYB and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of celecoxib during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Reference ID: 5482759 Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Administration of celecoxib to rats during early embryonic development resulted in increased pre- and postimplantation loss at oral doses ≥50 mg/kg/day, which was associated with plasma exposure (AUC) approximately 20 times that in humans at the maximum recommended dose (MRHD) of 120 mg/day. Administration of celecoxib to pregnant rats throughout the period of organogenesis resulted in increased incidences of a specific fetal malformation (diaphragmatic hernia) at oral doses ≥30 mg/kg/day, associated with plasma exposure (AUC) approximately 20 times that in humans at the MRHD. Administration of celecoxib to pregnant rabbits throughout organogenesis produced increased incidences of fetal visceral (ventricular septal defects) and skeletal malformations at oral doses ≥150 mg/kg/day, associated with maternal plasma AUC approximately 7 times that in humans at the MRHD. Celecoxib produced no evidence of delayed labor or parturition in rats at oral doses up to 100 mg/kg/day, which was associated with maternal plasma AUC approximately 25 times that in humans at the MRHD. 8.2 Lactation Risk Summary Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants who were 17 and 22 months of age did not show any adverse events. There is no information available regarding the effects of celecoxib on milk production. The developmental and health benefits of breastfeeding should be considered along with the Reference ID: 5482759 mother’s clinical need for ELYXYB and any potential adverse effects on the breastfed infant from the celecoxib or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ELYXYB, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including ELYXYB, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Disseminated intravascular coagulation has occurred in pediatric patients [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, treat for the fewest number of days per month, as needed, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.15)]. In the controlled clinical trials for migraine, approximately 70 patients were ≥ 65 years of age. Of the total number of patients who received celecoxib (for indications other than migraine) in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous postmarketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see Warnings and Precautions (5.4, 5.6)]. 8.6 Hepatic Impairment No dosage adjustment is needed for patients with mild hepatic impairment (Child-Pugh Class A). Reduce the dose of ELYXYB in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The use of ELYXYB in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. Reference ID: 5482759 8.7 Renal Impairment No dosage adjustment is needed for patients with mild or moderate renal impairment. ELYXYB is not recommended in patients with severe renal impairment [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. 8.8 Poor Metabolizers of CYP2C9 Substrates In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C93/3), based on genotype or previous history/experience with other CYP2C9 substrates (e.g., warfarin, phenytoin) reduce the dose of ELYXYB [see Dosage and Administration (2.3) and Clinical Pharmacology (12.5)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. No overdoses of celecoxib were reported during clinical trials. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%), dialysis is unlikely to be useful in overdose. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center. 11 DESCRIPTION ELYXYB is an oral solution of celecoxib, a nonsteroidal anti-inflammatory drug. Each unit dose of ELYXYB contains 120 mg of celecoxib. Celecoxib is a white or almost white, crystalline or amorphous powder with a pKa of 11. Celecoxib is hydrophobic (log P is 3.0) and practically insoluble in water. Celecoxib is chemically designated as p-[5-p-tolyl-3 (trifluoromethyl) pyrazol-1-yl] benzenesulfonamide. The empirical formula for celecoxib is C17H14 F3N3O2S, and the molecular weight is 381.37. It has the following chemical structure: Reference ID: 5482759 The inactive ingredients in ELYXYB include: acesulfame potassium, banana flavor, bubble gum flavor, ethyl alcohol, glycerin, glyceryl monocaprylate, L-menthol, lauroyl polyoxyl-32 glycerides, medium chain triglycerides, monoammonium glycyrrhizinate, peppermint flavor, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, propyl gallate, purified water, and sucralose. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Celecoxib is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action by which celecoxib exerts therapeutic effects in migraine patients is not fully understood but may involve inhibition of prostaglandin synthesis, primarily via inhibition of COX-2. 12.2 Pharmacodynamics Platelets In clinical trials using normal volunteers, celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib. Fluid Retention Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone. Reference ID: 5482759 12.3 Pharmacokinetics Celecoxib exhibits a dose-proportional increase in exposure after once daily oral administration of 120 to 240 mg doses (2 times the recommended dosage) of ELYXYB. Absorption Following administration of 120 mg of ELYXYB under fasting condition in 24 healthy subjects, the median time to peak plasma levels (i.e., Tmax) of celecoxib was 1 hour (range 0.67 to 3.00). Food Effect When ELYXYB was taken with a high-fat meal, the median time to peak plasma levels (i.e., Tmax) was delayed by 2 hours with an approximately 50% decrease in Cmax and no change in total absorption (i.e., AUC) compared to fasting conditions. However, in Study 1 and Study 2, ELYXYB was administered without regard to food [see Dosage and Administration (2.1), Clinical Studies (14)]. Distribution In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution following single dose administration of ELYXYB at fasting state is (Vz/F) is approximately 288 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells. Elimination Metabolism Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid, and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Excretion Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. The mean apparent elimination t½ of celecoxib from ELYXYB was approximately 6 hours independent of dosing condition and similar to that observed for Celebrex under fed conditions. Specific Populations Geriatric At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the younger subjects for celecoxib oral capsules. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. Reference ID: 5482759 Race Meta-analysis of pharmacokinetic studies conducted using celecoxib oral capsules has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of ELYXYB has not been evaluated. A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment conducted using celecoxib oral capsule has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. Renal Impairment In a cross-study comparison done for celecoxib oral capsules, celecoxib AUC was approximately 40% lower in patients with chronic renal impairment (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal impairment have not been studied [see Warnings and Precautions (5.6) and Use in Specific Populations (8.6)]. Drug Interaction Studies In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19, or 3A4. In vivo studies have shown the following: Aspirin When NSAIDs were administered with aspirin, the protein binding of NSAIDs was reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known [see Drug Interactions (7)]. Lithium In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg oral capsule twice daily as compared to subjects receiving lithium alone [see Drug Interactions (7)]. Fluconazole Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole [see Drug Interactions (7)]. Other Drugs The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, phenytoin, and tolbutamide have been studied in vivo using celecoxib oral capsules and clinically important interactions have not been found. Reference ID: 5482759 12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C92 and CYP2C93 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C93/3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C91/1 or I/3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 2, 5, 6, 9, and 11. It is estimated that the frequency of the homozygous 3/3 genotype is 0.3% to 1.0% in various ethnic groups [see Dosage and Administration (2.3) and Use in Specific Populations (8.8)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Celecoxib was not carcinogenic when administered orally for two years to rats at oral doses up to 200 mg/kg for males and 10 mg/kg for females (associated with plasma exposures (AUC) approximately 14 and 7 times, respectively, that in humans at the maximum recommended human dose (MRHD) of 120 mg/day) or in mice at oral doses up to 25 mg/kg for males and 50 mg/kg for females (associated with plasma AUCs approximately 4 times in humans at the MRHD). Mutagenesis Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow. Impairment of Fertility Administration of celecoxib to male and female rats prior to and during mating and continuing in females through implantation had no effect on fertility or male reproductive function at oral doses up to 600 mg/kg/day, which were associated with plasma AUCs approximately 40 times that in humans at the MRHD. Increased implantation loss was observed at doses ≥50 mg/kg/day, which was associated with plasma AUC approximately 20 times that in humans at the MRHD. 13.2 Animal Toxicology and/or Pharmacology An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules were seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown. Reference ID: 5482759 14 CLINICAL STUDIES 14.1 Migraine The efficacy of ELYXYB for the acute treatment of migraine with or without aura was demonstrated in two randomized, double-blind, placebo-controlled clinical trials [Study 1 (NCT03009019) and Study 2 (NCT03006276)]. In Study 1, patients were randomized to receive ELYXYB 120 mg (n=316) or placebo (n=315); in Study 2, patients were also randomized to receive ELYXYB 120 mg (n=311) or placebo (n=311). In both studies, patients were instructed to treat a migraine with moderate to severe pain intensity. Patients enrolled in the trials were predominantly female (86%) and White (74%), with a mean age of 40.6 years (range 18 to 75 years). The primary efficacy analyses were conducted in patients who treated a migraine with moderate to severe pain. The efficacy of ELYXYB was established by an effect on pain freedom at 2 hours post-dose and most bothersome symptom (MBS) freedom at 2 hours post-dose. Pain freedom was defined as a reduction of moderate or severe headache pain to no pain, and MBS freedom was defined as the absence of the self-identified MBS (photophobia, phonophobia, or nausea). Among patients who selected a MBS, the most commonly selected MBS was photophobia (56%), followed by nausea (25%), and phonophobia (18%). In both studies, the percentage of patients achieving MBS freedom at 2 hours post-dose was significantly greater among patients receiving ELYXYB, compared to those receiving placebo. In Study 2, the percentage of patients achieving headache pain freedom at 2 hours post-dose was significantly greater among patients receiving ELYXYB, compared to those receiving placebo (see Table 2). Table 2: Migraine Efficacy Endpoints for Study 1 and Study 2 Study 1 Study 2 Placebo ELYXYB 120 mg Placebo ELYXYB 120 mg Pain Free at 2 hours N 273 284 271 279 % Responders 25.3 32.4 21.0 35.1 Difference from placebo (%) 7 14 p-value 0.076a <0.001 Most Bothersome Symptom Free at 2 hours N 234 245 237 236 % Responders 44.4 58.0 43.9 56.8 Difference from placebo (%) 14 13 p-value 0.003 0.006 a Not statistically significant Reference ID: 5482759 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ELYXYB (celecoxib) oral solution, 120 mg/4.8 mL (25 mg/mL) is a clear colorless oral solution supplied in a disposable glass bottle with a child resistant cap. Each carton (NDC 69557-333-01) contains six (6) glass bottles, a Full Prescribing Information, Medication Guide, and Instructions for Use. 16.2 Storage and Handling Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Unused portion should be discarded immediately after use. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Administration Information For patients who are prescribed the recommended dosage of 120 mg, instruct them to drink the entire amount of ELYXYB directly from the bottle. For patients who are prescribed the reduced dosage (i.e., patients with moderate hepatic impairment or CYP2C9 poor metabolizers), instruct them to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform these patients that oral dosing syringes may be obtained from their pharmacy and that a household teaspoon is not an accurate measuring device. Instruct these patients to discard the unused portion of ELYXYB. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop ELYXYB and seek immediate medical therapy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Reference ID: 5482759 Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions, including DRESS Advise patients to stop taking ELYXYB immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9,5.10)]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month, including ELYXYB, may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary). Instruct patients to contact their healthcare provider if the frequency of their migraines increases; withdrawal of ELYXYB may be necessary [see Warnings and Precautions (5.11)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including ELYXYB, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of ELYXYB and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with ELYXYB is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of ELYXYB with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with ELYXYB until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 5482759 ELYXYB is a trademark of SCILEX Pharmaceuticals Inc. Manufactured by: Contract Pharmaceuticals Limited, Mississauga, Ontario, Canada Manufactured for: SCILEX Pharmaceuticals Inc., Palo Alto, CA 94303 Active Ingredient Made in India ©2023 SCILEX Pharmaceuticals Inc. All rights reserved. ELY-00083 XX/XXXX Reference ID: 5482759 Medication Guide ELYXYB (ee-lix'-ib)) (celecoxib) oral solution What is the most important information I should know about ELYXYB? ELYXYB contains celecoxib (a non-steroidal anti-inflammatory drug or NSAID). NSAIDs, including ELYXYB, can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take ELYXYB right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs, including ELYXYB, after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “antiplatelet drugs”, “anticoagulants”, “SSRIs” or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems ELYXYB should only be used: o exactly as prescribed o for the shortest time needed What is ELYXYB? ELYXYB is a prescription medicine used for the acute treatment of migraine attacks with or without aura in adults. • ELYXYB is not used as a preventive treatment of migraine. • It is not known if ELYXYB is safe and effective in children. Who should not take ELYXYB? Do not take ELYXYB: • if you are allergic to celecoxib or any of the ingredients in ELYXYB. See the end of this Medication Guide for a complete list of ingredients in ELYXYB. • If you are allergic to sulfonamides. • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking ELYXYB, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems. • have a history of stomach ulcer or bleeding in your stomach or intestines. • have heart disease or risk factors that increase your chance of getting heart disease. • have high blood pressure. • have asthma. • are pregnant or plan to become pregnant. Taking NSAIDs, including ELYXYB, at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the Reference ID: 5482759 amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. ELYXYB may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take ELYXYB. Tell your healthcare provider about all of the medicines you take, including prescription or over the-counter medicines, vitamins or herbal supplements. NSAIDs, including ELYXYB, and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. How should I take ELYXYB? See the detailed “Instructions for Use” on how to take ELYXYB solution. • Take ELYXYB exactly as your healthcare provider tells you to take it. • Take ELYXYB by mouth with or without food. • Do not take more than one dose in a 24-hour period. • Use ELYXYB for the fewest number of days a month, as needed. What are the possible side effects of ELYXYB? ELYXYB can cause serious side effects, including: See “What is the most important information I should know about ELYXYB? • liver problems including liver failure • new or worse high blood pressure • heart failure • kidney problems including kidney failure • life-threatening allergic reactions • asthma attacks in people who have asthma • life-threatening skin reactions • medication overuse headaches. Some people who use too much ELYXYB may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with ELYXYB. • low red blood cells (anemia) • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing ● slurred speech • chest pain ● swelling of the face or throat • weakness in one part or side of your body Stop taking ELYXYB and call your healthcare provider right away if you get any of the following symptoms: • nausea ● vomit blood • more tired or weaker than usual ● there is blood in your bowel movement or it • diarrhea is black and sticky like tar • itching ● unusual weight gain • your skin or eyes look yellow ● skin rash or blisters with fever • indigestion or stomach pain ● swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much ELYXYB, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over- the-counter NSAIDs for more than 10 days. Reference ID: 5482759 General information about the safe and effective use of ELYXYB Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ELYXYB for a condition for which it was not prescribed. Do not give ELYXYB to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about ELYXYB, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ELYXYB that is written for health professionals. Manufactured for: Dr. Reddy’s Laboratories Limited This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2020 Reference ID: 5482759	custom-source	2025-02-12T15:47:13.949678	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212157s003lbl.pdf', 'application_number': 212157, 'submission_type': 'SUPPL ', 'submission_number': 3}

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